Scott Schuetze, MD, PhD. Clinical Assistant Professor, Department of Internal Medicine, University of Michigan, Ann Arbor, is the Principal Investigator for this clinical trial for patients with advanced sarcomas which is open to accrual at sites across the United States.
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Trial Background
Dasatinib (Sprycel®) is a medication currently approved for use in treating certain types of leukemia (cancer that begins in the white blood cells) in people who can no longer benefit from other medications including imatinib (Gleevec) or who cannot take these medications because of severe side effects. At a molecular level, dasatinib is an inhibitor of a specific family of enzymes or proteins, called Src -tyrosine kinases.
The intracellular kinase SRC interacts with receptor tyrosine kinases (EGFR, PDGFR, c-KIT, etc.) and other cellular factors such as focal adhesion kinase (FAK) as a component of the pathways regulating proliferation, survival, angiogenesis and metastasis. Under normal conditions, the cell tightly regulates this activation. In certain sarcoma cell lines however, the signaling pathway involving src-tyrosine kinases becomes defective, regulation is lost and signaling becomes over-activated. That is why they are now a target for new treatments in clinical investigation for both bone and soft tissue sarcomas.
Dasatinib is a potent, small molecule that binds to and inhibits the growth-promoting activities of SRC, PDGFR, C-KIT, BCR-ABL and ephrin receptor kinases. This inhibition of signaling of receptor tyrosine kinases or FAK via interaction with SRC may inhibit growth of sarcoma, causing a hindrance of cell migration and invasion. Moreover, dasatinib was found to kill the cancerous cells in osteosarcoma and Ewing’s subset of bone sarcomas, indicating that these bone sarcoma cell lines are dependent on Src activity for survival.
These results show that dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. These findings indicate that dasatinib is a promising therapeutic agent for preventing growth and metastasis of a wide diversity of soft tissue and bone sarcomas. This is especially important because sarcoma subtypes such as alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, hemangiopericytoma and giant cell tumor of bone are resistant to currently available drugs and identification of active agents for these rare diseases is greatly needed. Additionally, after failure of imatinib and sunitinib, there are no effective therapies for GIST.
Trial
This trial will assess the effectiveness of Dasatinib in advanced, measurable sarcoma not curable by standard multidisciplinary treatment (surgery, radiation and/or chemotherapy). Patients enrolled in this study will take this medication by mouth, twice daily for 28 days (constitutes a cycle) for several cycles. Dasatinib will be provided free of charge by the study. The routine costs of care including clinic visits, laboratory studies and scans of sarcoma will not be paid for by the study.
Patients who are eligible to participate in the study will be registered into one of the following sub-type specific cohorts: GIST, leiomyosarcoma, MFH, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, osteosarcoma or “indolent sarcomas”. The indolent sarcoma sub-group will consist of alveolar soft part sarcoma, epithelioid sarcoma, chondrosarcoma, hemangiopericytoma, giant cell tumor of bone and chordoma.
Subjects will be seen before each cycle for medical history, physical exam and laboratory studies. Subjects will have to complete imaging tests of the tumor every 2 months (8 weeks) for the first 6 months and approximately every 3 months thereafter while on the treatment.
Subjects may continue therapy unless disease progression is documented, unacceptable toxicity occurs despite reduction in the dose of drug to 100 mg daily, subject voluntarily discontinues treatment or dies, or the investigator feels it is in the best interest of the subject to discontinue therapy.
A maximum of 502 subjects are expected to participate in this study throughout the US.
Participation in the trial
To be eligible to participate in this trial a patient must:
1. Have a confirmed diagnosis of unresectable, recurrent, or metastatic soft tissue or bone sarcoma of one of the following subtypes:
Leiomyosarcoma, Malignant fibrous histiocytoma (MFH)/pleomorphic undifferentiated sarcoma, Rhabdomyosarcoma, Malignant peripheral nerve sheath tumor (MPNST), Osteosarcoma (skeletal or extraosseous), Chondrosarcoma, Ewing's, Alveolar soft part sarcoma, Chordoma, Epithelioid sarcoma, Giant cell tumor of bone, Hemangiopericytoma/solitary fibrous tumor or GIST
2. Have measurable lesion(s) either by x-ray, CT, MRI or physical exam as defined by Choi criteria
3. If had prior radiation or chemotherapy treatment, more than two weeks should have elapsed since its administration and the patients must be recovered from any associated toxicities.
4. Weigh over 50 kg.
5. Be over 13 years of age.
6. Be able to carry out work of a light or sedentary nature, e.g., light house work, office work and may still be able to participate if he/she is restricted in physically strenuous activity.
7. Subjects with GIST must have received or been intolerant to Imatinib.
You will have blood tests, a physical exam, and scans before you are enrolled and your test results must be within the limits outlined for eligibility to participate in the study protocol.
Patients would NOT be able to participate in the study if they:
1. Are curable by conventional multidisciplinary management.
2. Are pregnant or nursing/breastfeeding.
3. Have a history of significant bleeding disorder unrelated to cancer or are taking medications that inhibit platelet function or anticoagulants because of a potential increased risk of bleeding from dasatinib.
4. Have problems with their heart
*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. Schuetze.
For more information contact SARC at 734.930.7600 or Dr. Schuetze at (734)936-0453.
This trial is registered at clinicaltrials.gov and can be found at the following URL:
http://www.clinicaltrials.gov/ct/show/NCT00464620?order=3
The full title is: A Phase II Trial of Dasatinib in Advanced Sarcoma (SARC009)
Glossary:
*Imatinib (Gleevec): The mesylate salt of imatinib, a tyrosine kinase inhibitor with antineoplastic activity. Imatinib binds to an intracellular pocket located within tyrosine kinases (TK), thereby inhibiting ATP binding and preventing phosphorylation and the subsequent activation of growth receptors and their downstream signal transduction pathways. This agent inhibits TK encoded by the bcr-abl oncogene as well as receptor TKs encoded by the c-kit and platelet-derived growth factor receptor (PDGFR) oncogenes. Inhibition of the bcr-abl TK results in decreased proliferation and enhanced apoptosis in malignant cells of Philadelphia-positive (Ph+) hematological malignancies such as CML and ALL; effects on c-kit TK activity inhibit mast-cell and cellular proliferation in those diseases overexpressing c-kit, such as mastocytosis and gastrointestinal stromal tumor (GIST).
*Toxicity: In medical treatment, the harmful effects of a medicine or treatment, especially at higher doses.