Clinical Trials in Soft Tissue Sarcomas

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to current clinical trials of the Cancer Trials Support Unit, a National Cancer Institute pilot program.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, online access is available at www.cancer.gov/cancer_information/pdq/, or contact the Cancer Information Service offices (1-800-4-CANCER).

Soft tissue sarcomas in adultsare rare malignancies with diverse histologies that have historically been classified together, mostlyforconvenience. In truth, however, these diseases are quite biologically distinctin their pathogenesis and clinical behavior. The molecular mechanisms underlyingsarcoma development are for the most part still poorly understood; however,recent studies have begun to elucidate the gene mutations responsible foroncogenesis in some of the histologic subtypes, including the SYT-SSX fusiongene in synovial sarcoma and c-KIT in gastrointestinal stromal tumors(GIST).[1-3] Recent studies in GIST are worthy of discussion, as they haveprovided a long-awaited proof of principle for molecular targeting of aberrantcellular pathways in solid tumors.

Gastrointestinal Stromal Tumors

Unresectable or metastatic GIST is a fatal disease that is refractory to allchemotherapeutic interventions. KIT is a cell-surface transmembrane receptorthat has tyrosine kinase activity and regulates cell proliferation andapoptosis. It was recently discovered that the c-KIT gene is mutated ordysregulated in nearly all patients with GIST; this leads to constitutiveactivation of KIT signaling, resulting in uncontrolled cell proliferation.[2]

Imatinib mesylate (Gleevec, Glivec) is a selective inhibitor of severaltyrosine kinases including KIT, bcr-abl, and platelet-derived growth factorreceptor. In a recently reported phase II trial, 147 patients with recurrent ormetastatic GIST treated with imatinib had an overall response rate of 54%, withanother 28% of patients achieving stable disease.[4] Based on early results fromthis study, two large phase III trials were collaboratively developed andconducted in North America and Europe. Together, these studies accruedapproximately 1,800 patients in less than 10 months.

These are remarkable achievements, demonstrating that rationally designedmolecularly targeted agents may have significant efficacy when patients whosecancers possess the critical target are appropriately assessed and selected fortherapeutic intervention. This also affirms the ability of the CooperativeGroups to rapidly conduct and complete important large-scale trials in theserare diseases.

State-of-the-Science Meeting

The scientific success and clinical results of the investigations in GISThave generated renewed excitement in sarcoma research, culminating recently in aNational Cancer Institute (NCI)-sponsored State-of-the-Science Meeting:"Soft Tissue Sarcoma: Building on Molecular and Clinical Progress."This conference brought together an international group of sarcoma experts froma wide variety of disciplines including biology, pathology, surgery, radiationoncology, imaging, and medical oncology. Among other issues, these expertsconsidered and discussed opportunities and obstacles for: (1) continuedidentification of aberrant molecular pathways in sarcomas; (2) translatingbasic research into clinical investigation; and (3) identifying the questionsthat are of highest priority for clinical investigation. Interested individualscan review the proceeds and summary recommendations of this meeting on theInternet at www.webtie.org/SOTS/index.htm.

Conclusions

Continued progress in these uncommon but important diseases will require thatall patients have the opportunity to participate in clinical trials. Thefollowing list includes currently active protocols for patients with newlydiagnosed/recurrent soft tissue sarcomas sponsored by the NCI’s Cancer TherapyEvaluation Program (CTEP). Several other exciting studies are in development andwill be availableto patients shortly. When activated, information about these clinical
trials will be available on the NCI website at www.cancer.gov orwww.clinicaltrials.gov.

Phase III

Title: A Phase III Randomized Double-Blind Study of Adjuvant STI571 (Gleevec)vs Placebo in Patients Following the Complete Resection of Moderate Risk PrimaryGastrointestinal Stromal Tumor (GIST) (active)
Protocol Number: ACOSOG-Z9001
Participating Institutions: American College of Surgeons Oncology TrialsGroup
Contact: Vijaya Chadaram, (919) 668-8670

Phase II

Title: A Multi-Institutional, Open-Label, Two-Group, Phase II Study ofPS-341 (LPDPS-341, NSC #681239) in Patients With Advanced or Metastatic Sarcoma(active)
Protocol Number: 1757
Participating Institutions: Memorial Sloan-Kettering Cancer Center
Contact: Robert Maki, (212) 639-5720

Title: A Phase II Evaluation of DMAP Plus GM-CSF in the Treatment ofAdvanced, Persistent, or Recurrent Leiomyosarcoma of the Uterus (active)
Protocol Number: GOG-0087K
Participating Institutions: Gynecologic Oncology Group
Contact: Harry J. Long, (507) 284-4320

Title: A Phase II Evaluation of Docetaxel and Gemcitabine Plus G-CSF in theTreatment of Recurrent or Persistent Leiomyosarcoma of the Uterus (active)
Protocol Number: GOG-0131G
Participating Institutions: Gynecologic Oncology Group
Contact: John Kellner, (215) 854-0770

Title: A Phase II Evaluation of Thalidomide (NSC#66847) in the Treatmentof Recurrent or Persistent Carcinosarcoma of the Uterus (active)
Protocol Number: GOG-0230B
Participating Institutions: Gynecologic Oncology Group
Contact: D. Scott McMeekin, (405) 271-8707

Title: A Phase II Evaluation of Thalidomide (NSC #66847) in the Treatmentof Recurrent or Persistent Leiomyosarcoma of the Uterus (active)
Protocol Number: GOG-0231B
Participating Institutions: Gynecologic Oncology Group
Contact: D. Scott McMeekin, (405) 271-8707

Title: A Phase II Study of Multimodality Therapy for Primary and RecurrentRetroperitoneal Sarcomas (active)
Protocol Number: RTOG S-0124
Participating Institutions: Radiation Therapy Oncology Group
Contact: Elaine Pakuris, (215) 574-3195

Phase I/II

Title: Phase I/II Study of Combination of MAP With ONYX-015 in PatientsWith Advanced Sarcoma (active)
Protocol Number: T99-0021
Participating Institutions: Mayo Clinic
Contact: Evanthia Galanis, (507) 284-2511

References:

1. Ladanyi M: Fusions of the SYT and SSX genes in synovial sarcoma.Oncogene 20(40):5755-5762, 2001.

2. Nakahara M, Isozaki K, Hirota S, et al: A novel gain-of-function mutationof c-kit gene in gastrointestinal stromal tumors. Gastroenterology115(5):1090-1095, 1998.

3. Nielsen TO, West RB, Linn SC, et al: Molecular characterisation of softtissue tumours: A gene expression study. Lancet 359(9314):1301-1307, 2002.

4. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety ofimatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med347(7):472-480, 2002.