Trial of Dasatinib in Advanced Sarcomas

Study Overview
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Brief Summary
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This study will examine the response rate and the 6-month progression-free survival rates of subjects with advanced sarcoma treated with dasatinib.

Detailed Description
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Further details provided by SARC (Sarcoma Alliance for Research through Collaboration): Treatment: Subjects take Dasatinib twice daily by mouth for 28 days per 28 day cycle. Subjects will be seen for interim medical history, physical exam and laboratory studies prior to each cycle. Subjects will undergo tumor imaging every 2 months (8 weeks) for the first 6 months and approximately every 3 months thereafter while on treatment. A blood sample for collection of specimens with which to later study serum level of Dasatinib and effects on biomarkers of drug activity will be obtained approximately 2 to 4 weeks after the start of treatment. Central collection of archival tumor with which to later study the frequency of expression and/or mutation of kinases inhibited by dasatinib will occur. Subjects will be followed for approximately every 3 months until 2 years from registration and then approximately yearly until 5 years from registration.

Official Title
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A Phase II Trial of Dasatinib in Advanced Sarcomas

Conditions
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Rhabdomyosarcoma, Malignant Peripheral Nerve Sheath Tumors, Chondrosarcoma, Sarcoma, Ewing's, Sarcoma, Alveolar Soft Part, Chordoma, Epithelioid Sarcoma, Giant Cell Tumor of Bone, Hemangiopericytoma, Gastrointestinal Stromal Tumor (GIST)

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unresectable, recurrent, or metastatic histologically-confirmed soft tissue or bone sarcoma of one of the following subtypes: Leiomyosarcoma --* NO LONGER ELIGIBLE* Liposarcoma--* NO LONGER ELIGIBLE* Malignant fibrous histiocytoma (MFH)/pleomorphic undifferentiated sarcoma--* NO LONGER ELIGIBLE* Rhabdomyosarcoma --* NO LONGER ELIGIBLE* Malignant peripheral nerve sheath tumor (MPNST) --* NO LONGER ELIGIBLE* Osteosarcoma (skeletal or extraosseous)--* NO LONGER ELIGIBLE* Ewing's --* NO LONGER ELIGIBLE* Chondrosarcoma Alveolar soft part sarcoma Chordoma Epithelioid sarcoma Giant cell tumor of bone Hemangiopericytoma/solitary fibrous tumor Gastrointestinal Stromal Tumor (GIST) --* NO LONGER ELIGIBLE* Documentation that subjects with leiomyosarcoma, liposarcoma, osteosarcoma, Ewing's, MPNST, rhabdomyosarcoma or MFH have received, not been eligible for or refused at least one prior chemotherapy regimen before participation in the dasatinib study. Subjects with GIST must have received or been intolerant to imatinib; prior treatment with other agents including sunitinib is not required.Neoadjuvant/adjuvant chemotherapy qualifies as prior therapy. Subjects must have unidimensionally measurable lesion(s) either by x-ray, computed tomography (CT), magnetic resonance imaging (MRI) or physical examination documented within 30 days prior to registration. Prior radiation will be allowed. More than two weeks should have elapsed since the administration of the last fraction of radiation therapy, and subjects must have recovered from grade 2 or higher associated toxicities. Measurable lesions, which are selected as target lesions, must be outside previously radiated fields or have documented progression no sooner than 6 weeks after completion of radiation. More than 2 weeks must have elapsed since the subject has received any prior systemic chemotherapy (6 weeks for mitomycin C), and the patient should have recovered from toxicities to the baseline prior to the last course of chemotherapy. Adequate hematologic function within 14 days prior to registration. Prothrombin Time (PT) (or INR) and Partial Thromboplastin Time (PTT) ≤ 1.5 times the institutional upper limit of normal (ULN) within 14 days prior to registration. Serum creatinine ≤ 2.0 times the institutional ULN within 14 days prior to registration. Serum magnesium, potassium and adjusted (or ionized) calcium ≥ the institutional lower limit of normal (LLN). (Supplementation of electrolytes prior to screening is allowed). Left ventricular ejection fraction ≥ 45% measured by echocardiogram or multiple gated acquisition (MUGA) within 30 days prior to registration (but must be performed after the last dose of an anthracycline) for subjects who have received an anthracycline (e.g. doxorubicin, epirubicin) or have a medical history of cardiac disease. The measurement of left ventricular ejection fraction is not required of subjects whom have not received cardiotoxic chemotherapy (e.g. anthracycline) and do not have a medical history of cardiac disease. Sexually active women and men of childbearing potential must agree to use an effective method of birth control during the course of the study and for up to 3 months following the last dose of the study drug, in a manner such that risk of pregnancy is minimized. Surgical sterilization, intrauterine device or barrier method (e.g. condom and/or diaphragm with spermicidal agents) are acceptable forms of birth control. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to treatment. A pregnancy test is not required for registration. Women who have not menstruated for more than 2 years will be considered postmenopausal, thus not of childbearing potential. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2. Weight ≥ 50 kg because there is limited experience with dasatinib in subjects weighing less than 50 kg. ≥13 years of age Minors will be required to sign an assent document prior to treatment. Subjects must be able to swallow whole tablets. Subjects must be informed of the investigational nature of the study and provide written, informed consent and authorization to release protected health information using a document(s) approved by the investigator's institution. A paraffin block, either from a previous surgery or recent biopsy, should be available for correlative studies. If a block of tumor is not available, at least 8 unstained slides of tumor sample, 1 H&E and three (3) 15 micron-thick sections in an eppendorf tube for DNA extraction from a representative portion of the sarcoma may be substituted after discussion with and approval from the study Principal Investigator. Exclusion Criteria: Subjects who are curable by conventional multidisciplinary management. Subjects with symptomatic central nervous system metastasis. Women who are pregnant or nursing/breastfeeding. History of significant bleeding disorder unrelated to cancer, including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) Subjects currently taking medications that inhibit platelet function (i.e., aspirin, dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab, ticlopidine, and any non-steroidal anti-inflammatory drug) because of a potential increased risk of bleeding from dasatinib. Subjects currently taking anticoagulants (warfarin, heparin/low molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, enoxaparin]) because of a potential increased risk of bleeding from dasatinib. Diagnosis of unstable angina or myocardial infarction within 6 months of study entry. Subjects currently taking one or more of the following drugs that are generally accepted to have a risk of causing Torsades de Pointes: Quinidine, procainamide, disopyramide Amiodarone, sotalol, ibutilide, dofetilide Erythromycins, clarithromycin Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. Diagnosed or suspected congenital long QT syndrome. Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 450 msec) within 30 days prior to study registration. Subjects unable or unwilling to suspend treatment with bisphosphonates for at least the first 8 weeks of treatment with study drug because of the risk of hypocalcemia caused by dasatinib.

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib, 70 mg, twice daily<br>Patients take 70 mg of Dasatinib, twice daily, for 28 day cycles | Drug: Dasatinib<br>* oral agent, continuous dosing, Cycles = 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate: Number of Participants With Objective Tumor Response | Assessment of objective tumor response for response rate with MRI or CT using Choi criteria: Complete Remission (CR) Complete disappearance of all measurable and evaluable disease for at least 4 weeks; Partial Remission (PR) A 10% or greater decrease from the baseline in the sum of the largest diameters of all measurable target lesions. | Up to 24 months | 
| 6 Month Progression-free Survival Rate of Indolent Sarcomas Treated With Dasatinib | Estimate the 6 month progression-free survival rate of indolent sarcomas treated with dasatinib. Progression is defined using Choi criteria, as a 10% or greater increase in the sum of all measurable target lesions over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline, or clear worsening of any evaluable disease, or unequivocal reappearance of any lesion which had disappeared, or appearance of any new lesions of greater than double slice thickness in size, or any new or enlarging solid nodule in a previously hypodense treated mass. | At 6 months | 
| 6 Month Progression-free Survival Rate of Gastrointestinal Stromal Tumors (GIST) | To estimate the 6 month progression-free survival rate of gastrointestinal stromal tumors (GIST). Progression is defined using Choi criteria, as a 10% or greater increase in the sum of all measurable target lesions over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline, or clear worsening of any evaluable disease, or unequivocal reappearance of any lesion which had disappeared, or appearance of any new lesions of greater than double slice thickness in size, or any new or enlarging solid nodule in a previously hypodense treated mass. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time-to-progression of Subjects With GIST Treated With Dasatinib. | To estimate the median time-to-progression of subjects with GIST treated with dasatinib. | Up to 30 months | 
| Overall Survival Rates at 2 and 5 Years From Registration of Subjects Treated With Dasatinib. | To estimate the overall survival rates at 2 and 5 years from registration of subjects treated with dasatinib. | At 2 and 5 years | 
| Median Time-to-progression of Subjects With Indolent Sarcomas Treated With Dasatinib. | To estimate the median time-to-progression of subjects with indolent sarcomas treated with dasatinib. | Up to 24 months | 
| 6 Month Progression-free Survival Rate of Subjects Enrolled in the Aggressive Subtype. | To estimate the 6 month progression-free survival rate of subjects with leiomyosarcoma, liposarcoma, osteosarcoma including high-grade chondrosarcomas, Ewing's sarcoma, Malignant fibrous histiocytoma (MFH), rhabdomyosarcoma and MPNST treated with dasatinib. | At 6 months | 
| Median Time-to-progression of Subjects Enrolled in the Aggressive Subtype. | To estimate the median time-to-progression of subjects with leiomyosarcoma, liposarcoma, osteosarcoma including high-grade chondrosarcomas, Ewing's sarcoma, MFH, rhabdomyosarcoma and MPNST treated with dasatinib. | Up to 37 weeks | 
| Overall Survival Rates at 2 and 5 Years From Registration of Subjects Enrolled in the Aggressive Subtype Treated With Dasatinib. | To estimate the overall survival rates at 2 and 5 years from registration of subjects enrolled in the aggressive subtype treated with dasatinib. | At 2 and 5 years | 
| Uni-dimensional and Bi-dimensional Tumor Size, Tumor Volumes and Tumor Average Density Determined by Computer-aided Automated Detection in a Subset of Subjects With Tumor Predominately Involving the Lung | To prospectively collect uni-dimensional and bi-dimensional tumor size, tumor volumes and tumor average density determined by computer-aided automated detection in a subset of subjects with tumor predominately involving the lung | Up to 37 weeks | 
| Plasma Level of Dasatinib and Inhibition of SRC and/or Focal Adhesion Kinase (FAK) in Peripheral Blood Mononuclear Cells | Obtain blood samples to characterize plasma level of dasatinib and inhibition of SRC and/or FAK in peripheral blood mononuclear cells 2 hours after ingestion of drug at 2-4 weeks from the start of treatment if activity of the drug in a sarcoma subtype warrants further study. | 2-4 weeks from start of treatment | 
| Number of Participants With Tumors With Kinase Expression | Obtain tumor tissue for creation of tissue microarrays to examine the frequency of kinase expression such as SRC and/or FAK in leiomyosarcoma, liposarcoma, osteosarcoma, MFH, rhabdomyosarcoma, MPNST, chondrosarcoma, Ewing's, Alveolar soft part sarcoma (ASPS), chordoma, epithelioid sarcoma, giant cell tumor of bone, hemangiopericytoma, and GIST if activity of the drug in a subtype warrants further study. The outcome measure demonstrates the number of participants who had tissue that was able to generate tissue microarray for kinase expression. | Up to 37 weeks | 
| Number of Participants With Tumors With Mutations in Kinases | Obtain tumor tissue to examine the frequency of mutations in kinases such as PDGFR in leiomyosarcoma, liposarcoma, osteosarcoma, MFH, rhabdomyosarcoma, MPNST, chondrosarcoma, Ewing's, ASPS, chordoma, epithelioid sarcoma, giant cell tumor of bone, hemangiopericytoma and GIST if activity of the drug in a subtype warrants further study. The outcome measure demonstrates the tissue that was able to generate tissue microarray for PDGFR analysis. | Up to 37 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dasatinib, Rhabdomyosarcoma, Malignant peripheral nerve sheath tumor, Chondrosarcoma, Ewing's, Alveolar soft part sarcoma (ASPS), Chordoma, Epithelioid sarcoma, Giant cell tumor of bone, Hemangiopericytoma/solitary fibrous tumor, Gastrointestinal Stromal Tumor (GIST)