Clinical trial NCT00464620: Trial of Dasatinib in Advanced Sarcomas
Official title: A Phase II Trial of Dasatinib in Advanced Sarcomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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)
Keywords: 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)
Lead sponsor: Sarcoma Alliance for Research through Collaboration
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2007-04-23
Enrollment: 366
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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\*
2. 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.
3. 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.
4. 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.
5. 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.
6. Adequate hematologic function within 14 days prior to registration.
7. 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.
8. Serum creatinine ≤ 2.0 times the institutional ULN within 14 days prior to registration.
9. Serum magnesium, potassium and adjusted (or ionized) calcium ≥ the institutional lower limit of normal (LLN). (Supplementation of electrolytes prior to screening is allowed).
10. 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.
11. 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.
12. 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.
13. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2.
14. Weight ≥ 50 kg because there is limited experience with dasatinib in subjects weighing less than 50 kg.
15. ≥13 years of age Minors will be required to sign an assent document prior to treatment.
16. Subjects must be able to swallow whole tablets.
17. 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.
18. 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:

1. Subjects who are curable by conventional multidisciplinary management.
2. Subjects with symptomatic central nervous system metastasis.
3. Women who are pregnant or nursing/breastfeeding.
4. 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)
5. 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.
6. 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.
7. Diagnosis of unstable angina or myocardial infarction within 6 months of study entry.
8. 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.
9. Diagnosed or suspected congenital long QT syndrome.
10. Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (\> 450 msec) within 30 days prior to study registration.
11. 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.

Primary outcomes:
measure: Response Rate: Number of Participants With Objective Tumor Response
timeFrame: Up to 24 months
measure: 6 Month Progression-free Survival Rate of "Indolent" Sarcomas Treated With Dasatinib
timeFrame: At 6 months
measure: 6 Month Progression-free Survival Rate of Gastrointestinal Stromal Tumors (GIST)
timeFrame: 6 months
Secondary outcomes:
measure: Median Time-to-progression of Subjects With GIST Treated With Dasatinib.
timeFrame: Up to 30 months
measure: Overall Survival Rates at 2 and 5 Years From Registration of Subjects Treated With Dasatinib.
timeFrame: At 2 and 5 years
measure: Median Time-to-progression of Subjects With "Indolent" Sarcomas Treated With Dasatinib.
timeFrame: Up to 24 months
measure: 6 Month Progression-free Survival Rate of Subjects Enrolled in the Aggressive Subtype.
timeFrame: At 6 months
measure: Median Time-to-progression of Subjects Enrolled in the Aggressive Subtype.
timeFrame: Up to 37 weeks
measure: Overall Survival Rates at 2 and 5 Years From Registration of Subjects Enrolled in the Aggressive Subtype Treated With Dasatinib.
timeFrame: At 2 and 5 years
measure: 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
timeFrame: Up to 37 weeks
measure: Plasma Level of Dasatinib and Inhibition of SRC and/or Focal Adhesion Kinase (FAK) in Peripheral Blood Mononuclear Cells
timeFrame: 2-4 weeks from start of treatment
measure: Number of Participants With Tumors With Kinase Expression
timeFrame: Up to 37 weeks
measure: Number of Participants With Tumors With Mutations in Kinases
timeFrame: Up to 37 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Outpatient Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: Washington
country: United States
facility: Washington Cancer Institute
state: District of Columbia
city: Atlanta
country: United States
facility: Winship Cancer Institute at Emory University
state: Georgia
city: Coeur d'Alene
country: United States
facility: Kootenai Cancer Center
state: Idaho
city: Park Ridge
country: United States
facility: Oncology Specialists
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Philadelphia
country: United States
facility: Pennsylvania Oncology Hematology Associates
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson
state: Texas
Study officials:
affiliation: University of Michigan
name: Scott Schuetze, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: