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Phase I/II Trial and Pharmacokinetic Study of Cixutumumab in Pediatric Patients With Refractory Solid Tumors and Ewing Sarcoma: A Report From the Children's Oncology Group

This phase I/II study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab (IMC-A12) in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels—6 and 9 mg/kg—were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. Results were as follows: Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. Conclusion: Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.

Prognostic Value of Tc-99m-MIBI Performed During Middle Course of Preoperative Chemotherapy in Patients With Malignant Bone and Soft-Tissue Tumors

This study was aimed to determine whether Tc-99m-hexakis-2-methoxyisobutylisonitrile (MIBI) scintigraphy performed in the middle of preoperative chemotherapy has a prognostic value in patients with malignant bone and soft tissue tumors (MBST). In 90 patients with MBST, Tc-99m-MIBI scintigraphy was performed 15 minutes after tracer injection before the first and after the third chemotherapy cycles. After 5 cycles of chemotherapy and tumor resection, therapeutic effect was assessed by histopathology. The percent reduction of uptake ratio (ΔUR) was calculated according to the following equation: 100 × ([prechemotherapy UR − post–middle course of chemotherapy UR]/prechemotherapy UR). Results were as follows: The average follow-up for the entire population was 52 months. Twenty-one patients had clinically detectable metastases at initial presentation (primary metastasis). Kaplan-Meier analysis demonstrated that absence of metastasis was associated with good survival in all patients, in patients with bone tumor, and those with soft tissue tumor (P < 0.0001, P < 0.0001, and P = 0.0003, respectively), and ΔUR ≧30% was also associated with survival in all patients and patients with bone tumor (P = 0.011 and P = 0.047, respectively), but was marginal in those with soft tissue tumor (P = 0.091). Multivariate analysis showed that primary metastasis was the most powerful independent predictor of a lethal clinical outcome in all patients, in both patients with bone and soft tissue tumors (hazard ratio [HR]: 4.9, 95% confidence interval [CI]: 2.61–9.08, P < 0.0001; HR: 15.1, CI: 4.86–52.7, P < 0.0001; HR: 3.7, CI: 1.45–8.94, P = 0.0069, respectively) and showed that Tc-99m-MIBI scintigraphy had a good independent long-term prognostic value in all patients and patients with bone tumor (HR: 2.2, CI: 1.14–4.43, P = 0.017; HR: 6.0, CI: 2.01–21.6, P = 0.0009, respectively) but not in those with soft tissue tumor (HR: 1.5, CI: 0.61–4.09, P = 0.38). Good disease-free survival was associated with ΔUR ≧30% in all patients and patients with soft tissue tumor (P = 0.0093 and P = 0.017, respectively) but not in those with bone tumor (P = 0.19). Conclusions: Tc-99m-MIBI scintigraphy at the middle course of preoperative chemotherapy could be used as a prognostic indicator in patients with MBST.

 

Sorafenib for Patients with Advanced Angiosarcoma: A Phase II Trial from the French Sarcoma Group (GSF/GETO)

Angiosarcomas account for <2% of all soft tissue sarcomas. This subtype is one of the most aggressive forms of soft tissue sarcoma. The prognosis for angiosarcoma patients in the advanced phase remains poor with current cytotoxic agents (progression-free survival [PFS] time of approximately 4 months and overall survival [OS] time of approximately 8 months). The investigators of this study investigated the antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas in a phase II trial. They conducted a stratified phase II trial. The primary endpoint was the progression-free rate (PFR) at 9 months according to the Response Evaluation Criteria in Solid Tumors. A two-stage design (optimal Simon design) was used. Patients received sorafenib (400 mg twice daily) for 9 months until unacceptable toxicity or tumor progression. Central pathological and radiological reviews were performed. Data on stratum A (superficial angiosarcoma) and stratum B (visceral angiosarcoma) are currently available. This trial is registered with ClinicalTrials.gov (identifier, NCT00874874). Results were as follows: Strata A and B recruited 26 and 15 patients, respectively. The median age was 63 years (range, 31–82 years), with 17 male and 24 female patients. Fourteen cases arose in irradiated fields. Thirty patients (73.0%) had been pretreated with conventional chemotherapy. No unexpected toxicity occurred. The PFR at 9 months was 3.8% in stratum A and 0.0% in stratum B. The median PFS times were 1.8 months and 3.8 months, respectively, whereas the median OS times were 12.0 months and 9.0 months, respectively. No responses were observed in chemotherapy-naïve patients, whereas a 40% tumor control rate and 23% response rate were observed in the pretreated population. In this cohort, no activating mutation of the KDR gene (exons 15, 16, 24) was detected. Conclusions: Sorafenib showed limited antitumor activity in pretreated patients only, for both visceral and superficial angiosarcoma, but tumor control was of short duration.

 

Comprehensive analysis of published phase I/II clinical trials between 1990-2010 in osteosarcoma and Ewing sarcoma confirms limited outcomes and need for translational investment

High grade primary bone sarcomas are rare cancers that affect mostly children and young adults. Osteosarcoma and Ewing sarcoma are the most common histological subtypes in this age group, with current multimodality treatment strategies achieving 55-70% overall survival. As there remains an urgent need to develop new therapeutic interventions, the authors of this paper have reviewed published phase I/II trials that have been reported for osteosarcoma and Ewing sarcoma in the last twenty years. Results were as follows: They conducted a literature search for clinical trials between 1990 and 2010, either for trials enrolling bone sarcoma patients as part of a general sarcoma indication or trials specifically in osteosarcoma and Ewing sarcoma. They identified 42 clinical trials that fulfilled their search criteria for general sarcoma that enrolled these patient groups, and eight and twenty specific trials for Ewing and osteosarcoma patients, respectively. For the phase I trials which enrolled different tumor types their results were incomplete, because the sarcoma patients were not mentioned in the PubMed abstract. A total of 3,736 sarcoma patients were included in these trials over this period, 1,114 for osteosarcoma and 1,263 for Ewing sarcoma. As a proportion of the worldwide disease burden over this period, these numbers reflect a very small percentage of the potential patient recruitment, approximately 0.6% for Ewing sarcoma and 0.2% for osteosarcoma. However, these data show an increase in recent activity overall and suggest there is still much room for improvement in the current trial development structures. Conclusions: Lack of resources and commercial investment will inevitably limit opportunity to develop sufficiently rapid improvements in clinical outcomes. International collaboration exists in many well founded co-operative groups for phase III trials, but progress may be more effective if there were also more investment of molecular and translational research into disease focused phase I/II clinical trials. Examples of new models for early translational and early phase trial collaboration include the European based EuroBoNeT network, the Sarcoma Alliance for Research through Collaboration network (SARC) and the new European collaborative translational trial network, EuroSarc.

 

Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1—2 trial

Spinal stereotactic body radiation therapy (SBRT) is increasingly used to manage spinal metastases, yet the technique's effectiveness in controlling the symptom burden of spinal metastases has not been well described. The investigators of this study investigated the clinical benefit of SBRT for managing spinal metastases and reducing cancer-related symptoms. 149 patients with mechanically stable, non-cord-compressing spinal metastases (166 lesions) were given SBRT in a phase 1—2 study. Patients received a total dose of 27—30 Gy, typically in three fractions. Symptoms were measured before SBRT and at several time points up to 6 months after treatment, by the Brief Pain Inventory (BPI) and the M D Anderson Symptom Inventory (MDASI). The primary endpoint was frequency and duration of complete pain relief. The study is completed and is registered with ClinicalTrials.gov, number NCT00508443. Results were as follows: Median follow-up was 15•9 months (IQR 9•5—30•3). The number of patients reporting no pain from bone metastases, as measured by the BPI, increased from 39 of 149 (26%) before SBRT to 55 of 102 (54%) 6 months after SBRT (p<0•0001). BPI-reported pain reduction from baseline to 4 weeks after SBRT was clinically meaningful (mean 3•4 [SD 2•9] on the BPI pain-at-its-worst item at baseline, 2•1 [2•4] at 4 weeks; effect size 0•47, p=0•00076). These improvements were accompanied by significant reduction in opioid use during the first 6 months after SBRT (43 [28•9%] of 149 patients with strong opioid use at baseline vs. 20 [20•0%] of 100 at 6 months; p=0•011). Ordinal regression modeling showed that patients reported significant pain reduction according to the MDASI during the first 6 months after SBRT (p=0•00003), and significant reductions in a composite score of the six MDASI symptom interference with daily life items (p=0•0066). Only a few instances of non-neurological grade 3 toxicities occurred: nausea (one event), vomiting (one), diarrhea (one), fatigue (one), dysphagia (one), neck pain (one), and diaphoresis (one); pain associated with severe tongue oedema and trismus occurred twice; and non-cardiac chest pain was reported three times. No grade 4 toxicities occurred. Progression-free survival after SBRT was 80•5% (95% CI 72•9—86•1) at 1 year and 72•4% (63•1—79•7) at 2 years. Conclusions: SBRT is an effective primary or salvage treatment for mechanically stable spinal metastasis. Significant reductions in patient-reported pain and other symptoms were evident 6 months after SBRT, along with satisfactory progression-free survival and no late spinal cord toxicities.

 

A phase II study single agent of aflibercept (VEGF Trap) in patients with recurrent or metastatic gynecologic carcinosarcomas and uterine leiomyosarcoma

The aim of this multi-institutional non randomized phase II trial was to determine the efficacy and safety of single agent aflibercept (VEGF Trap), a recombinant fusion protein that blocks multiple vascular endothelial growth factor isoforms, in women with gynecologic soft tissue sarcoma. Patients were enrolled in two cohorts each with Simon two stage designs: uterine leiomyosarcoma and carcinosarcoma of endometrial, ovarian or fallopian tube origin. Eligibility criteria included ≤2 prior lines of chemotherapy for metastatic disease and ECOG performance status ≤2. Aflibercept 4mg/kg was administered intravenously on day 1 of a 14 day cycle. Primary endpoints were objective response and disease stabilization (Progression Free Survival (PFS) at 6months). Results were as follows: 41 patients with uterine leiomyosarcoma and 22 patients with carcinosarcoma (19 uterine, 3 ovarian) were enrolled on study. In the leiomyosarcoma cohort, eleven (27%) patients had stable disease (SD), 4 with SD lasting at least 24weeks. The 6month PFS was 17%, with median time to progression (TTP) of 1.8 (95% CI:1.6-2.1) months. In the carcinosarcoma cohort, two (9%) patients had SD, one lasting >24weeks, median TTP was 1.6 months (95%CI: 1.1-1.7) No partial responses were observed in patients from either cohort. Grade 3 or more aflibercept related toxicity was uncommon and included hypertension, fatigue, headache and abdominal pain. Conclusions: Single agent aflibercept has modest activity in patients with uterine leiomyosarcoma and minimal activity in women with carcinosarcoma

 

First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: A Phase I/II open-label and double-blind study

Conatumumab is a fully human monoclonal agonist antibody that binds to death receptor 5 and induces apoptosis in sensitive cells. This study evaluated the safety and efficacy of doxorubicin with or without conatumumab as first-line systemic therapy for metastatic or locally advanced/unresectable soft-tissue sarcoma. In Phase I, six patients received doxorubicin (75mg/m2) with conatumumab (15mg/kg) every 3weeks. In Phase II, patients were randomized (2:1) to receive doxorubicin with either double-blind conatumumab 15mg/kg (conatumumab–doxorubicin; n=86) or placebo (placebo–doxorubicin; n=42). Patients who progressed on placebo–doxorubicin could receive open-label conatumumab monotherapy post-chemotherapy (n=21). Results were as follows: The expected histopathologic subtypes (e.g. leiomyosarcoma, liposarcoma, others) were represented in this trial. No unexpected adverse events were noted in either Phase I or II. Median progression-free survival in Phase II was 5.6 and 6.4 months in the conatumumab–doxorubicin and placebo–doxorubicin arms, respectively (stratified HR: 1.00; p=0.973), with more early progressions noted in the first 3.5months in the conatumumab–doxorubicin arm. Median overall survival was not reached after 8.6months median follow-up in either arm. Common adverse events were nausea (conatumumab–doxorubicin: 66%; placebo–doxorubicin: 80%), alopecia (55%; 63%), fatigue (60%; 38%) and neutropenia (32%; 50%). Post-chemotherapy results were not notably improved by conatumumab dosing. Conclusions: Addition of conatumumab to doxorubicin appeared to be safe but did not improve disease control in a heterogeneous unselected group of patients with soft tissue sarcomas. The results of this trial are very useful for estimating the outcomes of first-line therapy of sarcoma patients treated with standard doxorubicin.

 

A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma

The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. This study reports on the results of a non-randomized phase II study on neo-adjuvant treatment for high-risk STS. Patients with potentially curative high-risk STS (size ≥ 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m2 iv days 1 and 4, ifosfamide 1500 mg/m2 iv days 1 - 4, doxorubicin 50 mg/m2 day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA. Results were as follows: Between 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far. Conclusions: The current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account.

 

V9N1 ESUN Copyright © 2012 Liddy Shriver Sarcoma Initiative.

Clinical Trials News Research Corner Sarcoma Community Updates Stories of Courage and Hope The Sarcoma Calendar

Call for Participation

Sunitinib or Cediranib for
Alveolar Soft Part Sarcoma

Lauren Powell, a Clinical Research Coordinator at The National Cancer Institute, made us aware of this following study. If you are interested in more details about it, you may contact her at: 301-451-0992 or lauren.powell@nih.gov

Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor accounting for less than 1% of soft tissue sarcomas. There is no effective systemic treatment for patients with metastatic ASPS. Little is known with regards to relevant molecular markers as potential therapeutic targets. Cediranib (AZD2171) and sunitinib (SU011248), oral small molecule inhibitors of VEGF receptor tyrosine kinases, are showing preliminary evidence of activity in patients with ASPS.

Objectives: This study has several objectives: Determine the objective response rate (ORR) of single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS; Determine the ORR of cediranib in patients who progress on the sunitinib arm, and determine the ORR of sunitinib in patients who progress on the cediranib arm; Determine the progression-free survival (PFS) at 6 months in Part I and in Part II of the study for single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS; and Evaluate gene expression in tumor biopsies obtained at baseline and after treatment (at the Clinical Center, NCI only).

Eligibility: Patients age greater than or equal to 16 years with histologically or cytologically confirmed metastatic ASPS. Patients must not have received treatment with any VEGF receptor tyrosine kinase inhibitor (e.g., cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment with bevacizumab is allowed.

 

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Study Results

Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas

Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas. Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated. Results were as follows: A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue. Conclusion: Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.

R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration Study

The type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). The investigators conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT. Patients ≥ 2 years of age with refractory or recurrent ESFT received R1507 at doses of 9 mg/kg intravenously one a week or 27 mg/kg intravenously every three weeks. Response was measured by using WHO criteria. Tumor imaging was performed every 6 weeks for 24 weeks and then every 12 weeks. Results were as follows: From December 2007 through April 2010, 115 eligible patients from 31 different institutions were enrolled. The median age was 25 years (range, 8 to 78 years). The location of the primary tumor was bone in 57% of patients and extraskeletal in 43% of patients. A total of 109 patients were treated with R1507 9 mg/kg/wk, and six patients were treated with 27 mg/kg/3 wk. The overall complete response/partial response rate was 10% (95% CI, 4.9% to 16.5%). The median duration of response was 29 weeks (range, 12 to 94 weeks), and the median overall survival was 7.6 months (95% CI, 6 to 9.7 months). Ten of 11 responses were observed in patients who presented with primary bone tumors (P = .016). The most common adverse events of grades 3 to 4 were pain (15%), anemia (8%), thrombocytopenia (7%), and asthenia (5%). Conclusion: R1507 was a well-tolerated agent that had meaningful and durable benefit in a subgroup of patients with ESFT. The identification of markers that are predictive of a benefit is necessary to fully capitalize on this approach.

 

 

Preliminary Efficacy of the Anti-Insulin–Like Growth Factor Type 1 Receptor Antibody Figitumumab in Patients With Refractory Ewing Sarcoma

Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES. Patients with sarcoma 10 to 18 years old were enrolled in two dose escalation cohorts (20 and 30 mg/Kg intravenously every 4 weeks) in the phase 1 portion of the study. Patients with ES 10 years old or older were enrolled in the phase 2 portion of the study. The primary phase 2 objective was objective response rate (ORR). Results were as follows: Thirty-one patients with ES (n = 16), osteosarcoma (n = 11), or other sarcomas (n = 4) were enrolled in the phase 1 portion of the study. Dose escalation proceeded to 30 mg/kg every 4 weeks with no dose-limiting toxicity identified. In the phase 2 portion of the study, 107 patients with ES received figitumumab at 30 mg/kg every 4 weeks for a median of 2 cycles (range, 1 to 16). Sixty three percent of phase 2 patients had received at least three prior treatment regimens. Of 106 evaluable patients, 15 had a partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. Importantly, patients with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n = 14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n = 84) had a median OS of 10.4 months (P < .001). Conclusion: Figitumumab had modest activity as single agent in advanced ES. A strong association between pretreatment serum IGF-1 and survival benefit was identified.

 

153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients

Bone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months. Twenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the 153Sm-EDTMP infusion. Results were as follows: The median PFS was 61 days (18–436 days) and the median overall survival (OS) was 189 days (31–1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16–50] and 76% (95% CI 52–89) at 4 months, respectively. No statistical differences emerged according to 153Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months. Conclusions: Based on our series, the PFS is dramatically short even when higher activity of 153Sm-EDTMP is administered. This would mean that, even at high level, 153Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.

 

Physical Exercise for Cancer Patients with Advanced Disease: A Randomized Controlled Trial

Physical exercise can improve cancer patients' functioning and reduce their symptom levels. A randomized, controlled trial was launched to test the hypothesis that physical exercise reduces fatigue and improves physical performance in cancer patients with advanced and incurable disease. Cancer patients (n = 231) with a life expectancy ≤2 years were randomized to a physical exercise group (PEG, n = 121) or a control usual care group (UCG, n = 110). The PEG exercised under supervision 60 minutes twice a week for 8 weeks. Assessments were performed before and after the intervention. The primary outcome was physical fatigue (PF) measured by the Fatigue Questionnaire. Physical performance was a secondary outcome measured by the Shuttle Walk Test (SWT) and hand grip strength (HGS) test. Analyses were performed after multiple imputations for missing data. The trial is registered with ClinicalTrials.gov (identifier, NCT00397774). Findings: Thirty-six percent of the PEG were lost to follow-up compared with 23% of the UCG, primarily as a result of disease progression. Seventy-eight PEG and 85 UCG patients completed the intervention. Analyses showed no significant between-group effects in PF. However, clinically and statistically significant between-group effects were found for the SWT and HGS test. Interpretation: Fatigue was not reduced but physical performance (SWT and HGS test) was significantly improved after 8 weeks of physical exercise. Physical exercise might therefore be a suitable approach for maintaining physical capacity in cancer patients with incurable and advanced disease.

 

Clinical Trial Participation and Time to Treatment Among Adolescents and Young Adults With Cancer: Does Age at Diagnosis or Insurance Make a Difference?

Because adolescent and young adult (AYA) patients with cancer have experienced variable improvement in survival over the past two decades, enhancing the quality and timeliness of cancer care in this population has emerged as a priority area. To identify current trends in AYA care, the authors of this paper examined patterns of clinical trial participation, time to treatment, and provider characteristics in a population-based sample of AYA patients with cancer. Using the National Cancer Institute Patterns of Care Study, the authors used multivariate logistic regression to evaluate demographic and provider characteristics associated with clinical trial enrollment and time to treatment among 1,358 AYA patients with cancer (age 15 to 39 years) identified through the Surveillance, Epidemiology, and End Results Program. Results were as follows: 14% of patients age 15 to 39 years had enrolled onto a clinical trial; participation varied by type of cancer, with the highest participation in those diagnosed with acute lymphoblastic leukemia (37%) and sarcoma (32%). Multivariate analyses demonstrated that uninsured, older patients and those treated by nonpediatric oncologists were less likely to enroll onto clinical trials. Median time from pathologic confirmation to first treatment was 3 days, but this varied by race/ethnicity and cancer site. In multivariate analyses, advanced cancer stage and outpatient treatment alone were associated with longer time from pathologic confirmation to treatment. Conclusion: The study identified factors associated with low clinical trial participation in AYA patients with cancer. These findings support the continued need to improve access to clinical trials and innovative treatments

 

Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma

This was a phase II study of temsirolimus conducted in children and adolescents with high-grade glioma, neuroblastoma or rhabdomyosarcoma. Temsirolimus 75 mg/m2 was administered once weekly until disease progression or intolerance. Using the Simon 2-stage design, further enrolment in each disease cohort required 2 objective responses within the first 12 weeks for the first 12 evaluable patients (those who received 3 temsirolimus doses). Results were as follows: Fifty-two heavily pretreated patients with relapsed (12%) or refractory (88%) disease, median age 8 years (range 1–21 years), were enrolled and treated. One patient with neuroblastoma achieved confirmed partial response within the first 12 weeks; thus, none of the 3 cohorts met the criterion for continued enrolment. Disease stabilization at week 12 was observed in 7 of 17 patients (41%) with high-grade glioma (5 diffuse pontine gliomas, 1 glioblastoma multiforme and 1 anaplastic astrocytoma), 6 of 19 (32%) with neuroblastoma and 1 of 16 (6%) with rhabdomyosarcoma (partial response confirmed at week 18). In the three cohorts, median duration of stable disease or better was 128, 663 and 75 d, respectively. The most common treatment-related adverse events were thrombocytopaenia, hyperlipidaemia and aesthenia. Pharmacokinetic findings were similar to those observed in adults. Conclusions: Temsirolimus administered weekly at the dose of 75 mg/m2 did not meet the primary objective efficacy threshold in children with high-grade glioma, neuroblastoma or rhabdomyosarcoma; however, meaningful prolonged stable disease merits further evaluation in combination therapy.

 

A Phase II trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: A report from the Children’s Oncology Group

The purpose of this trial was to determine the toxicity, efficacy and pharmacokinetics of trabectedin given over 24h every 3 weeks to children with recurrent rhabdomyosarcoma, Ewing sarcoma, or non-rhabdomyosarcoma soft tissue sarcomas. Trabectedin was administered as a 24-h intravenous infusion every 21days. Two dose levels were evaluated (1.3 and 1.5mg/m2) for safety; efficacy was then evaluated using a traditional 2-stage design (10+10) at the 1.5mg/m2 dose level. Pharmacokinetics (day 1 and steady state) were performed during cycle 1. Results were as follows: Fifty patients were enrolled, eight patients at 1.3mg/m2 and 42 at 1.5mg/m2. Dose limiting toxicities (DLTs) in the dose finding component included fatigue and reversible GGT elevation in 1/6 evaluable patients at 1.3mg/m2 and 0/5 at 1.5mg/m2. Efficacy was evaluated in 42 patients enrolled at the 1.5mg/m2 dose of whom 22% experienced reversible grade 3 or 4 toxicities that included AST, ALT, or GGT elevations, myelosuppression and deep venous thrombosis. One patient with rhabdomyosarcoma had a partial response and one patient each with rhabdomyosarcoma, spindle cell sarcoma and Ewing sarcoma had stable disease for 2, 3 and 15 cycles, respectively. Conclusion: Trabectedin is safe when administered over 24h at 1.5mg/m2. Trabectedin did not demonstrate sufficient activity as a single agent for children with relapsed pediatric sarcomas.

V8N6 ESUN Copyright © 2011 Liddy Shriver Sarcoma Initiative.

Clinical Trials News Research Corner Sarcoma Community Updates Stories of Courage and Hope The Sarcoma Calendar

A Phase I Study of the Safety and Pharmacokinetics of the Hypoxia-Activated Prodrug TH-302 in Combination with Doxorubicin in Patients with Advanced Soft Tissue Sarcoma

The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m2 with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. The results were as follows: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m2. DLTs at 340 mg/m2 were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Conclusions: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.

 

Threshold Pharma initiates phase III TH-302 combination trial in advanced soft tissue sarcoma

Threshold Pharmaceuticals, Inc. announced that Threshold, in collaboration with Sarcoma Alliance for Research through Collaboration (SARC), have initiated a phase III randomized clinical trial of TH-302 in patients with soft tissue sarcoma. This international pivotal trial will enroll patients with metastatic or locally advanced unresectable soft tissue sarcoma who have not previously received chemotherapy outside the adjuvant or neoadjuvant setting. The trial is designed to evaluate the efficacy and safety of TH-302 in combination with doxorubicin, compared to doxorubicin alone.

TH-302 has been tested in over 550 patients with cancer including over 100 patients to date treated in a phase I/II trial in patients with soft tissue sarcoma. As presented at the American Society of Clinical Oncology meeting in June 2011, 60 patients from the phase II component of the study had at least one evaluable post-treatment tumour assessment. There was one complete response (2%), 18 partial responses (30%) and 32 stable disease (53%). Median progression free survival was 6.4 months (95% confidence interval: 5.6 to 8.1 months). Median overall survival was 16.1 months (95% CI: 10.4 months to upper limit not yet reached). Just under half (47%) of patients continued to receive TH-302 alone after completing the full doxorubicin regimen of 6 cycles. Myelosuppression was dose limiting with 15 per cent grade 4 neutropenia and 13% grade 4 thrombocytopenia. Collectively, these data contribute to the rationale for initiating the registration study.

The phase III trial will be a 450 patient, randomized, open-label, multi-centre trial comparing two treatment regimens for patients with metastatic and/or advanced unresectable soft tissue sarcoma who have not received prior systemic therapy. This trial is designed to demonstrate the clinical benefit of TH-302 in combination with doxorubicin compared to doxorubicin alone based on a primary efficacy endpoint of overall survival. The trial includes an interim futility analysis based on progression-free survival expected to occur about half-way into enrollment and an interim analysis based on overall survival expected to occur at the end of enrollment. Both interim analyses will be conducted by an independent data monitoring committee. Patients will be randomized to receive TH-302 (300 mg/m2 on days 1 and 8 of a 21 day cycle) in combination with doxorubicin (75 mg/m2 on day 1 of the 21 day cycle) or doxorubicin alone.

“Combining TH-302, a selective hypoxia-targeting prodrug, with doxorubicin, an agent with known activity in sarcoma, has a strong scientific rationale. TH-302 represents a novel concept in anti-cancer treatment. It was designed to deliver a cytotoxic agent to areas of a tumour that are often inaccessible to standard chemotherapies. We therefore expect that doxorubicin and TH-302 will complement one another by targeting the vascular components and hypoxic components, respectively, of a patient's sarcoma,” said William D Tap, MD, Section Chief of Sarcoma Oncology at Memorial Sloan-Kettering Institute and principal investigator for this trial.

“The proposed study is designed to confirm the encouraging results that we have previously reported in the phase I/II study of soft tissue sarcoma patients treated with TH-302 in combination with doxorubicin,” said Sant P Chawla, MD, Sarcoma Oncology Centre and principal investigator for the initial phase I/II study. “The treatment of soft tissue sarcoma is a therapeutic challenge. Besides the approval of imatinib mesylate which was limited to gastrointestinal stromal tumours, there have been no new approved agents in first-line soft tissue sarcoma over the last 20 years. We look forward to working with Threshold and SARC.”

 

 

Preoperative Versus Postoperative Radiotherapy in Soft-Tissue Sarcoma: Multi-Institutional Analysis of 821 Patients

The purpose of this study was to assess the impact of radiotherapy (RT) sequencing with surgery on overall survival (OS), cause-specific survival (CSS), local failure, and distant failure in soft-tissue sarcoma (STS). A retrospective analysis was conducted using the National Oncology Database, a proprietary database of aggregated tumor registries owned by IMPAC Medical Systems (Sunnyvale, CA). Patients with STS of all major anatomic sites who received definitive surgery and either preoperative (preop) or postoperative (postop) RT were included. Patients were also required to have known stage and grade. Prognostic factors for survival were identified using multivariate techniques. Survival was calculated using the Kaplan-Meier method, and compared for statistical significance (p < 0.05) using the log-rank test. The results were as follows: A total of 821 patients met inclusion criteria. The median follow-up time was 63 months. Age, stage, histology, gender, tumor size, and RT sequence were independent predictors for OS (p < 0.05). Preop RT was associated with significantly improved OS and CSS compared with postop RT (hazard ratio [HR] = 0.72, 95% confidence interval [CI] 0.56–0.91, p < 0.01, and HR = 0.64, 95% CI 0.46–0.88, p < 0.01, respectively). The 5-year CSS was 79% and 74%, in favor of preop RT (log–rank, p < 0.05). Preop RT was also significantly associated with a reduced risk for local and distant relapse compared with postop RT. Conclusion: Preoperative RT is associated with a reduced cancer-specific mortality compared with postoperative RT in STS. The results of this study may serve as motivation to conduct future prospective studies with larger patient numbers.

 

Phase II study of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma

The purpose of this prospective multicenter phase II study was to evaluate the efficacy and toxicity of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma. Patients with advanced soft tissue or bone sarcoma, previously treated with ifosfamide and anthracycline-based chemotherapies, were treated with docetaxel (35 mg/m2 over 60 min) and gemcitabine (1,000 mg/m2 over 100 min) on days 1 and 8 of every 3-week cycle. The results were as follows: From September 2008 to August 2010, 30 patients were enrolled; 24 (80.0%) were men and median patient age was 45 years (range 17–70 years). The patients received a total of 136 cycles of therapy (median 4 cycles per patient; range 1–15 cycles). Of these 30 patients, none achieved complete response (CR) and 5 achieved a partial response (PR), making the overall response rate 16.7% (95% CI, 2.5–30.8%). Twelve patients had stable disease (SD), resulting in tumor control (CR or PR or SD) in 17 of 30 patients (56.7%). Median progression-free survival was 2.5 months (range 0.8–15.3 months), and median overall survival was 8.4 months (range 1.4–22.3 months). Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were observed in 17 (56.7%), 13 (43.4%), and 4 (13.3%) patients, respectively. None of these patients, however, had febrile neutropenia or bleeding events, and all non-hematologic toxicities were manageable. Conclusions: The combination of weekly docetaxel and fixed dose rate gemcitabine was tolerable and may be an active regimen in patients with previously treated advanced sarcoma.

 

Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes

Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. This study assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma. In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1•4 mg/m2 over 2—5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov, number NCT00413192. The results were as follows: Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31•6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46•9%) of 32 patients with adipocytic sarcoma, four (21•1%) of 19 with synovial sarcoma, and five (19•2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3—4 adverse events were neutropenia (66 [52%] of 127 patients evaluable for safety), leucopenia (44 [35%]), anaemia (nine [7%]), fatigue (nine [7%]), febrile neutropenia (eight [6%]), abnormal alanine aminotransferase concentrations (six [5%]), mucositis (four [3%]), and sensory neuropathy (four [3%]). Conclusions: Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma.

 

Prediction of tumor necrosis fractions using metabolic and volumetric 18F-FDG PET/CT indices, after one course and at the completion of neoadjuvant chemotherapy, in children and young adults with osteosarcoma

The utility of combined metabolic and volumetric 18F-FDG PET/CT indices for predicting tumor necrosis fractions following neoadjuvant chemotherapy has not been extensively studied in osteosarcoma. Furthermore, little is known of the early PET/CT responses after only one chemotherapy course. Enrolled in this study were 20 children and young adults with resectable osteosarcoma who had undergone 18F-FDG PET/CT scans before and after neoadjuvant chemotherapy. Maximum standardized uptake value (mSUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. From among the 20 patients, 14 were prospectively recruited and underwent an additional PET/CT scan after one chemotherapy course. Histopathological necrosis fractions were compared with the above-mentioned PET/CT indices and their ratios. The results were as follows: MTV at the SUV threshold of 2 g/ml was closely correlated with the magnetic resonance image volumes before therapy (r = 0.91). In the prospective cohort, five patients were classified as good responders and nine as poor responders. All the metabolic indices (mSUV and its ratio) and combined metabolic/volumetric indices (MTV, TLG, and their ratios) except the mSUV ratio determined after therapy showed significant differences between good and poor responders (P <0.05). Differences were also noted for all of these indices determined after one chemotherapy course. Furthermore, most of these indices determined after therapy as well as after one chemotherapy course had good sensitivity, specificity, positive predictive value and negative predictive value with respect to predicting histological response to chemotherapy. Conclusion: In this osteosarcoma patient population, 18F-FDG PET/CT indices (either combined metabolic/volumetric or metabolic indices) determined after neoadjuvant chemotherapy were useful in predicting tumor responses. This held true after only one chemotherapy course.

 

Adjuvant therapy for resectable high-risk soft tissue sarcoma: feasibility and efficacy of a sandwich chemoradiotherapy strategy

Radical definitive surgery is the only curative treatment approach in resectable soft tissue sarcoma. Despite complete resection, patients with grade 2 and 3 soft tissue sarcoma are at high risk of local or distant recurrence. Local and systemic adjuvant treatment includes radiotherapy and chemotherapy, but the optimal scheduling is not known. In this phase II clinical trial, the investigators combined surgery with adjuvant chemotherapy and radiotherapy in a novel trimodality treatment sequence. Two to 6 weeks after surgery, patients received 2 cycles of chemotherapy containing doxorubicin and ifosfamide, then 50.4 Gy of percutaneous radiotherapy followed by additional 2 cycles of chemotherapy. The results were as follows: Chemotherapy and radiotherapy-related toxicity was generally mild, without treatment delays in the majority of patients. After a median follow-up of 57 months, 81.5% of patients are alive in complete remission. Conclusions: The sandwich chemoradiation protocol proved to be feasible with manageable toxicity. The patient outcome compared favorably with other adjuvant trials in preventing relapse, particularly distant relapse which is predictive of poor outcome. This multidisciplinary approach warrants further investigation in a larger randomized trial.

 

Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer

Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)–dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. Patients in sequential cohorts (“3 + 3” design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD). The results were as follows: Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3. Conclusions: Temsirolimus combined with cixutumumab was well tolerated. The investigators are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.

 

Nanobiotix Starts Clinical Trial With Lead Product NBTXR3

On September 13th, Nanobiotix, a company developing cancer novel nanotherapeutics, announced that its lead compound NBTXR3 has received the formal authorization from the French Medicine Agency to start the first clinical trial. 27 patients diagnosed with soft tissue sarcoma will be enrolled in the Phase I study and will receive NBTXR3 as an intra-tumoral injection with radiotherapy prior to surgery (first-line treatment). The primary endpoints of the clinical trial are the feasibility of NBTXR3 administration and safety. Preliminary data are expected by the end of 2012. The trial is a prospective, open-label, dose-escalation, single arm, nonrandomized trial. NBTXR3 will be administered to the patients prior to surgery by a single intra-tumor injection followed by standard radiotherapy procedure. After completion of the regular treatment procedure, the patients will undergo surgery to resect the soft tissue sarcoma. Along with the safety and feasibility endpoints, the primary tumor tissue will then be available for the evaluation of the pathological response rate. Further clinical trials are in preparation in Europe and in the US. NBTXR3 has been classified in the EU as class III medical device. In the US, it has been classified as a drug by the FDA.

NBTXR3, the most advanced compound of Nanobiotix´ NanoXray pipeline is intended to enhance the local destruction of the tumor mass during radiotherapy. NBTXR3 is a nanoparticle consisting of hafnium oxide crystals. Once injected into the tumor, NBTXR3 accumulates in the cancer cells. Due to the physical properties of hafnium oxide, the particles emit huge amounts of electrons upon radiation. This leads to the formation of radicals within the tumor cell, which in turn damage the cancer cells and cause their targeted destruction. NBTXR3 particles are inert and emit electrons only during their exposure to radiotherapy. As a result, the destructive power of standard radiation therapy could be locally and selectively enhanced within the tumor cells. "This approach has the potential to solve one of the biggest problems in treating radioresistant tumors with radiotherapy: how to increase the dose inside the tumor without harming the surrounding healthy tissue," said Prof. Bo LU, Radiation oncologist and Director for the Molecular Radiation Biology Division, Thomas Jefferson Hospital, USA. "Therefore, it may represent a breakthrough in radiotherapy where no major achievements have been made for the last decades."

 

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A Pilot Study of Genetically Engineered NY-ESO-1 Specific (c259) T Cells in HLA-A2+ Patients With Synovial Sarcoma

This recently opened Phase I clinical trial is for patients aged 4-25 with HLA-A2 and NYESO-1 expressing tumors and will be conducted at the NCI with Drs. Crystal Mackall and Natalie Merchant. In August, Adaptimmune expects a second clinical site to open up at Washington University, St. Louis, with Dr. Gerry Linette to allow enrollment of adult patients (aged 18-55). They also plan to open a third site at the Children's Hospital of Philadelphia in the fall. The regulatory sponsor of the trial is Dr Carl June at the University of Pennsylvania and Adaptimmune Ltd of the UK is the financial sponsor. The trial is an immunotherapy trial utilizing a patient's own T cells, which are genetically modified to recognize the HLA-A2 and NYESO-1 positive cells. During the trial, an enhanced T cell receptor will be deployed to target a CT antigen called NYESO‐1. T cell manufacturing will be performed at the Clinical Cell and Vaccine Production Facility at the Perelman School of Medicine at the University of Pennsylvania, directed by Dr. Bruce Levine.

 

Randomized Phase II Study Comparing Gemcitabine Plus Dacarbazine Versus Dacarbazine Alone in Patients With Previously Treated Soft Tissue Sarcoma: A Spanish Group for Research on Sarcomas Study

The purpose of this Phase II study was to assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter study using DTIC alone as a control arm. Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1,800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1,200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. The results were as follows: From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. Conclusion: The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.

 

Phase 1 clinical trials for sarcomas: the cutting edge

Few standard second-line treatment options exist for advanced sarcoma patients. Some of these patients are offered early-phase clinical trials involving targeted or nontargeted agents. This review article outlines recent phase 1 trials involving sarcoma patients, explores current challenges and highlights future opportunities in sarcoma developmental therapeutics. Recent findings: New molecularly targeted phase 1 studies have demonstrated efficacy in sarcomas. For instance, insulin-like growth factor-1 receptor (IGF1R) antibodies have produced single agent activity in Ewing's sarcoma. Other promising novel agents include an agonist for the apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) for chondrosarcoma, small molecule inhibitor crizotinib for anaplastic lymphoma kinase (ALK)-rearranged inflammatory myofibroblastic tumor, cedarinib for alveolar soft part sarcoma, and rexin-G, a tumor targeted retrovector for osteosarcoma. In addition, different combinations of chemotherapy in combination with newer agents such as trabectedin exhibited efficacy in advanced soft tissue sarcoma. Summary: Patients with refractory sarcoma demonstrate benefit from treatment with targeted drugs even in the setting of phase 1 trials. Sarcomas that have a defined translocation and those that express specific activated kinases are particularly promising tumors for targeted therapy. The primary challenge is identifying the biomarkers predictive of response or resistance, matching them with specific patient histology, resulting in successful translation of biology into clinical benefit.

 

Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen

The purpose of this study was to assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated. Thirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m2 was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m2, bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m2, every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry. The results were as follows: The median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome.  The study concludes: The combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.

 

Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect

The purpose of this study was to confirm sunitinib activity in alveolar soft part sarcoma (ASPS) and to report on new insights into the molecular bases thereof. From July 2007, nine patients with progressive metastatic ASPS received sunitinib 37.5 mg/day, within a named use program. Cryopreserved material was available for five naive patients, among whom three received sunitinib. Immunofluorescence (IF)/confocal microscopy, biochemical, and molecular/cytogenetic analyses were carried out, complemented by antiproliferative and activation assays in a short-term culture derived from one case. The results were as follows: All patients were eligible for response. Best RECIST response was partial response in five cases, stable disease in three, and progression in one. The median progression-free survival was 17 months. Positron emission tomography results were consistent. Two cases of interval progressions were recorded. Antiproliferative assays and biochemistry on short-term culture showed that sunitinib is able to markedly impair ASPS cells growth and switch-off PDGFRB. IF/confocal microscopy demonstrated coexpression and physical association between PDGFRB/vascular endothelial growth factor receptor 2 (VEGFR2) and RET/VEGFR2 in ASPS cells, which was validated by biochemistry. PDGFRB, RET, and MET ligand-dependent activation was confirmed. The study concludes: There is clinical efficacy of sunitinib in ASPS, mediated by PDGFRB, VEGFR2, and RET, which are all expressed in tumor cells. A direct antitumor effect was shown in a short-term cell culture.

 

A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study

After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, this study explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. Patients >14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan–Meier method. All tests were two sided. The results were as follows:  Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2–5) and 7 (95% CI 7–8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (<30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥6 months. Noteworthy, tumor density reduction and [18F]2-fluoro-2-deoxy-d-glucose–positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. The study concludes: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

 

Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma

The purpose of this trial was to evaluate neoadjuvant trabectedin (1.5 mg/m2 24-h i.v. infusion every 3 weeks; three to six cycles) in patients with locally advanced myoxid liposarcoma (ML) previously untreated with chemotherapy or radiation. Primary efficacy end point was pathological complete response (pCR) or tumoral regression rate. Objective response according to RECIST (v.1.0) was a secondary end point. The results were as follows: Three of 23 assessable patients had pCR [13%; 95% confidence interval (CI), 3% to 34%]. Furthermore, very good and moderate histological responses were observed in another 2 and 10 patients, respectively. Histological decrement in the cellular and vascular tumor component and maturation of tumor cells to lipoblasts were observed in both myoxid and myoxid/round cell variants. Seven patients had partial response according to RECIST (objective response rate of 24%; 95% CI, 10% to 44%). No disease progression was reported. Neoadjuvant trabectedin was usually well tolerated, with a safety profile similar to that described in patients with soft tissue sarcoma or other tumor types. The study concludes: Trabectedin 1.5 mg/m2 given as a 24-h i.v. infusion every 3 weeks is a therapeutic option in the neoadjuvant setting of ML.

 

Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer

The mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human IgG1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. Thus, the objectives of this Phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. Patients in sequential cohorts ("3+3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At MTD, 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and FDG-PET/CT scans for pharmacodynamic analyses (PD). The results were as follows: Forty-two patients with advanced cancer (19M/23F, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. DLTs included Grade 3 mucositis, febrile neutropenia, and Grade 4 thrombocytopenia. Most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGFBP3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P =0.1213) with a one-unit increase in absolute change of SUV from baseline to Day 3. Conclusions: Temsirolimus combined with cixutumumab was well tolerated. The investigators are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.

 

Phase I and Pharmacokinetic Study of Sunitinib in Pediatric Patients with Refractory Solid Tumors: A Children's Oncology Group Study

Purpose:  Sunitinib is an oral multi-targeted receptor tyrosine kinase inhibitor.  The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary anti-tumor activity of sunitinib in a pediatric population.  Experimental Design: Patients 2-21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements.  Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle.  Dose levels of 15 and 20 mg/m2/day were evaluated, with dose escalation based on a 3+3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle.   Results:   Twenty-three patients were treated (median age 13.9 years; range, 3.9 – 20.6 years).   The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue.  Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with prior exposure to anthracyclines or cardiac radiation.  In patients without these cardiac risk factors, the maximum tolerated dose was 15 mg/m2/day.   Steady-state plasma concentrations were reached by day 7.  No objective responses were observed.  Four patients with sarcoma and glioma had stable disease for 2 - 9 cycles.  Conclusions:  Cardiac toxicity precluded determination of a recommended dose for pediatric patients with prior anthracycline or cardiac radiation exposure.  The maximum tolerated dose of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m2/day for 28 days followed by a 14-day break.

 

A Phase I, Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-IGF-1R Monoclonal Antibody, in Patients with Advanced Solid Tumors

Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic and pharmacodynamic profiles, and identify a recommended phase II dose (RD). Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of ≥3 patients each and received intravenous dalotuzumab weekly, every two weeks or every three weeks. Plasma was collected for pharmacokinetic analysis. Paired baseline and on-treatment skin and tumor biopsies were collected for pharmacodynamic analyses. Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1-3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels >5 mg/kg, dalotuzumab mean terminal half-life was ≥95 hours, mean Cmin was >25 µg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling and Ki67 expression were observed. 18FDG-PET metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiological response. The RDs were 10, 20, and 30 mg/kg for the weekly, Q2W and Q3W schedules, respectively. Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and demonstrated clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals.

 

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Oral Ridaforolimus, an Investigational Candidate, Achieved Primary Endpoint of Improved Progression-Free Survival in Patients with Metastatic Soft-tissue or Bone Sarcomas

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The SUCCEED (Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus) trial was a randomized (1:1), placebo-controlled, double-blind study of oral ridaforolimus administered at 40 mg/day (five of seven days per week) in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy. Oral ridaforolimus was granted a Special Protocol Assessment (SPA) by the FDA for the SUCCEED trial. Based on 552progression-free survival (PFS) events in 711 patients,(ridaforolimus(N=347), placebo (N=364))determined by an independent radiological review committee, the study achieved its primary endpoint of improvement in PFS, with a statistically significant (p=0.0001) 28 percent reduction in the risk of progression or death observed in those treated with ridaforolimus compared to placebo (hazard ratio=0.72). Median PFS was 17.7 weeks for those treated with ridaforolimus compared to 14.6 weeks in the placebo group. Furthermore, based on the full analysis of PFS determined by investigator assessment, there was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression or death compared to placebo (hazard ratio=0.69). In the investigator assessment analysis, median PFS was 22.4 weeks for those treated with ridaforolimus compared to 14.7 weeks in the placebo group. The independent radiological committee review analysis showed that the proportion of patients alive and free from disease progression in the ridaforolimus group compared to placebo was greater after three months (70 percent versus 54 percent), and six months (34 percent versus 23 percent).

 

PALETTE: A randomized, double-blind, phase III trial of pazopanib versus placebo in patients (patients) with soft-tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy

Background: Pazopanib, a multi targeted angiogenesis inhibitor, has demonstrated single-agent activity in patients with advanced STS. The efficacy and safety of pazopanib versus placebo as second or later line treatment were evaluated in patients with metastatic STS in a multi-center, international, double-blind, placebo-controlled phase III trial. Methods: Patients ≥18 years of age with angiogenesis inhibitor-naïve, histologically proven, metastatic STS, who failed at least one anthracycline containing regimen, could enter the study. They should have ≥1 measurable baseline lesion (per RECIST v1.0), WHO PS 0-1, adequate bone marrow, coagulation, hepatic and renal function, no poorly controlled hypertension, no bleeding diathesis, and no CNS involvement. The study has been conducted by EORTC and GSK in collaboration with 72 sarcoma centers worldwide. Patients were randomized 2:1 to receive either pazopanib 800 mg once daily or placebo until tumor progression, unacceptable toxicity, death, or pt’s request. Results: A total of 369 randomized patients (246 pazopanib, 123 placebo), median age of 56 years, participated in the study (EORTC 45 %, other 55%). Median duration of follow-up at clinical cut-off date is 15 months. The primary endpoint of progression-free survival (PFS) per independent review is significantly prolonged with pazopanib (median: 20 versus 7 weeks; HR=0.31, 95% CI 0.24-0.40 ; P<0.0001). The interim analysis for overall survival shows a statistically non-significant improvement of pazopanib vs placebo (median: 11.9 versus 10.4 months, HR=0.83, 95% CI 0.62-1.09). Main on-therapy grade 3-4 toxicities in the pazopanib versus placebo arm respectively: fatigue (13%, 6%), hypertension (7%, nil), anorexia (6%, nil), and diarrhea (5%, 1%). Similarly, thromboembolic events (grade 3-5 ) (3%, 2%), LVEF drop of >15% (8%, 3%). Median relative dose intensity of pazopanib was 768 mg daily. Conclusions: Pazopanib is an active drug in anthracycline pretreated metastatic STS patients with an increase in median PFS of 13 weeks.

 

A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study

After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, the investigators of this trial explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. Patients >14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan–Meier method. All tests were two sided. The results were as follows: Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2–5) and 7 (95% CI 7–8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (<30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥6 months. Noteworthy, tumor density reduction and [18F]2-fluoro-2-deoxy-d-glucose–positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. The investigators conclude: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

 

Randomized Phase II Study Comparing Gemcitabine Plus Dacarbazine Versus Dacarbazine Alone in Patients With Previously Treated Soft Tissue Sarcoma: A Spanish Group for Research on Sarcomas Study

The purpose of this Phase II trial was to assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter study using DTIC alone as a control arm. Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1,800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1,200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. The results were as follows: From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. The investigators conclude: The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.

 

Phase I Dose Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors

E7080, an oral multi-targeted receptor tyrosine kinase inhibitor, has anti-angiogenic and anti-tumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics, and efficacy in patients with advanced solid tumors. In this sequential, dose-escalation, open-label study E7080 was administered orally twice-daily (bid) in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and progenitors (CEP) were measured for biomarker analysis. The results were as follows: Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional three-patient cohorts. During cycle 1, no Grade 3/4 toxicity was observed up to 13 mg bid. DLTs included Grade 3 AST/ALT increase in one patient at 16 mg bid and Grade 3 platelet count decrease in two patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, Cmax and AUC increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect. Conclusion: E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested anti-angiogenic activity correlated with anti-tumor activity in patients with a wide range of solid tumors.

 

Tumor Regression in Patients With Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1

Adoptive immunotherapy using tumor-infiltrating lymphocytes represents an effective cancer treatment for patients with metastatic melanoma. The NY-ESO-1 cancer/testis antigen, which is expressed in 80% of patients with synovial cell sarcoma and approximately 25% of patients with melanoma and common epithelial tumors, represents an attractive target for immune-based therapies. This trial was carried out to evaluate the ability of adoptively transferred autologous T cells transduced with a T-cell receptor (TCR) directed against NY-ESO-1 to mediate tumor regression in patients with metastatic melanoma and synovial cell sarcoma. A clinical trial was performed in patients with metastatic melanoma or metastatic synovial cell sarcoma refractory to all standard treatments. Patients with NY-ESO-1–positive tumors were treated with autologous TCR-transduced T cells plus 720,000 iU/kg of interleukin-2 to tolerance after preparative chemotherapy. Objective clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). The results were as follows: Objective clinical responses were observed in four of six patients with synovial cell sarcoma and five of 11 patients with melanoma bearing tumors expressing NY-ESO-1. Two of 11 patients with melanoma demonstrated complete regressions that persisted after 1 year. A partial response lasting 18 months was observed in one patient with synovial cell sarcoma. The investigators conclude: These observations indicate that TCR-based gene therapies directed against NY-ESO-1 represent a new and effective therapeutic approach for patients with melanoma and synovial cell sarcoma. This represents the first demonstration of the successful treatment of a non-melanoma tumor using TCR-transduced T cells.

 

 

V8N3 ESUN Copyright © 2011 Liddy Shriver Sarcoma Initiative.

Randomized Phase II Window Trial of Two Schedules of Irinotecan With Vincristine in Patients With First Relapse or Progression of Rhabdomyosarcoma: A Report From the Children's Oncology Group

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The purpose of this study was to compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression. Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m2/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m2 administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m2/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen. The results were as follows: Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%). The investigators conclude: There was no difference in the response rates between the two irinotecan-vincristine schedules. They recommend the shorter, more convenient regimen (1B) for further investigation.

 

Embryonal rhabdomyosarcoma with metastases confined to the lungs: Report from the CWS Study Group

Embryonal rhabdomyosarcoma [RME] is the most common pediatric soft tissue sarcoma. Whereas the prognosis of localized rhabdomyosarcoma has improved, it remains poor for metastatic disease. In this study, the authors analyzed RME-patients with isolated pulmonary metastases [PRME] treated in four consecutive CWS-trials. Treatment included multiagent chemotherapy and local treatment of the primary tumor. Therapy of lung metastases after induction chemotherapy depended on response and individual decisions. The results were as follows: Twenty-nine patients <21 years had PRME. Their median age was six years, the median follow-up nine years. Twenty-eight children had their primary tumor located in an unfavorable site and 22 of the primaries were >5cm. In addition to conventional chemotherapy, seven patients received high-dose treatment and eight patients oral metronomic chemotherapy. The lung metastases were in remission after induction chemotherapy in 22 individuals. 19 patients received no local treatment of metastases; 3 patients had pulmonary metastasectomy and lung radiation was administered to 9 individuals. In total, 24/29 patients achieved a complete remission [CR]. Actuarial 5-year event-free and overall survival for all patients was 37.9 ± 18% and 48.7 ± 18%, respectively; it was 45.8 ± 20% and 58.3 ± 20% for the 24 patients who achieved a CR. Local treatment of metastases had no impact on the failure pattern. Younger age, good response, achievement of CR and maintenance-treatment were favorable prognostic factors in univariate analysis. The authors conclude: Children with PRME have a fair prognosis. Local treatment of metastases did not improve outcome in our sample. Metronomic treatment may be an attractive option for PREM-patients.

Results of the Intergroup Rhabdomyosarcoma Study Group D9602 Protocol: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group

Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. In this study, IRSG D9602 protocol (1997 to 2004), the objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients. Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients. The results were as follows: Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77). The investigators conclude: Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients.

Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG)

Data regarding the role of chemotherapy (CT) in patients with recurrent and/or unresectable desmoid tumors (DTs) are scarce. Records of patients with DT who were treated with CT in centers from the French Sarcoma Group were reviewed. The results were as follows: Sixty-two patients entered the study. The two most common locations were extremities (35.5%) and internal trunk (32.5%). Twelve patients (19.5%) were diagnosed with Gardner syndrome. Thirty-seven patients (54.7%) received previously one or more lines of systemic therapies (nonsteroidal anti-inflammatory drugs: 43.5%, antiestrogens: 43.5% and imatinib: 30.5%). Combination CT was delivered in 44 cases (71%) and single agent in 18 patients (29%), respectively. Thirteen patients (21%) received an anthracycline-containing regimen. The most frequent nonanthracycline regimen was the methotrexate–vinblastine combination (n = 27). Complete response, partial response, stable disease and progressive disease were observed in 1 (1.6%), 12 (19.4%), 37 (59.6%) and 12 (19.4%) patients, respectively. The response rate was higher with anthracycline-containing regimens: 54% versus 12%, P = 0.0011. Median progression-free survival (PFS) was 40.8 months. The sole factor associated with improved PFS was the nonlimb location: 12.1 months (95% confidence interval 5.6–18.7) versus not reached, P = 0.03. The investigators conclude: CT has significant activity in DT. Anthracycline-containing regimens appear to be associated with a higher response rate.

 

 

V8N2 ESUN Copyright © 2011 Liddy Shriver Sarcoma Initiative.

 

February 2011

Call for Participation

PICASSO3: Palifosfamide Treatment of Soft Tissue Sarcoma

This is a global, Phase III pivotal, randomized, double-blind, placebo-controlled study of safety and efficacy in patients with metastatic, previously untreated soft tissue sarcoma. All patients receive doxorubicin on Day 1 of each 21 day cycle. Patients also either receive palifosfamide or placebo on Days 1-3 of each cycle. A maximum of six cycles can be administered. All patients have a response evaluation after every even cycle, and are followed for overall survival.

This study is a follow on to a previous Phase II study (PICASSO) that compared doxorubicin alone to doxorubicin plus palifosfamide, as first- or second-line treatment in patients with STS. A total of 66 patients were treated; 33 with doxorubicin along and 33 with doxorubicin plus palifosfamide. Interim progression-free survival (PFS) results showed a hazard ratio of 0.43 favoring the palifosfamide combination (p=0.019), along with a clinically meaningful 3.4 month difference in median PFS. The most common grade 3+ events were neutropenia and elevated creatinine.

Main Inclusion Criteria:
• Age ≥18 years
• Histological documentation of soft tissue sarcoma
• Metastatic disease for which the patient has not received any prior treatment, and for whom treatment with doxorubicin is considered medically acceptable
• Calculated creatinine clearance > 60 mL/minute as per Cockcroft and Gault

Main Exclusion Criteria:
• Histological subtypes including but not limited to: alveolar soft-part sarcoma, chondrosarcoma, dermatofibrosarcoma, Ewing sarcoma, GIST, Kaposi sarcoma, mixed mesodermal tumor/carcinosarcoma, osteosarcoma.
• Prior chemotherapy, immunotherapy, or investigational therapy for metastatic STC

Objective:
To compare the safety and efficacy of the combination of doxorubicin plus palifosfamide in patients with front-line metastatic soft tissue sarcoma

Key Endpoints:
Primary: Overall survival (OS) with an interim assessment of progression-free survival (PFS).
Secondary: Quality of life (QoL), phamacokinetics, and safety, including QTc intervals.

Brian L. Hamilton MD, PhD SVP Medical Operations Phone: 617-259-1098

Jill Buck Sr. Director Clinical Operations Phone: 617-259-1984

On the web: www.picasso3trial.com

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Study Results

National Cancer Institute researchers extend use of gene therapy to treat a soft tissue tumor

Researchers at the National Cancer Institute have published results of an intermediate stage clinical trial of several dozen people which provides evidence that a method that has worked for treating patients with metastatic melanoma can also work for patients with metastatic synovial cell sarcoma. This study is the first to use genetically modified immune cells, in a technique known as adoptive therapy, to cause cancer regression in patients with a solid cancer as opposed to melanoma. This approach represents a method for obtaining immune cells from any cancer patient and converting them into ones that can recognize cancer cells expressing the target antigen, NY-ESO-1. The study appeared in the Jan. 31, 2011, issue of the Journal of Clinical Oncology. NY-ESO-1 is a protein found in up to 50 percent of melanomas and cancers of the breast, prostate, esophagus, lung, and ovary, and in 80 percent of synovial sarcomas. "Since NY-ESO-1 is expressed in a substantial number of cancers, beside melanoma and synovial sarcoma, it is an attractive target for immune-based therapies against these cancers as well," said lead investigator Steven Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research.

This work builds upon previously published results in patients with metastatic melanoma. Those studies showed that metastatic melanoma patients could be treated by infusion with their own genetically modified T cells, or white blood cells, that had receptors on their surfaces that recognized an antigen on the melanoma cells. In this study, 17 patients with synovial cell sarcoma or metastatic melanoma, whose tumors expressed NY-ESO-1, received therapy with their own immune cells engineered to express a T cell receptor capable of recognizing the NY-ESO-1 antigen. To perform this treatment, the investigators isolated normal white blood cells, called lymphocytes, from each patient’s blood and modified these cells by inserting the gene encoding the anti-tumor T cell receptor into them. These genetically modified cells were then able to recognize and destroy NY-ESO-1-expressing cancer cells. The results showed tumor regression in four of the six patients with synovial cell sarcoma and in five of the 11 melanoma patients. A partial response that lasted 18 months was observed in one of the synovial cell sarcoma patients, while two of the melanoma patients demonstrated complete ongoing regression responses that lasted 20 months or longer, which for patients with these diseases, is significant. "Now that we have shown that a patient’s own cells genetically engineered to express a receptor against the NY-ESO-1 antigen can mediate tumor regression, we will be optimizing this treatment and extending it to the treatment of patients with other common cancers," said Rosenberg.

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Testing new regimens in patients with advanced soft tissue sarcoma: analysis of publications from the last 10 years

The prognosis of advanced soft tissue sarcoma remains poor. Many phase II trials investigating new regimens have been published in the last 10 years. In this paper, full English-language reports of phase II clinical trials from January 1999 to October 2009 were reviewed. The paper defined those that provided 3- and 6-month progression-free survival rates (PFSR) >39% and 14%, respectively, as promising second-line regimens. For studies enrolling both chemonaive and pretreated patients, we have compared the reported PFSR3 to the expected PFSR3 of an active treatment administered in the same proportions of pretreated and nonpretreated patients. The results were as follows: Forty-nine trials were identified. Among the trials investigating new regimens in pretreated patients alone, the promising second-line regimens were ifosfamide, brostallicin, pazopanib (except in liposarcoma), temozolomide, trabectedin, dacarbazine–gemcitabine and docetaxel (Taxotere)–gemcitabine combinations (in uterine leiomyosarcoma). Among the trials enrolling both chemonaive and pretreated patients, most regimens reached the level of efficacy; moreover, in three trials, the reported PFSR3 was particularly high: weekly paclitaxel (Taxol) in angiosarcoma, docetaxel–gemcitabine combination (in uterine leiomyosarcoma) and oral perifosine. The authors conclude: In the past 10 years, several drugs or combinations have demonstrated promising activity in exploratory phase II trials and warrant further investigation in appropriate phase III trials.

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Combination mTOR and IGF-1R inhibition: Phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors

Preclinical models demonstrate synergistic anti-tumor activity with combination blockade of mTOR and IGF-1R signaling. This study sought to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of the combination of figitumumab, a fully human IgG2 anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary anti-tumor effects of the combination were evaluated. This was a Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Inter-cohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1. The results were as follows: No does limiting toxicities were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17-300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab. The investigators conclude: Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting anti-tumor activity warranting further investigation.

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Phase I Study of Pazopanib in Combination with Weekly Paclitaxel in Patients with Advanced Solid Tumors

The purpose of this trial was to evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel. Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m2) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate. The tesults were as follows: Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m2 paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m2. At the MTR, coadministration of 800 mg pazopanib and 80 mg/m2 paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve. The study concludes: Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m2 when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.

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Overall survival benefit with masitinib mesylate in imatinib-naive, locally advanced, or metastatic gastrointestinal stromal tumor (GIST): 4-years follow-up of the French Sarcoma Group phase II trial.

Masitinib is a novel tyrosine kinase inhibitor which, in vitro, has greater activity and selectivity than imatinib (IM) against both wild-type KIT receptor and its mutated form in the juxtamembrane region (IC 50=100 nM versus 200 nM for IM, 3 nM versus 27nM and 40 nM versus 120nM, respectively, for exons 9,11, and 13). This multicenter phase II study evaluated efficacy and safety of masitinib as a first-line treatment of advanced GIST. IM-naïve patients with inoperable, locally advanced or metastatic GIST received oral masitinib (7.5 mg/kg/day) until progression, refusal or toxicity. Efficacy variables included response rate, best response (RECIST), progression-free survival (PFS) and overall survival (OS). Initial results were previously reported in EJC 2010. Presented here are the same series with updated PFS and OS (median follow up of 48 months). The results were as follows: 30 patients with a median age of 58 years (60% of males) were included from June 2005 to April 2007 in five French institutions. At the cut-off date (31 august 2010), 9 patients are still under treatment with a median treatment duration of 41 months (min=33, max=52). Two additional progressions have been reported for a total of 14 events (13 progressions and 1 death). Updated median PFS is 41 months (95% CI: [17.5; NR]) with PFS rates of 60% [39; 77], 56% [35; 73] and 45% [24; 64] respectively at 2, 3 and 4 years. With 8 patients dead, median OS is not yet reached with OS rates of 90% [72; 97], 87% [68; 95] and 74% [52; 87], respectively, at 2, 3, and 4 years. The main frequent relevant grade 3 toxicities were: rash (10%), neutropenia (7%) and abdominal pain (7%) with one patient presented a grade 4 skin exfoliation. No other relevant long-term toxicities were reported and no more patients discontinued treatment due to suspected toxicity. The study concludes: The long term results observed with masitinib confirm a very interesting activity with prolonged PFS and OS. These results support the head to head comparison with imatinib in the currently ongoing phase III randomized clinical trial in first line locally advanced or metastatic GIST patients.

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Reporting of Serious Adverse Drug Reactions of Targeted Anticancer Agents in Pivotal Phase III Clinical Trials

Oncologists prescribe anticancer drugs based on results of phase III randomized clinical trials (RCTs), but some safety concerns appear only later in updated drug labels. In this study, the investigators analyzed adverse drug reactions (ADRs) of targeted anticancer agents from updated drug labels and their reporting in corresponding pivotal RCTs. The investigators searched the US Food and Drug Administration (FDA) Web site for approved targeted anticancer drugs with updates of their labels related to safety in 2008 and 2009 and at least one RCT referenced in the updated drug label. For each drug, serious ADRs, including potentially fatal ADRs, were identified from the updated label. Published reports of RCTs referenced in the label were searched to determine whether they described these ADRs. The results were as follows: The investigators identified 12 eligible targeted anticancer agents with 36 corresponding RCTs referenced in updated drug labels. There were 76 serious ADRs reported in updated drug labels, and 50% (n = 38) were potentially fatal. Of these, 39% (n = 30) of all serious ADRs and 39% (n = 15) of potentially fatal ADRs were not described in any published report of RCTs, whereas 49% and 58%, respectively, were not described in initial drug labels. After a median 4.3 years between initial approval and update of drug labels, 42% (n = 5) of targeted cancer agents acquired one or more boxed warnings (the highest level of FDA alert). The investigators conclude: Published reports of pivotal RCTs and initial drug labels contain limited information about serious ADRs of targeted anticancer agents. Rare but serious ADRs may be important causes of morbidity and mortality in general oncologic practice.

 

V8N1 ESUN Copyright © 2011 Liddy Shriver Sarcoma Initiative.

December 2010

SARC Clinical Trial for People with Malignant Peripheral Nerve Sheath Tumors (MPNST)

SARC (Sarcoma Alliance for Research through Collaboration) is a non-for profit consortium that facilitates the conduct of clinical trials in sarcoma. Dr. Brigitte Widemann, Investigator, Pediatric Oncology Branch, National Cancer Institute, is the Principal Investigator for this SARC clinical trial that is exploring treatment of patients with malignant peripheral nerve sheath tumors (MPNST).

Trial Background
MPNST is a type of soft tissue sarcoma (a type of cancer) that develops in cells that form a protective covering (sheath) around peripheral nerves. Peripheral nerves are those that are outside of the central nervous system (brain and spinal cord). These tumors most commonly occur in the arms and legs. However, they can also arise in the abdomen as well as other locations. This tumor can be associated with a condition called neurofibromatosis type 1 (NF1).

Neurofibromatosis type 1 is a genetic disorder that primarily affects the development and growth of nerve tissues. This disorder can cause tumors to grow on the nerves and produce other abnormalities such as skin changes and bone deformities, and can affect other organ systems.

MPNSTs are rare in the general population, but occur with greater frequency in people who have NF1. MPNSTs comprise approximately 5-10% of all soft tissue sarcomas. Half of these will occur in people with NF1. The best treatment for MPNSTs is complete surgical resection. For MPNSTs that cannot be completely resected the question arises, if chemotherapy can help shrink the MPNST in order to make surgery feasible. It is not known to date how well MPNSTs respond to chemotherapy. There are some data to suggest that an MPNST that occurs in people with NF1 versus an MPNST that occurs in people who do not have NF1 may respond differently to treatment. This study is designed to define the response to treatment with chemotherapy in MPNST, and to explore if there is a difference in response between people with MPNST who have or do not have NF1.

Trial
Responses (tumor shrinkage) of MPNSTs to doxorubicin/ifosfamide and ifosfamide/etoposide chemotherapy have been reported suggesting that MPNST may be responsive to standard chemotherapy drugs used to treat other sarcomas. The main goal of this study is to determine the clinical response rate of high grade, unresectable or metastatic MPNSTs, or potentially resectable MPNSTs not previously treated with chemotherapy for this malignancy. Response will be separately evaluated in people who have NF1 and do not have NF1. Children and adults with measurable high-grade, unresectable, or metastatic MPNST, or those with a potentially resectable MPNST for which neoadjuvant chemotherapy is determined to be the best treatment option are eligible to participate in this trial.

In this trial, combination chemotherapy of doxorubicin and ifosfamide and etoposide and ifosfamide will be given to consented, eligible and enrolled patients. These drugs are all Food and Drug Administration approved drugs for the treatment of various types of cancer. As part of this study, up to 4 cycles of each combination (total of 8 cycles) will be given. After the 4th cycle, patients may undergo local control measures at the discretion of their doctor, which could be surgery, radiation treatment, or both. Information (data) from patients with NF and MPNST will be compared with information (data) from patients who have MPNST but do not have NF1 to determine if their response to treatment is different.

Participation in the trial*
To be eligible to participate in this trial a person must:

1. Have confirmed diagnosis of MPNST (NF1 associated or sporadic)
2. Have not received previous treatment with chemotherapy for this MPNST
3. Must have disease which is measurable on imaging studies such as CT or MRI
4. Can be any age
5. Be active, able to perform light physical activity (such as light housework or office work)

People would NOT be able to participate in the study if they are pregnant or breast feeding females.

*this represents only a partial list of requirements to be included or excluded from the study. A complete list is available from SARC or Dr. Widemann.

For more information contact SARC at 734.930-7600 or Dr. Widemann at: widemanb@mail.nih.gov, phone: 301-496-7387, fax: 301-480-8871

This trial is registered at www.clinicaltrials.gov. There are several sites across the United States conducting this trial. To find a site near you, call SARC at 734-930-7600 or email: sarc@sarctrials.org

The full title is: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 associated high grade malignant peripheral nerve sheath tumors (SARC006)

 

The attitudes of 1066 patients with cancer towards participation in randomised clinical trials

Background: Barriers to randomised clinical trial (RCT) recruitment include failure to identify eligible patients, reluctance of staff to approach them and attitudes of some health-care professionals and patients. As part of a larger UK prospective study examining the communication and involvement in RCTs of 22 multidisciplinary teams in Wales, we also assessed the attitudes of patients they treat towards trials.

Methods: Out of 1146 patients attending outpatient departments who were approached, 1146 (93%) completed the seven-item Attitudes to Randomised Trials Questionnaire (ARTQ), probing their general attitudes towards medical research and likely participation in a hypothetical two-arm RCT.

Results: Randomisation initially deterred many patients from endorsing a willingness to participate. However, if information about the trial logic, voluntary nature and rights to withdraw were provided, together with further treatment details, 83% (886 out of 1066) would potentially participate.
Other variables associated with a positive inclination towards participation included previous trial experience (P < 0.01), male gender (P < 0.01) and younger age, with patients X70 years less likely to consider trial entry (P <0.01).

Conclusion: The majority of patients were receptive to RCT participation. Many of those initially disinclined because of randomisation would consider joining if given further details that form part of standard GCP consent guidelines. These data show the importance and need for clear communication and information to encourage RCT participation. Evidence-based training courses are available to assist with this.

 

Pharmacokinetically Guided Phase 1 Trial of the IGF-1 Receptor Antagonist RG1507 in Children with Recurrent or Refractory Solid Tumors

Purpose: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieve exposures equivalent to those achieved in adults at recommended doses.

Experimental Design: Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 [3 and 9mg/kg/week, and 16 mg/kg every 3 weeks (q3W)] as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the 1st dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/week and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred.

Results: Thirty-one evaluable patients ages 3-17 years were enrolled at 3 mg/kg/week (n=3), 9 mg/kg/week (n=18), or 16 mg/kg q3W (n=10). There were no DLTs. At 9 mg/kg/wk the mean AUC0-7d (21,000 mcg•h/mL) exceeded the target (16,000 mcg•h/mL). At 16 mg/kg q3W, the mean AUC0-21d (70,000 mcg•h/mL) exceeded the target (59,400 mcg•h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks.

 

Phase 1 Study of Valproic Acid in Pediatric Patients with Refractory Solid or CNS Tumors: A Children’s Oncology Group Report

Purpose: The primary purpose of this trial was to define and describe the toxicities of oral valproic acid (VPA) at doses required to maintain trough concentrations of 100-150 mcg/ml or 150-200 mcg/ml in children with refractory solid or CNS tumors. Secondary objectives included assessment of free and total VPA pharmacokinetics and histone acetylation in peripheral blood mononuclear cells (PBMC) at steady state.

Experimental design: Oral VPA, initially administered twice daily and subsequently three times daily, was continued without interruption to maintain trough concentrations of 100-150 mcg/ml. First-dose and steady state pharmacokinetics were studied. Histone H3 and H4 acetylation in PBMCs was evaluated using an ELISA technique.

Results: Twenty six children, 16 of whom were evaluable for toxicity, were enrolled. Dose-limiting somnolence and intra-tumoral hemorrhage were associated with VPA troughs of 100-150 mcg/ml. Therefore, the final cohort of six children received VPA to maintain troughs of 75-100 mcg/ml and did not experience any dose-limiting toxicity. First-dose and steady state VPA pharmacokinetic parameters were similar to values previously reported in children with seizures. Increased PBMC histone acetylation was documented in 50% of patients studied. One confirmed partial response (glioblastoma multiforme) and one minor response (brainstem glioma) were observed.

Conclusions: VPA administered three times daily to maintain trough concentrations of 75-100 mcg/ml was well tolerated in children with refractory solid or CNS tumors. Histone hyper-acetylation in PBMCs was observed in half of the patients at steady state. Future trials combining VPA with chemotherapy and/or radiation therapy should be considered, especially for CNS tumors.

 

V7N6 ESUN Copyright © 2010 Liddy Shriver Sarcoma Initiative.

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October 2010

Therapeutics, Targets, and Chemical Biology: Zoledronic Acid as a New Adjuvant Therapeutic Strategy for Ewing's Sarcoma Patients

American Association for Cancer Research Cancer Res; 70(19) October 1, 2010

A group of French researchers has undertaken a study to determine whether zoledronic acid (a bisphosphonic acid marketed as Zometa and Reclast) is beneficial when used in combination with current therapies in the treatment of Ewings Sarcoma and Osteosarcoma. Following are excerpts from the study highlighting the results of the findings and results.

The experiments were done in vivo (used a living organism - mice).  The authors’ note, "Two experimental models of ES were developed (in soft tissue and in bone) to reproduce as closely as possible the pathologic variants observed in patients. The in vivo experimental results obtained in the tumor model induced by A673 cells are presented in this article, but were confirmed in at least another ES model (Supplementary Data*)."

The results of three experiments:

Zoledronic acid is not as effective in soft tissue as it is in bone Histology analysis confirmed the protective effect of zoledronic acid on bone, leading to the prevention of tumor cell invasion in the bone marrow ... However, it cannot protect against tumor progression in soft tissue; thus, chemotherapy is needed in combination with zoledronic acid in this case,” the authors write.

Zoledronic acid does prevent development of Ewings Sarcoma in bone, even when used alone.  The authors describe the measure of success in this case, saying  “…zoledronic acid alone (100 μg/kg, four times a week for 9 weeks) strongly inhibits tumor development as shown by a 97% reduction in mean tumor volume 46 days after tumor cell inoculation …. Osteoclasts were clearly evident at the tumor site in control animals but were absent in zoledronic acid–treated mice.”

In combination with ifosfamide, zoledronic acid does prevent bone tumor relapse
Regarding the agent’s effectiveness against relapse, the authors state, “Zoledronic acid alone exerted a stronger inhibitory effect on tumor progression (−65%, P < 0.01 at day 30 posttumor cell inoculation) than ifosfamide alone (−45% at the same day, P < 0.01; Fig. 5A). Moreover, ifosfamide efficacy declined over F5 time, and relapse was observed from day 18. When zoledronic acid was combined with ifosfamide, the mean tumor volume curve could be superimposed on that of zoledronic acid alone, suggesting that zoledronic acid combined with ifosfamide prevents the early relapse that occurs with ifosfamide alone.”   They go on to say, “When mice were treated with zoledronic acid alone or combined with ifosfamide, a protection from bone lesions was observed with an absence of cortical disruption, increased cortical bone density, and lack of fractures (Fig. 5B). In these cases, the bone architecture was conserved, even with extensive ectopic bone formation in the zoledronic acid + ifosfamide group.”

In Discussion, the authors indicate that treatment with zoledronic acid should reduce side effects while effectively treating tumors that may not be operable due to location.  They state, “Among the new investigational approaches to improve therapy in ES and OS, bone-specific agents may improve survival and/or quality of life on “continuation” therapy.  This would include regimens with fewer short- and long-term side effects and better results for tumors in difficult locations and patients with recurrent disease.”

In summary, they conclude that, “….bisphosphonates may be useful as adjuvant therapy to target osteoclasts and consequently to diminish the bone lesions associated with these tumors, or to prevent the development of bone metastases (26, 27).”  Furthermore, they state that, “The results presented here, showing that all these ES cell lines were sensitive to zoledronic acid whatever their p53 mutation or p16 deletion status, are encouraging for treating a large cohort of ES patients.”

As regards treatment of soft tissue versus bone tumors, they say, “On the contrary, the same doses of zoledronic acid had no inhibitory effect on ES progression in soft tissue. This result is consistent with data from other models of soft tissue tumors or visceral metastases. Indeed, the inhibitory effect of bisphosphonate on tumor growth is still inconsistent for soft tumors (33–35). Even at the clinical level, few data have reported an antitumor effect of zoledronic acid against visceral metastases (36, 37), and conflicting results have been highly discussed (38).”

In conclusion, they offer that zoledronic acid may be used as part of the initial treatment for Ewings Sarcoma patients with bone tumors, saying “Our study shows, by complementary fundamental and preclinical analyses, that zoledronic acid represents a promising therapeutic agent for ES patients as a first-line therapy in combination with chemotherapy to limit bone lesions and to prevent bone tumor relapse, and also as an adjuvant therapy for the treatment of bone or medullary metastases. This is particularly important in the context of the EuroEWING99 protocol, which is nearing completion, and for the choice of new future strategies, especially for patients at high risk of relapse.”

Major Deficiencies in the Design and Funding of Clinical Trials: A Report to the Nation Improving on How Human Studies Are Conducted Findings of the Eliminating Disparities in Clinical Trials Project (EDICT)

Chronic Disease Prevention and Control Research Center at Baylor College of Medicine in collaboration with the Intercultural Cancer Council, April 1, 2008

The authors of this EDICT publication aim to address flaws in the American clinical trial process.  They summarize their position, stating, "the deficiencies in the way clinical trials are designed, carried out and funded in the U.S. have received little direct, systematic or sustained intervention. Compounding the situation, the limited collaboration between the federal government and the pharmaceutical industry about research priorities has led to major gaps in research priorities, especially for diseases, such as liver and kidney cancers that feature high disparities and high-case fatality rates. This fragmented approach to resource allocation leaves many populations under-represented in clinical trials, especially those who bear a disproportionate burden of disease."

According to the Baylor College of Medicine EDICT overview, "The Chronic Disease Prevention and Control Research Center (CDPCRC) at Baylor College of Medicine and the Intercultural Cancer Council (ICC) in Houston are conducting this four-year (2005-2009) research project that addresses problems and solutions related to improving participation of minority and underserved patients in oncology and asthma clinical trials. The four-year study is funded by Genentech, Inc"

The authors discuss the well-known problem of recruiting and retaining clinical trial participants.  However, they do not stop at that.  They go on to note the impact of the Human Genome Project on the clinical trial process, pointing out that sequencing of the human genome has led to a finding that ethnicity "has biomedical consequences when studying health outcomes".  Moreover, in comparing the clinical data obtained from clinical trials to date, they find that participants in trials for specific diseases, under the existing system, may not represent the population most likely to encounter these diseases.

Low participation in clinical trials has been a problem for a long time.  The EDICT project identifies specific actions that can be taken to improve what the authors' call "the three R's of clinical trial participation: 1) recruitment, 2) retention, and 3) return (post-trial benefit)" for those patients that are currently under-represented.

Some statistics that appear in this paper (applicable only to US trials and participants):

• Out of 80,000 clinical trials, 2.3 million Americans participate - which is -1% of the entire population.
• Of the 10.1 million adults with cancer, 3-5% participate in trials
• Of these cancers, 60% are found in older Americans.  In 2003, 25% of those in cancer studies were over age 65.

The authors explain trial types and the goals of those trials.  Each type of trial has challenges in recruiting the people who stand to benefit most from them:

• Treatment trials: New treatment options such as drugs, radiotherapy and surgery
• Prevention trials: Prevent a disease from occurring or returning
• Diagnostic trials: Best methods to arrive at accurate diagnoses
• Screening trials:  Test disease detection strategies
• Quality of life trials:  Interventions that give those chronic diseases a higher quality of life

The groups commonly under-represented in trials are women, minorities (ethnic and racial), rural folk and the elderly.  The authors state emphatically that, “Scientifically, it makes no sense to develop new treatments among populations of patients who are different from those who will be using them.”

They propose that barriers to entry in clinical trials need to be addressed by policy changes to address the most prevalent reasons for lack of participation:

• Lack of trust in medical research
• The forms are too complex and are available only in English
• Their doctors don't refer them
• Insurers, including Medicare and Medicaid, don't provide clear, concise information on how costs may be covered
• Criteria for inclusion in a trial is too strict, excluding people for reasons including age, language barriers or medical problems other than the one addressed by the trial.
• Institutional Review Boards may overlook the fact that any given proposed trial doesn't include the correct makeup of participants.

The authors identify nine distinct areas for improvement, each of which they discuss in detail.

“Nine Priority Areas for Action

• Implement regulatory changes to improve the way research trials are designed and conducted.
• Increase the collaboration between government and industry in the design and implementation of clinical research.
• Foster community involvement in clinical trials.
• Implement new policies so that peer-reviewed medical/science journals address the issue of the representation of trial subjects in clinical research studies.
• Invest in specialized training for Institutional Review Boards.
• Reallocate research funding to avoid duplication and address disparities.
• Enhance public education about clinical trials.
• Implement participant navigation as a critical element of the clinical trial process.
• Assure insurance coverage of the costs associated with clinical trials.”

While we recognize the obvious benefits of the proposed policy changes to improve clinical trial processes, there are some reasons for those of us dealing with rare cancers to be concerned. In their discussion of #6 above, the authors say, "Congress will be able to ensure that federal research funding complements private sector funding and gives priority to diseases with the greatest disparities and the highest case fatality rates." What would this mean for sarcomas, which are by definition rare? Would it require finding to be directed elsewhere? Would it recognize that research into the molecular pathways of sarcoma is bringing new information to researchers of other cancers as well? It would be interesting to hear what the authors have to say in response to these questions.

Efficacy of imatinib in aggressive fibromatosis: results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial

Aggressive fibromatoses (AF, desmoid tumors) are rare clonal neoplastic proliferations of connective tissues that can be locally aggressive despite wide surgical resection and/or radiation therapy. SARC initiated a prospective phase II trial to investigate the outcome of patients treated with imatinib, a multiple tyrosine kinase inhibitor, in patients with AF, or one of ten sarcoma subtypes. Here, they report specifically on the outcome of patients with AF as well as evaluations undertaken to examine the mechanism of imatinib. Patients > 10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg BID (BSA>1.5m2), 200 mg BID (BSA=1.0-1.49m2), or 100 mg BID (BSA<1.0m2). Response outcomes at two and four months were assessed. Tissue specimens were analyzed by immunohistochemistry for expression of c-kit, PDGFRα, PDGFRβ, AKT, PTEN, FKHR, and beta catenin. Tumor DNA was analyzed for PDGFRα exon 18 and APC mutations by allelic discrimination PCR. The results were as follows: 51 patients were enrolled. The median number of prior regimens was 1. Kaplan-Meier estimates of two and four month progression-free survival rates were 94% and 88%, respectively, and one year progression-free survival was 66%. Objective response rate was 6% (3/51). Expression and polymorphisms of target proteins were identified in tissue samples, but no significant correlation with outcome was observed using the samples available. The investigators conclude: Imatinib may have a role in the management of unresectable or difficult to resect desmoid tumors.

Randomized Phase II Window Trial of Two Schedules of Irinotecan With Vincristine in Patients With First Relapse or Progression of Rhabdomyosarcoma: A Report From the Children's Oncology Group

The purpose of this Phase II trial was to compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression. Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m2/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m2 administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m2/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen. The results were as follows: Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%). The investigators conclude: There was no difference in the response rates between the two irinotecan-vincristine schedules. They thus recommend the shorter, more convenient regimen (1B) for further investigation.

V7N5 ESUN Copyright © 2010 Liddy Shriver Sarcoma Initiative.

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August 2010

Phase II Study of Cediranib (AZD2171) in Patients With Alveolar Soft Part Sarcoma

From Shivaani Kummar, MD - Principal Investigator: The National Cancer Institute’s Center for Cancer Research is working to find an effective systemic treatment for patients with alveolar soft part sarcoma, which has prompted us to conduct a clinical research study of an experimental drug called cediranib. Cediranib may slow or stop tumor growth by blocking the creation of new blood vessels. This is important in treating alveolar soft part sarcoma because the cancer relies heavily on new blood vessels to grow and spread through the body.

We are now actively seeking patients for this clinical study. There is no charge for treatment at the National Cancer Institute (NIH) Clinical Center. Patients will be responsible for travel cost for their initial screening visits.

Eligibility for this trial includes patients with confirmed and measurable alveolar soft part sarcoma that is not curable by surgery. Some patients with surgically resectable tumors with metastasis may also be eligible and will be considered for the study on a case-by-case basis.

To refer a patient, please contact:

Janelle Bingham, R.N.
Referral Coordinator
Telephone: 301-435-2715
Fax: 301-451-5433
E-mail: jbingham@mail.nih.gov

Agnes Strassberger, R.N.
Research Nurse
Telephone: 301-435-5664
Fax: 301-480-7281
E-mail: astrassberger@mail.nih.gov

Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial

The purpose of this study was to improve the poor prognosis of patients with primary disseminated multifocal Ewing sarcomas (PDMES) with a dose-intense treatment concept. From 1999 to 2005, 281 patients with PDMES were enrolled onto the Euro-EWING 99 R3 study. Median age was 16.2 years (range, 0.4 to 49 years). Recommended treatment consisted of six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), one cycle of vincristine, dactinomycin, and ifosfamide (VAI), local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by autologous stem-cell transplantation (HDT/SCT). The results are as follows: After a median follow-up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27% ± 3% and 34% ± 4% respectively. Six VIDE cycles were completed by 250 patients (89%); 169 patients (60%) received HDT/SCT. The estimated 3-year EFS from the start of HDT/SCT was 45% for 46 children younger than 14 years. Cox regression analyses demonstrated increased risk at diagnosis for patients older than 14 years (hazard ratio [HR] = 1.6), a primary tumor volume more than 200 mL (HR = 1.8), more than one bone metastatic site (HR = 2.0), bone marrow metastases (HR = 1.6), and additional lung metastases (HR = 1.5). An up-front risk score based on these HR factors identified three groups with EFS rates of 50% for score 3 (82 patients), 25% for score more than 3 to less than 5 (102 patients), and 10% for score 5 (70 patients; P < .0001). Conclusion: PDMES patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of metastatic spread are relevant risk factors. A score based on these factors may facilitate risk-adapted treatment approaches.

Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up

In this trial, imatinib was evaluated as a new treatment option in patients with recurrent or established progressive aggressive fibromatosis/desmoid tumor (AF/DT). Forty patients with unresectable and progressive symptomatic AF/DT were treated with imatinib (400 mg/day for 1 year) in a Simon's optimal two-stage phase II study. The primary end point was non-progressive at 3 months (RECIST). The results were as follows: The study population consisted of 28 women and 12 men, with a mean age of 41 (range 20–72 years). Most of the primary sites were extra-abdominal (24, 54.5%). Familial adenomatous polyposis was observed in six (15%) cases. The median follow-up was 34 months. Imatinib toxicity was similar to that previously reported in literature. Tumor assessment was validated by a central independent radiology committee for 35 patients. At 3 months, one (3%) complete and three (9%) partial confirmed responses were observed. The non-progression rates at 3, 6 and 12 months were, respectively, 91%, 80% and 67%. The 2-year progression-free and overall survival rates were 55% and 95%, respectively. Two patients with mesenteric AF/DT died from progressive disease. Conclusion: Imatinib is active in the treatment of recurrent and progressive AF/DT, providing objective response and long-term stable disease in a large proportion of patients.

Long-term Survivors of Childhood Ewing Sarcoma: Report From the Childhood Cancer Survivor Study

The survival of Ewing sarcoma (ES) patients has improved since the 1970s but is associated with considerable future health risks. This study population consisted of long-term (5-year) survivors of childhood ES diagnosed before age 21 from 1970 to 1986. The cause-specific mortality was evaluated in eligible survivors (n = 568). In addition, subsequent malignant neoplasms, chronic health conditions, infertility, and health status were evaluated in the subset participating in the Childhood Cancer Survivor Study (n = 403). Outcomes were compared with the US population and sibling control subjects (n = 3899). Logistic, Poisson, or Cox proportional hazards models, with adjustments for sex, age, race/ethnicity, and potential intrafamily correlation, were used. Statistical tests were two-sided. The results were as follows: Cumulative mortality of ES survivors was 25.0% (95% confidence interval [CI] = 21.1 to 28.9) 25 years after diagnosis. The all-cause standardized mortality ratio was 13.3 (95% CI = 11.2 to 15.8) overall, 23.1 (95% CI = 17.6 to 29.7) for women, and 10.0 (95% CI = 7.9 to 12.5) for men. The nonrecurrence-progression non-external cause standardized mortality ratio (subsequent non-ES malignant neoplasms and cardiac and pulmonary causes potentially attributable to ES treatment) was 8.7 (95% CI = 6.2 to 12.0). Twenty-five years after ES diagnosis, cumulative incidence of subsequent malignant neoplasms, excluding nonmelanoma skin cancers, was 9.0% (95% CI = 5.8 to 12.2). Compared with siblings, survivors had an increased risk of severe, life-threatening, or disabling chronic health conditions (relative risk = 6.0, 95% CI = 4.1 to 9.0). Survivors had lower fertility rates (women: P = .005; men: P < .001) and higher rates of moderate to extreme adverse health status (P < .001). The authors conclude: Long-term survivors of childhood ES exhibit excess mortality and morbidity.

MabVax Therapeutics Initiates Phase II Clinical Trial Of Vaccine To Prevent Recurrent Sarcoma

On July 23rd, MabVax Therapeutics Inc., a privately held clinical stage biotechnology company focused on the development of vaccine and antibody based therapies, announced that the first patients have been enrolled in a Phase II clinical trial aimed at assessing the efficacy and safety of its vaccine to prevent or delay the recurrence of sarcoma. The clinical trial will enroll 126 metastatic sarcoma patients, 16 years or older in a randomized, multicenter, double-blind Phase II study of a trivalent vaccine specifically developed to target and kill residual circulating cancer cells and micrometastases thought to cause recurrent cancer. The vaccine is a trivalent ganglioside vaccine administered with an immunological adjuvant in a series of 10 subcutaneous injections given over an 84-week period. The vaccine is intended to instruct the patient's immune system to make antibodies against the three ganglioside antigens present on the surface of sarcoma cells. The antibodies will then seek out and kill the residual circulating cancer cells and micrometastases with the objective of preventing disease recurrence. The vaccine was developed at Memorial Sloan-Kettering Cancer Center (MSKCC) where preclinical and early clinical development work was completed in 2009. MabVax exclusively licensed the sarcoma vaccine, along with additional vaccines targeting other neuroectodermal and epithelial cancers, from the Sloan-Kettering Institute for Cancer Research in 2008. MabVax has recruited 12 leading academic medical centers across the country as investigative sites to conduct the Phase II clinical trial. MabVax expects enrollment to require approximately 15 months. The primary objective is to determine the 1-year Progression Free Survival Rate in patients with metastatic sarcoma who are without evidence of disease and who are treated with the vaccine plus adjuvant or with the adjuvant alone. Secondary objectives are to determine Overall Survival, Disease Free Survival, and Disease Specific Survival, along with Progression Free Survival at the 3-year time point. MabVax has engaged Clinsys Clinical Research, Inc. as the contract clinical research organization to help it manage the study.

V7N4 ESUN Copyright © 2010 Liddy Shriver Sarcoma Initiative.

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June 2010

Preclinical Evidence that Use of TRAIL in Ewing's Sarcoma and Osteosarcoma Therapy Inhibits Tumor Growth, Prevents Osteolysis, and Increases Animal Survival

Despite improvement in therapy for osteosarcoma and Ewing's sarcoma, the five-year survival rate is only 20% for patients not responding to treatment or presenting with metastases. In this study, the efficacy of tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily with strong antitumoral activity and minimal toxicity to most normal cells and tissues, was investigated by complementary approaches both in vitro and in preclinical models. The sensitivity of osteosarcoma and Ewing’s sarcoma cell lines to TRAIL was investigated in vitro by determining TRAIL receptor expression together with TRAIL effects on cell viability and apoptosis. Complementary preclinical studies were carried out in respective tumor models by inoculation of osteosarcoma or Ewing’s sarcoma tumor cells in paraosseous location. In addition, a model of lung nodule dissemination was developed by i.v. injection of osteosarcoma cells. The results were as follows: In vitro, both osteosarcoma and Ewing’s sarcoma cells that express the TRAIL death receptors were highly sensitive to TRAIL-induced caspase-8–mediated apoptosis. TRAIL administered in vivo by nonviral gene therapy inhibited primary bone tumor incidence and growth by 87% and prevented tumor-induced osteolysis, leading to a significant 2-fold increase in animal survival 40 days after tumor induction. Furthermore, TRAIL inhibited tumor nodule dissemination in lungs and increased survival in an osteosarcoma model. The authors conclude: These findings suggest that TRAIL is a promising candidate for the development of new therapeutic strategies in the most frequent malignant primary bone tumors.

 

Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma

BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. The investigators of this study performed a multi-centre, multi-tumor phase II trial to investigate the efficacy, safety and pharmacokinetics of BI 2536 in five solid tumor types. Patients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumor-specific criteria. They were at least 18 years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments more than 4 weeks ago. BI 2536 200–250mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point. The results were as follows: Seventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3–4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). There were no observed confirmed objective responses. All cohorts were closed after the entry of 14–15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behavior and a rapid distribution of BI 2536. The investigators conclude: BI 2536 showed limited antitumor activity according to the design of this trial in five different tumor types. Derivatives of BI 2536 with a more favorable pharmacological profile are currently explored further in prospective studies.

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April 2010

Imatinib Mesylate in Advanced Dermatofibrosarcoma Protuberans: Pooled Analysis of Two Phase II Clinical Trials

Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB). This study reports on two phase II trials of imatinib in DFSP patients.  Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment.  The results were as follows: Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (46%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%. The investigators conclude: Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day.

 

Impact of Dynamic 18F-FDG PET on the Early Prediction of Therapy Outcome in Patients with High-Risk Soft-Tissue Sarcomas After Neoadjuvant Chemotherapy: A Feasibility Study

In this study, dynamic PET (dPET) studies with 18F-FDG were performed in patients with soft-tissue sarcomas who received neoadjuvant chemotherapy early in the course of therapy. The goal of the study was to evaluate the impact of early dPET studies and assess their value with regard to the therapy outcome using histopathologic data. The evaluation included 31 patients with nonmetastatic soft-tissue sarcomas, who were treated with neoadjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin. Patients were examined before the onset of therapy and after the completion of the second cycle. Histopathologic response served for reference and was available for 25 of 31 patients. Response was defined as less than 10% viable tumor tissue in the resected tumor tissue. The following parameters were retrieved from dPET studies: standardized uptake value (SUV); fractal dimension; 2-compartment model with computation of K1, k2, k3, and k4 (unit, 1/min); fractional blood volume; and influx according to Patlak. The results were as follows: The mean SUV was 4.6 before therapy and 2.8 after 2 cycles. The mean influx was 0.059 before therapy and 0.043 after 2 cycles. The mean SUV was 3.9 in the responders and 5.5 in the nonresponders before therapy. After therapy, responders revealed a mean SUV of 2.5, whereas nonresponders had a mean SUV of 3.5. We used linear discriminant analysis to categorize the patients into 2 groups: response (n = 12) and nonresponse (n = 13). The correct classification rate of the responders (positive predictive value) was generally higher (>67%) than that for the nonresponders. Finally, the combined use of the 2 predictor variables, namely SUV and influx, of each study led to the highest accuracy of 83%. This combination was particularly useful for the prediction of responders (positive predictive value, 92%). The use of the percentage change in maximum SUV led to an accuracy of 58%. The investigators conclude: On the basis of these results, only a multiparameter analysis based on kinetic 18F-FDG data of a baseline study and after 2 cycles is helpful for the early prediction of chemosensitivity in patients with soft-tissue sarcomas receiving neoadjuvant chemotherapy.

 

Participants’ uptake of clinical trial results: a randomized experiment

Participants are showing great interest these days in obtaining the results of clinical trials. The aim of this study was to assess patients’ uptake and understanding of the results of the trial in which they have participated and the impact of a letter offering patients the possibility of consulting the trial results on a specific website. Breast cancer patients participating in a trial on the efficacy of Trastuzumab were randomly subdivided into an Internet group (who received the letter of invitation) and a control group (who did not receive it). Among 115 HER2-positive women from 21 centers, 107 (93%) answered a self-administered questionnaire. The results were as follows: Most of the patients in both groups had access to the Internet (72.0%). The majority (97.2%) stated that receiving information about the trial results would be useful, and the oncologist was the most frequently preferred information provider. The Internet group’s declared uptake of the trial results was only slightly higher (47.1% vs. 33.9%; P¼0.166); however, they understood the results significantly more accurately (18.8% vs. 5.6%; P¼0.039). The author’s interpretation: Although the Internet was not the respondents’ preferred source of information, the possibility of using this source slightly increased the uptake and understanding of the results.

V7N2 ESUN Copyright © 2010 Liddy Shriver Sarcoma Initiative.

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February 2010

Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: A Children's Oncology Group phase I consortium study

In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. This study examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m2 administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. The results were as follows: On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m2/day combined with temozolomide 100 mg/m2/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m2/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m2/day, temozolomide 150 mg/m2/day × 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m2/day, the mean SN-38 AUCinf was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received 6 courses. The investigators conclude: The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.

 

Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study

Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signaling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumor activity of IGF-1R-targeting drugs in these diseases. This article reports on the results of a Phase I study of figitumumab. Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumor phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumor activity (best response by Response Evaluation Criteria in Solid Tumors [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760. The results were as follows: 29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6·1, range 1—24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumors. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilization (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer. The investigators conclude: Figitumumab is well tolerated and has antitumor activity in Ewing's sarcoma, warranting further investigation in this disease.

 

Cancer Therapy: Preclinical NVP-BEZ235 as a New Therapeutic Option for Sarcomas

Maria C. Manara, Giordano Nicoletti, Diana Zambelli, Selena Ventura, Clara Guerzoni, Lorena Landuzzi, Pier-Luigi Lollini, Saveur-Michel Maira, Carlos García-Echeverría, Mario Mercuri, Piero Picci, and Katia Scotlandi

In this study, the compound NVP-BEZ235 is shown to be effective in stopping the growth and spread of musculoskeletal tumor cells.  Used alone, it doesn’t produce cell death; therefore, it should be used in combination with conventional therapies Vincristine and Doxorubicin.

The purpose of Italian and Swiss researchers (see above) in this preclinical trial was "To evaluate the in vitro and in vivo effects of NVP-BEZ235, a dual pan-phosphoinositide 3-kinase–mammalian target of rapamycin inhibitor in the three most common musculoskeletal tumors (osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma)." NVP-BEZ235 is described as "a synthetic small molecular mass compound belonging to the class of imidazoquinolines that potently and reversibly inhibits class 1 PI3K catalytic activity by competing at its ATP-binding site. NVP-BEZ235 also inhibits mammalian target of rapamycin (mTOR) catalytic activity (14), and this makes the compound particularly interesting for sarcomas (15)."

Data is provided in the study to support a finding "that NVPBEZ235 is active against the three most common musculoskeletal sarcomas by inhibiting tumor cell growth, migration, and metastasis."   The drug was tested in combination therapies, with and without Vincristine or Doxorubicin, and against chemo-resistant cells.

"In conclusion, our investigation could pave the way for using dual PI3K/mTOR inhibitors to improve the therapeutic outcome of sarcoma patients. Activation of PI3K/mTOR signaling appears as a common feature of Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines. Its inhibition reduces cell proliferation, migration, and metastasis. However, as a single agent, the drug induces only disease stasis, due to the lack of apoptotic effects and increased activation of MAPK pathway. Thus, association with conventional drugs (vincristine or doxorubicin) or with other signaling inhibitors (anti–IGF-IR drugs or other specific MAPK  inhibitors) is highly recommended to obtain therapeutic improvements in the cure of sarcoma patients."

 

New Clinical Trials for Sarcomas

The following studies have been added to open clinical trials since the last issue of ESUN was published:

Phase II

• Study of RAD001 in Soft Tissue Extremity and/or Retroperitoneal Sarcomas
• Temsirolimus and Cixutumumab in Treating Patients With Locally Advanced, Metastatic, or Recurrent Soft Tissue Sarcoma or Bone Sarcoma

Phase I or Phase I/II

• Proton Beam Radiation Therapy in Treating Patients With Retroperitoneal Sarcoma
• Temozolomide, Cixutumumab, and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma
• Ridaforolimus in Patients With Hepatic Insufficiency
• PCI-24781 in Combination With Doxorubicin to Treat Sarcoma
  

V7N1 ESUN Copyright © 2010 Liddy Shriver Sarcoma Initiative.

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December 2009

Calls for Participation

Request for Volunteers for Ewing's Sarcoma/PNET Research Study at Children's Hospital Los Angeles

Children's Hospital Los Angeles is taking a fresh look at the role of genetics as a risk factor for Ewing's Sarcoma.   The Hospital is now collecting blood samples from patients with Ewing's Sarcoma and their families in search of evidence that DNA sequence changes associated with Ewing's Sarcoma/PNET may be inherited.

In a recent request for volunteers, Melissa Warden, M.S. states "In particular, copy number variations, which are large gains and losses of DNA sequence, are known to play a role in many human diseases, and we believe they may also be important in the development of Ewing's Sarcoma. By identifying a genetic susceptibility risk factor to Ewing's Sarcoma, we hope to improve our understanding of this disease, which could lead to improvement in treatment of future patients."

Anyone interested in participating in the study can contact Melissa by email at mwarden@chla.usc.edu or call her at (323) 361-5642.  The Hospital will cover the costs of blood collection and shipping.

 

Clinical Trial for patients with advanced, dedifferentiated liposarcoma to be announced

Infinity Pharmaceuticals is planning to initiate a Phase 2 clinical study to evaluate the efficacy and safety of IPI-504 (retaspimycin hydrochloride), an investigational Hsp90 inhibitor,  in patients with advanced, dedifferentiated liposarcoma.   They hope to start enrolling patients by early 2010.  Trial participants must have received at least one but no more than two prior chemotherapies.  Patients could have been treated with an unlimited number of targeted drugs or therapies that are not chemotherapies.  They plan to enroll approximately 40 patients at 6-8 centers in the United States (at this time there is no plan to have sites outside of the U.S.). Hsp90 supports and stabilizes cancer-causing proteins.  Inhibiting Hsp90 destabilizes these proteins, which stops tumor growth and  causes cancer cell death.  Hsp90 chaperone inhibition may represent an important new strategy for treating patients with cancer. For more information, contact Suzanne Sheirr at 617 453 1249 in Cambridge, Massachusetts.

 

Study Results

ZIOPHARM Presents Positive Palifosfamide Sarcoma Randomized Phase II Interim Data At CTOS

On November 9th, ZIOPHARM Oncology, Inc. presented positive interim data from the multicenter randomized Phase II trial of palifosfamide (ZymafosTM, ZIO-201) treating patients with unresectable or metastatic soft tissue sarcoma at the 15th Annual Connective Tissue Oncology Society (CTOS) Meeting. A panel of international sarcoma experts, and the Company's Medical Advisory Board determined that the data are compelling and sufficient to proceed to a pivotal study in support of product registration and to conclude enrollment in the trial.

The randomized Phase II trial treats patients with unresectable or metastatic soft tissue sarcoma in the front- and second-line setting. Patients are randomized either to doxorubicin (the only currently FDA-approved agent in sarcoma) or to palifosfamide in combination with doxorubicin. As of the October 5th cut-off date, there were 67 patients randomized to the trial, with 65 treated and 61 eligible for analysis. The 61 patients were evaluated for progression-free survival (PFS) with 20 documented PFS events (doxorubicin alone = 14 events; palifosfamide + doxorubicin = 6 events). With this analysis of all randomized and eligible patients, the hazard ratio is 0.63 favoring palifosfamide + doxorubicin (two-sided Wilcoxon-Gehan p-value = 0.026), statistically supporting that palifosfamide prolongs PFS by at least 50%.

The median PFS for doxorubicin is 4.4 months, the median PFS for palifosfamide + doxorubicin has not yet been reached; the 1st quartile PFS was 1.5 months for doxorubicin vs. 3.5 months for palifosfamide + doxorubicin (PFS more than doubled at this level). PFS is a biologically important end point in sarcoma, and has been well demonstrated to be a relevant measurement of the effect of treatment on outcome.

The interim safety data indicate that the addition of palifosfamide does not add to the toxicity of single agent doxorubicin. The most frequently reported side effects in both arms of the study include neutropenia and fatigue, hypokalemia, nausea, anemia, leucopenia, and alopecia. Palifosfamide is easily administered as an out-patient treatment, and generally well-tolerated.

"These interim results are very promising, indicating a potentially new drug to help control this life-threatening disease with acceptable safety and quality of life," commented George Demetri, MD, Director of the Center for Sarcoma and Bone Oncology and the Ludwig Center at the Dana-Farber Cancer Institute and Harvard Medical School, and a member of ZIOPHARM's Medical Advisory Board. "These data are not only encouraging for sarcoma but hopefully palifosfamide may also work in treating other cancers. This is particularly interesting if the oral form is successful in the clinic," added Lawrence Einhorn, MD, Distinguished Professor at the Simon Cancer Center of Indiana University Medical Center, Lance Armstrong Foundation Chair in Oncology, former President of ASCO and also a member of ZIOPHARM's Medical Advisory Board.

The Company is in the process of finalizing a registration trial plan in soft tissue sarcoma for review by the appropriate U.S. and international regulatory authorities.

 

Oncolytics Biotech(R) Inc. Collaborators Present Positive Phase II Sarcoma Trial Results At CTOS

On November 7th, Oncolytics Biotech Inc. announced updated results from a Phase II study of intravenous REOLYSIN(R) in patients with sarcomas metastatic to the lung in a poster presentation at the 15th Annual Connective Tissue Oncology Society (CTOS) Meeting. The poster presentation, entitled "A Phase II Study of Intravenous REOLYSIN (Wild-type Reovirus) in the Treatment of Patients with Bone and Soft Tissue Sarcomas Metastatic to the Lung", was delivered by Dr. Kamalesh Sankhala, part of principal investigator Dr. Monica Mita's team at the Institute of Drug Development (IDD), the Cancer Therapy and Research Center at the University of Texas Health Science Center, (UTHSC), San Antonio, Texas.

The investigators reported that the treatment has been well tolerated to date, and that 19 of 44 evaluable patients experienced stable disease ranging from two to 20 months, resulting in a total clinical benefit rate (complete response + partial response + stable disease) of 43%. The response objective for the study was three or more patients having prolonged stabilization of disease (greater than 6 months) or better, for the agent to be considered. The trial exceeded its established objective with six patients experiencing stable disease for more than six months. Two patients have experienced stable disease for more than 19 months. One has synovial cell sarcoma that relapsed following surgery, while the other has Ewing's Sarcoma and had previously progressed following multiple treatments.

"We were very happy to participate in the study," said Dr. Mita. "REOLYSIN is a promising option for patients with sarcoma as shown by the results of this study. As a single agent the virus had a clinical benefit rate of 43% and it was very well tolerated. Further studies combining REOLYSIN with chemotherapy are contemplated in order to integrate the virus in the panoply of agents used for sarcoma treatment."

"These results are consistent with what we observed on an interim basis when we reported data on the first 16 patients back in June 2008," said Dr. Brad Thompson, President and CEO of Oncolytics. "It is encouraging that we are observing stable disease in a range of sarcomas and the clinical benefit is not isolated to any specific type."

 

Threshold Pharmaceuticals Presents Interim Data From a Phase 1/2 Clinical Trial of TH-302 at CTOS

On November 6th, Threshold Pharmaceuticals, Inc. announced clinical trial results related to Threshold's clinical stage hypoxia-activated prodrug, TH-302 at the 15th Annual Connective Tissue Oncology Society (CTOS) Meeting. The trial is investigating TH-302 in combination with doxorubicin in patients with soft tissue sarcoma who have not received prior doxorubicin. Twelve patients have had at least one evaluable post-treatment tumor assessment, including 3 (25%) with a partial response (PR) as measured by RECIST (Response Evaluation Criteria In Solid Tumors). Two of the PRs are confirmed, including one patient who has remained on study for 33 weeks. One of the PRs was unconfirmed due to progression at the subsequent assessment. Five of the 12 patients continue to receive TH-302 after receiving TH-302 for 3 to 13 three-week cycles. Seven (58%) patients achieved stable disease while 2 (17%) had progressive disease. Additional patients are being enrolled to better define the extent of the tumor response activity.

"For sarcoma patients, median survival is about one year regardless of stage of disease, so we are definitely in need of new agents to help these patients. We believe that TH-302 may 'complement' doxorubicin, the standard of care in sarcoma, and treat that portion of the tumor that typically does not respond to this traditional chemotherapy agent," said John Curd, M.D., Threshold's chief medical officer. "This clinical trial has thus far established that TH-302 can be safely combined with full doses of doxorubicin, and the preliminary data suggests that TH-302 may add to the activity and durability of doxorubicin."

TH-302 continues to be tolerated and there have been no new unexpected adverse events in the 14 patients assessed for safety. Nausea was the most commonly reported adverse event and was reported in 8 (57%) patients. After observing significant, but not dose limiting toxicity at a TH-302 dose of 240 mg/m2, prophylactic growth factor support was initiated. Two dose limiting toxicities, grade 3 cellulitis with grade 4 neutropenia and grade 4 thrombocytopenia, were observed in 2 of 4 patients treated at a TH-302 dose of 340 mg/m2. The maximum tolerated dose (MTD) was then established at 300 mg/m2. Skin toxicity is common with 9 of 14 (64%) patients having at least one skin adverse event. All were grade 1 or 2 with the exception of the one patient with grade 3 cellulitis. Eight (57%) patients had a mucosal adverse event; all were grade 1 or 2.

The 403 trial is a Phase 1/2, multicenter, dose escalation trial to determine the safety, efficacy and pharmacokinetics of TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. The trial was initiated in September 2008. The trial will enroll up to 36 patients including 12 patients treated at the MTD as part of the dose expansion component of the trial. TH-302 is administered intravenously on days 1 and 8 of a 21 day cycle. Doxorubicin is dosed according to its package insert (75 mg/m2 on day 1 of the 21 day cycle). The Phase 1/2 clinical trial has completed the dose escalation component, reached the MTD and is currently enrolling patients in the dose expansion cohort.

The Company has two additional ongoing clinical trials of TH-302. The Company is in the process of completing a Phase 1/2 clinical trial of TH-302 in combination with various chemotherapies in patients with advanced solid tumors. The Company is also continuing a Phase 1/2 clinical trial of TH-302 as monotherapy in patients with advanced solid tumors.

 

Orphan Drug Status

European Medicines Evaluation Agency Grants ARQ 197 Orphan Drug Designation

On October 14th, ArQule, Inc. announced that the European Medicines Evaluation Agency (EMEA) has designated ARQ 197 as an orphan medical product for the treatment of soft tissue sarcoma. Under the guidelines of the EMEA, medicinal products are designated as orphan drugs when they are used to treat illnesses affecting small numbers of patients, such as soft tissue sarcoma. Such designation provides for incentives for investment in the research and development of such drugs, including exclusive distribution rights throughout the European Union for ten years, during which period no other product with the same active ingredient would be authorized for use for the same therapeutic application.

ArQule is conducting a Phase 2 clinical trial with ARQ 197 in a sub-group of soft tissue sarcoma known as MiT (Microphthalmia Transcription Factor)-associated tumors. The designation of ARQ 197 as an orphan medical product in soft tissue sarcoma, combined with the evaluation of clinical data from this trial expected to be available in early 2010, will inform the decisions related to the advancement of the program.

New Clinical Trials for Sarcomas

The following studies have been added to open clinical trials since the last issue of ESUN was published:

Phase III

• Study in Localized and Disseminated Ewing Sarcoma (EWING 2008) - Germany

Phase II

• Therapeutic Angiotensin-(1-7) in Treating Patients With Sarcoma That is Metastatic or Cannot Be Removed by Surgery (Wake Forest, NC)
• Study of MK8669 (Ridaforolimus) With Metastatic Bone or Soft-tissue Sarcoma Patients (Japan)

Phase I or Phase I/II

• Study of Lung Chemotherapy in the Treatment of Advanced Lung Cancer and Metastatic Sarcoma (Buffalo, NY)
• Study of Pazopanib and Ixabepilone in Patients With Solid Tumors (Minneapolis, MN)
• Quantitative MR Biomarkers for Sarcoma Treatment (Ann Arbor, MI)
• Adjuvant Valproate for High Grade Sarcomas (New York, NY)
• Functional and Clinical Long-Term Outcome of Ewing Sarcoma Treatment (Observational Study in Germany)
  
  

V6N6 ESUN Copyright © 2009 Liddy Shriver Sarcoma Initiative.