Trial of Dasatinib in Advanced Sarcomas

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.

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.