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Abstracts by Tom Swartz
[Editor's Note: Readers who regularly read our Clinical Trial News column, know that we abstract a large number of clinical trials that deal with sarcoma. However, we have typically not included studies dealing specifically with GIST. We are remedying this omission in this issue of ESUN. In future issues of ESUN, GIST studies will be included in the Clinical Trail News column.]
Adjuvant Imatinib in High-Risk GIST With c-Kit Mutation This Phase II trial is currently recruiting patients. The presence of c-kit mutation is an independent poor prognostic factor for relapse, in addition to large size (> 5 cm) and high mitotic rate (> 5/50HPF) in localized GIST patients who have undergone complete surgical resection. In addition, the localized GIST which had exon 11 c-kit mutation and features of high-risk for relapse according to NIH consensus guideline (tumor size > 10 cm or mitotic count > 10/50HPF) also have high-risk of relapse. Until recently, there has been no effective therapy for advanced, unresectable GISTs. However, imatinib mesylate (Gleevec), has shown promise in the metastatic setting, and c-kit exon 11 mutation is the strongest prognostic factor for better response and survival. The purpose of this trial is to try imatinib for these high risk GIST patients. Further study details can be provided by the Asan Medical Center; contact Yoon-Koo Kang, M.D., Ph.D., 82-2-3010-3210. GIST patients 18 years of age and older with the above high risk characteristics are eligible. The total expected enrollment is 47 patients, and this trial is taking place at centers in South Korea.
Study of AMN107 With Imatinib in Gastrointestinal Stromal Tumors (GIST) This Phase I trial is currently recruiting patients. AMN107 is an investigational oral compound being developed by Novartis, which inhibits the activity of tyrosine kinases, including Bcr-Abl, KIT, and platelet derived growth factor receptor (PDGFR). This trial is an open-label, multicenter, Phase I dose-escalation study of the combination of AMN107 and imatinib (STI571) in patients with imatinib-resistant GIST. This study is designed to determine the Phase II dose of AMN107 and imatinib when administered together in patients with imatinib-resistant GIST, and to characterize the safety, tolerability and pharmacokinetic (PK) profile of this combination. Patients 18 years of age and older are eligible. This trial is taking place at Dana Farber Cancer Institute, Boston, Massachusetts, and Fox Chase Cancer Center, Philadelphia, Pennsylvania.
This Phase II trial is currently recruiting patients. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Oblimersen may help imatinib mesylate kill more tumor cells by making tumor cells more sensitive to the drug. The purpose of this trial is to study how well giving imatinib mesylate together with oblimersen works in treating patients with advanced gastrointestinal stromal tumor that cannot be removed by surgery. Patients are stratified according to extent of disease progression (limited vs. generalized). Patients receive oblimersen IV continuously on days 1-14. Patients also receive oral imatinib mesylate on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients are followed for survival. A total of 96 patients (48 per stratum) will be accrued for this study. Patients 18 years of age and older are eligible. This trial is taking place at Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, Mayo Clinic Cancer Center, Rochester, Minnesota, Memorial Sloan-Kettering Cancer Center, New York, New York, M.D. Anderson Cancer Center at University of Texas, Houston, Texas.
Safety Study of IPI-504 for Gastrointestinal Stromal Tumors (GIST) This Phase I trial is currently recruiting patients. IPI-504 is a novel, water-soluble analog of 17-AAG and a potent inhibitor of Hsp90. Hsp90’s role in the cell is to control the proper folding, function, and viability of various “client” proteins. Many of these client proteins (such as AKT, Her-2, Bcr-Abl, PDGFR-α, and c-Kit) are oncoproteins or important cell signaling proteins. In patients with GIST, mutations in the tyrosine kinase receptor Kit play a critical role in the pathogenesis of this disease. Inhibition of Kit signaling with the tyrosine kinase inhibitor Imatinib (IM) is a very effective treatment for GIST patients. However, new mutations arise in Kit conferring resistance to IM treatment which results in disease progression. Kit is a client protein of Hsp90 and is sensitive to IPI-504. This provides a scientific rationale for Phase I clinical testing of IPI-504 in patients with metastatic and/or unresectable GIST who have failed prior therapies. Thus, the purpose of this trial is to determine the safety and maximum tolerated dose (MTD) of IPI-504 in GIST patients who have failed prior therapies. The treatment protocol is not outlined. The total expected enrollment is 40 patients. Patients 18 years of age and older are eligible. This trial is taking place at Dana-Farber Cancer Institute, Boston, Massachusetts.
PTK787/ZK222584 in the Treatment of Metastatic Gastrointestinal Stromal Tumors Resistant to Imatinib This Phase II trial is currently recruiting patients. The purpose of this trial is to evaluate the safety and efficacy of a novel tyrosine kinase inhibitor, PTK787/ZK222584, in the treatment of GIST (gastrointestinal stromal tumor) that is resistant to imatinib mesylate (Gleevec). The study participants are required to have histologically confirmed GIST with prior imatinib treatment for metastatic GIST. PTK787/ZK222584 is administered orally 1250 mg/day. Six patients will first enter the study. If clinical benefit is obtained in >1 of 6 patients, 9 and 30 additional patients will be entered into the protocol in two stages (a maximum of 45 patients will be entered). Patients who benefit from the study treatment will be treated with PTK787/ZK222584 until treatment failure. Patients 18 years of age and older are eligible. This trial is taking place at Helsinki University Central Hospital, Helsinki, Finland.
This Phase II trial is currently recruiting patients. Sorafenib is a synthetic compound targeting growth signaling and angiogenesis. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis. Thus, Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. The purpose of this trial is to study how well sorafenib works in treating patients with malignant gastrointestinal stromal tumor that progressed during or after previous treatment with imatinib mesylate. Patients are stratified according to response to prior treatment with imatinib mesylate (imatinib mesylate-responsive disease vs. primary imatinib mesylate-refractory disease). Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically. A total of 42 patients will be accrued for this study. Patients 18 years of age and older are eligible. This trial is taking place at the University of Chicago Cancer Research Center, Chicago, Illinois.
FR901228 in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma This Phase II trial is currently recruiting patients. FR901228 is a type of depsipeptide and belongs to the family of drugs called histone deacetylase inhibitors. Depsipeptide binds to and inhibits histone deacetylase, thereby affecting the regulation of gene expression and inducing cell differentiation, cell cycle arrest, and apoptosis. This agent also inhibits hypoxia-induced angiogenesis and depletes several HSP90-dependent oncoproteins. The purpose of this trial is to study how well FR901228 works in treating patients with metastatic or unresectable soft tissue sarcoma, including GIST. Patients receive FR901228 IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response (CR) receive 6 additional courses beyond documentation of CR. After completion of study treatment, patients are followed every 2 months. A total of 18-36 patients will be accrued for this study within approximately 1 year. Patients 18 years of age and older are eligible. This trial is taking place at centers in Arizona, California, Georgia, Illinois, North Carolina, Ohio, South Carolina, and Virginia.
This Phase III trial is currently recruiting patients. In this study, patients who have been diagnosed with gastrointestinal stromal tumor (GIST) will be randomly allocated in a 1:1 ratio to receive imatinib (Gleevec) either for 12 or for 36 months following surgery. The study participants are required to have a histologically verified GIST with high to very high risk of GIST recurrence despite complete removal of all macroscopic GIST tissue at surgery. The high/very high risk of recurrence is defined as one of the following: 1) the largest tumor diameter is over 10 cm; 2) the mitosis count is high (over 10 mitoses per 50 high power microscope fields, HPFs); 3) the largest tumor diameter over 5 cm and the mitosis count is over 5/50 HPFs; 4) tumor spillage has taken place into the abdominal cavity at the time of surgery or following spontaneous tumor rupture; 5) intra-abdominal metastases are present but they could all be removed along with the primary surgery. All study participants will receive imatinib 400 mg/day orally, but the duration of imatinib administration will be determined randomly (either for 12 or for 36 months). The study participants will be followed up using blood tests and computed tomography (or MRI) of the abdomen. The computed tomography examinations will be performed at 6 month intervals for a median of 5 years. A total of 240 patients will be entered into the study. The study hypothesis is that adjuvant imatinib may prevent some of the GIST recurrences, and that there may be a difference in the rate of GIST recurrence between the two groups. Patients 18 years of age and older are eligible. This trial is taking place at Lund University Hospital, Lund, Sweden.
This Phase II trial is currently recruiting patients. This is a multicenter, post-marketing, clinical study aimed to evaluate the safety and efficacy of postoperative adjuvant therapy with Imatinib Mesylate in GIST patients in terms of relapse-free survival in high-risk GIST patients receiving 400 mg of Imatinib Mesylate for one year (48 weeks), by confirmation of tumor recurrence and survival for 3 years after surgery for their primary tumors. Also, this study aims to assess the overall survival, relapse-free survival rate and overall survival rate in these patients and the safety of the study drug. Patients 20 years of age to 74 are eligible. This trial is taking place at unspecified centers in Japan.
Open-Label Trial of Glivec With Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors This Phase III trial is currently recruiting patients. The purpose of this trial is to assess the clinical and biological activity of Imatinib in GIST patients and to compare the data with historic data. Additionally this study has been designed to gain more experience with the treatment of GIST in several Central and Eastern European Countries. Patients will receive Imatinib 400 mg p.o./day for a period of up to 24 months provided that in the opinion of the investigator the patient is benefiting from treatment with Imatinib, and in the absence of any safety concerns. Treatment after completion of the 24 months study is at the discretion of the investigator. Imatinib should be increased to 600 mg p.o./day and then to 400 mg b.i.d if the patient is progressing on the respective dose level. Approximately 150 patients will enter the trial. Patients 18 years of age and older are eligible. This trial is taking place at centers in Austria, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Lithuania, Romania, Serbia and Montenegro, Slovakia, and Slovenia.
This Phase II trial is currently recruiting patients. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Giving imatinib mesylate before and after surgery may shrink the tumor so it can be removed and may kill any tumor cells remaining after surgery. The purpose of this trial is to study the effectiveness of neoadjuvant and adjuvant imatinib mesylate in treating patients who are undergoing surgery for primary or recurrent malignant gastrointestinal stromal tumor. Patients receive oral imatinib mesylate once daily. Treatment continues for 8 weeks in the absence of disease progression. Patients with disease progression are considered for immediate surgical resection. Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. Two to four weeks after surgery, patients receive oral imatinib mesylate once daily for 2 years. Patients are followed every 3 months for 2 years and then every 6 months for 3 years. A total of 63 patients will be accrued for this study within 2 years. Patients 18 years of age and older are eligible. This trial is taking place at centers in Massachusetts, Oregon, and Pennsylvania.
This Phase III trial is currently recruiting patients. Imatinib mesylate (Gleevec; STI571) may interfere with the growth of tumor cells and may be an effective treatment for patients with primary gastrointestinal stromal tumor that has been completely removed by surgery. The purpose of this trial is to study imatinib mesylate (Gleevec; STI571) to see how well it works compared to placebo in treating patients with primary gastrointestinal stromal tumor that has been completely removed by surgery. This is a randomized, double-blind, placebo-controlled, crossover, multicenter study. Patients are stratified according to tumor size (3 cm but less than 6 cm vs. 6 cm to less than 10 cm vs. 10 cm or greater). Patients are randomized to 1 of 2 treatment arms as follows:
Patients are followed every 3 months for 2 years and then every 6 months for 8 years. A total of 732 patients will be accrued for this study. Patients 18 years of age and older are eligible. This trial is taking place at centers in Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Florida, Georgia, Hawaii, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oregon, Pennsylvania, South Carolina, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, Wisconsin and Canada.
This Phase I trial is currently recruiting patients. Drugs used in chemotherapy, such as doxorubicin and flavopiridol, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Flavopiridol may also help doxorubicin work better by making tumor cells more sensitive to the drug. Giving more than one drug may kill more tumor cells. The purpose of this trial is to study the side effects and best dose of flavopiridol when given with doxorubicin in treating patients with metastatic or recurrent sarcoma that cannot be removed by surgery, including gastrointestinal stromal tumors (patients with gastrointestinal stromal tumors should receive therapy with imatinib mesylate first if eligible for both types of therapy). This is an open-label, dose-escalation study of flavopiridol. Patients receive doxorubicin IV over 5-10 minutes and flavopiridol IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients reaching a cumulative doxorubicin dose of 600 mg/m^2 or experiencing cardiotoxicity may receive flavopiridol alone at the discretion of the investigator. Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Ten additional patients receive treatment at the MTD. Patients are followed every 3 months for 1 year. A total of 3-36 patients will be accrued for this study within 1-2 years. Patients 18 years of age and older are eligible. This trial is taking place at Memorial Sloan-Kettering Cancer Center, New York, NY.
This Phase III trial is currently recruiting patients. Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving imatinib mesylate after surgery may kill any remaining tumor cells. It is not yet known whether imatinib mesylate is more effective than observation only in treating gastrointestinal stromal tumor. The purpose of this trial is to study imatinib mesylate to see how well it works compared to observation only in treating patients who have undergone surgery for localized gastrointestinal stromal tumor. This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, risk category (high vs. intermediate), tumor site (gastric vs. other), and resection level (R0 vs. R1). Patients are randomized to 1 of 2 arms as follows:
After completion of study treatment, patients in arm I are followed every 3 months for 2 years. All patients are then followed every 4 months for 3 years and at least annually thereafter. A total of 400 patients will be accrued for this study within 5 years. Patients 18 years of age and older are eligible. This trial is taking place at centers in Australia, Belgium, Denmark, France, Germany, Italy, the Netherlands, Poland, Spain, and the United Kingdom.
Imatinib Mesylate in Treating Patients With Locally Advanced Gastrointestinal Stromal Tumor This Phase II trial is currently recruiting patients. Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving imatinib mesylate before surgery may shrink the tumor so that it can be removed. The purpose of this trial is to study how well imatinib mesylate works in treating patients with locally advanced gastrointestinal stromal tumor. This is a nonrandomized, open-label, multicenter study. Patients receive oral imatinib mesylate once or twice daily for 4-6 months in the absence of disease progression or unacceptable toxicity. Within 2-3 weeks after completion of imatinib mesylate, patients with responding or stable disease undergo surgical resection. After completion of study treatment, patients are followed at 4 weeks, 6 months, and then at 1 year. A total of 40 patients will be accrued for this study. Patients 18 years of age and older are eligible. This trial is taking place at centers in Austria and Germany.
Study Of SU011248 Administered In A Daily Regimen In Patients With Gastrointestinal Stromal Tumor This Phase II trial is currently recruiting patients. SU011248 is a novel angiogenesis inhibitor. The purpose of this trial is to evaluate the antitumor activity of SU011248 in advanced, imatinib mesylate-resistant GIST when administered in a continuous treatment regimen. Further study details are provided by pharmaceutical maker Pfizer. The total expected enrollment is 60 patients. Patients 18 years of age and older are eligible. This trial is taking place at centers in Massachusetts, France and Italy.
Gleevec Administered Preoperatively to Reduce Gastrointestinal Stromal Tumor (GIST) This Phase II trial is currently recruiting patients. The aim of this study is to demonstrate that the use of Gleevec in initially non-resectable gastrointestinal stromal tumors can lead to allow complete resection in 20% of cases. Gastrointestinal stromal tumor (GIST) is a specific, immunohistochemically KIT+ mesenchymal neoplasm of the gastrointestinal tract. The identification of KIT+ tumor has become more important after introduction of target treatment with KIT tyrosine kinase inhibitor Imatinib mesylate (Gleevec). Despite this progress, GIST patients presenting a tumor larger than 5 cm have a 10 year survival between 10% and 30%. Indeed, the risk of microscopic spreading of the tumor during surgery is very high since intra-abdominal organs are in close relation to each others. To improve survival, it seemed logical to use preoperative Gleevec to reduce tumor size and improve efficacy of the surgical procedure. The total expected enrollment is 50 patients. Patients 18 years of age and older are eligible. This trial is taking place at Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
Evaluate the Efficacy of AMG 706 to Treat Advanced Gastrointestinal Stromal Tumors This Phase II trial is currently recruiting patients. AMG 706 is an orally bioavailable multiple-receptor tyrosine kinase inhibitor with potential antineoplastic activity. AMG 706 selectively targets and inhibits vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR), kit, and Ret receptors, thereby inhibiting angiogenesis and cellular proliferation. The purpose of the study is to evaluate the safety and efficacy of AMG 706 in patients with gastrointestinal stromal tumor that have not been controlled while taking imatinib mesylate. Further study details are provided by pharmaceutical maker Amgen. The total expected enrollment is 35 patients. Patients 20 years of age and older are eligible. This trial is taking place at unspecified sites in Japan.
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