Dasatinib in Treating Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma

PRIMARY OBJECTIVES:

I. To determine the therapeutic efficacy of dasatinib in all patients (i.e., stages 1B and 2
combined) with recurrent/progressive glioblastoma (GBM) as measured by 6-month
progression-free survival.

SECONDARY OBJECTIVES:

I. To determine the therapeutic efficacy of dasatinib for stage 1B patients with
recurrent/progressive GBM as measured by a hybrid endpoint of 6-month progression-free
survival OR objective response of (complete response [CR] or partial response [PR]) rate.

II. To determine patient overall survival. III. To determine the toxicity of dasatinib in the
treatment of patients with GBM.

IV. To determine radiographic response rate to treatment. V. To determine patient
progression-free survival. VI. To explore molecular correlates of clinical outcome. VII. To
explore pharmacokinetic correlates of dosing, toxicity, and efficacy.

OUTLINE:

Patients receive dasatinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every
28 days in the absence of disease progression and unacceptable toxicity.

After the completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Histologically proven diagnosis of GBM; gliosarcoma is also an eligible diagnosis

- The patient must consent to submission of tissue for central pathology review

- Patients who have already undergone central pathology review through their enrollment
on another Radiation Therapy Oncology Group (RTOG) GBM trial do not need to consent to
having their material re-reviewed by the central pathologist for this study

- All patients must consent to molecular analysis of pre-dasatinib tumor tissue

- Patients accrued to stage I (closed to accrual) or stage IB (opened to accrual May 5,
2009) must have tumors overexpressing at least 2 known dasatinib targets (i.e., SRC
proto-oncogene, non-receptor tyrosine kinase [SRC], v-kit Hardy-Zuckerman 4 feline
sarcoma viral oncogene homolog [KIT], platelet-derived growth factor receptor [PDGFR],
or ephrin type-A receptor 2 [EPHA2])

- Patients accrued to stage II (cohort closed; not currently applicable) do not require
overexpression of SRC, KIT, PDGFR, or EPHA2

- History and physical examination, including height and weight, within 10 days prior to
registration on study

- Brain magnetic resonance imaging (MRI) with and without gadolinium within 10 days
prior to registration on study

- Contrast-enhanced computed tomography (CT) scans are allowed for patients who cannot
undergo MRI scanning

- Karnofsky performance status >= 60

- Absolute neutrophil count (ANC) >= 1,000 cells/mm^3

- Platelets >= 75,000 cells/mm^3

- Hemoglobin (Hgb) >= 8.0 g/dl; (note: the use of transfusion or other intervention to
achieve Hgb >= 8.0 g/dl is acceptable)

- Leukocytes >= 3,000 cells/mm^3

- Absolute lymphocyte count (ALC) >= 500 cells/mm^3

- Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 institutional upper limit of normal

- Creatinine =< 3 X institutional upper limit of normal or creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- All patients must have undergone prior treatment with radiotherapy and temozolomide;
no other prior treatments are allowed

- There must be unequivocal radiographic evidence for tumor progression by MRI or CT
scan, and the same type of scan (i.e., MRI or CT) must be used throughout the period
of protocol treatment for tumor measurement; patients must be on a stable or
decreasing dose of corticosteroids for at least 5 days before the baseline MRI/CT is
performed

- Patients having undergone recent surgery for recurrent/progressive disease are
eligible as long as they have recovered from the effects of surgery; patients who
recently underwent resection without measurable disease post-operatively are also
eligible

- Measurable disease is not required for eligibility in patients who recently underwent
resection as long as the following conditions are met as applicable:

- Progression of disease led to the surgery

- Gliadel wafers were not placed during the most recent surgery

- Neither convection enhanced delivery nor catheters for infusion of chemotherapy
were used during the most recent surgery

- Radioactive seeds were not placed during the most recent surgery

- The histology of the most recent surgery documented
recurrent/persistent/progressive malignant glioma

- Women of childbearing potential must have a negative beta human chorionic gonadotropin
(B HCG) pregnancy test =< 3 days prior to registration

- Patient must sign study-specific informed consent prior to study entry

Exclusion Criteria:

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity,
or cervix are all permissible)

- Radiotherapy within 4 weeks or temozolomide within 14 days prior to registration or
failure to recover from adverse events of either radiotherapy or temozolomide

- Patients may not be receiving any other investigational agents

- Severe, active comorbidity, defined as follows:

- Any clinically significant cardiovascular disease including the following:

- Unstable angina and/or congestive heart failure requiring hospitalization
within the past 6 months

- Transmural myocardial infarction or ventricular tachyarrhythmia within the
past 6 months

- Prolonged corrected QT interval (QTc) > 480 msec (Fridericia correction)

- Ejection fraction less than institutional normal

- Major conduction abnormality (unless a cardiac pacemaker is present)

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this protocol

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; breastfeeding should
be discontinued if the mother is treated with dasatinib

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dasatinib

- Patients who require concurrent treatment with any medications or substances that are
potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4
(CYP3A4) are ineligible

- Patients must not be taking hepatic enzyme inducing antiepileptic drugs (EIAEDs); if
patients were previously on EIAEDs that have been discontinued, patients must have
been off EIAEDs for >= 2 weeks prior to initiation of dasatinib

- Patients who require antacids should use short-acting, locally active agents (e.g.,
Maalox, Mylanta etc.); however, these agents should not be taken within either 2 hours
before or 2 hours after the dasatinib dose

- Use of antithrombotic and/or antiplatelet agents (e.g., warfarin, heparin, low
molecular weight heparin, aspirin, clopidogrel, ticlopidine, Aggrenox)

- Use of ibuprofen or non-steroidal anti-inflammatory drugs (NSAIDs)

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for intravenous [IV] alimentation,
prior surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow and retain dasatinib tablets are excluded

- Prior treatment with stereotactic radiosurgery (including Gamma-Knife, Cyberknife, or
other variants) or brachytherapy