Phase I/Randomized Phase II Trial of Either Dasatinib or Placebo Combined With Standard Chemo-Radiotherapy for Newly Diagnosed Glioblastoma Multiforme (GBM)

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed glioblastoma multiforme (GBM)

- Grade 4 astrocytoma

- No grade 4 oligoastrocytoma or GBM with oligodendroglial features

- Newly diagnosed disease

- Measurable or evaluable disease by gadolinium MRI or contrast CT scan

- Patients who have had a gross total resection are eligible on the basis of
evaluable disease

- No pleural or pericardial effusion of any grade

- No prior surgery for CNS neoplasms other than surgery related to the current GBM
diagnosis

- If Gliadel wafers are placed at time of primary resection this would be
considered prior therapy and patient would be ineligible

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Absolute neutrophil count (ANC) ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin > 9.0 g/dL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST ≤ 2.5 times ULN

- Creatinine ≤ 1.5 times ULN

- INR ≤ 1.5

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 12 weeks after
completion of study treatment

- No immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be HIV positive and currently receiving antiretroviral
therapy

- Patients known to be HIV positive, but without clinical evidence of an
immunocompromised state, are eligible for this trial

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- No history of any of the following conditions:

- Congestive heart failure requiring use of ongoing maintenance therapy for
life-threatening ventricular arrhythmias

- Congenital long QT syndrome

- Clinically significant ventricular arrhythmias (e.g., ventricular tachycardia,
ventricular fibrillation, or Torsades de pointes)

- Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)

- Hypokalemia or hypomagnesemia

- Patients may not have any clinically significant cardiovascular disease including the
following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Ejection fraction less than institutional normal

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

- New York Heart Association classification ≥ class II congestive heart failure

- Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of
breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with
or without stress test as needed in addition to electrocardiogram (ECG) to rule
out QTc prolongation

- Patients with underlying cardiopulmonary dysfunction should be excluded
from the study

- No comorbid systemic illnesses or other severe concurrent disease that, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens including, but not limited to, any of the
following:

- History of bleeding diathesis

- Concurrent chronic systemic anticoagulation therapy that can not be discontinued
(i.e., antiplatelet agents or aspirin)

- Concurrent t chronic nonsteroidal anti-inflammatory drugs (NSAIDs) that cannot
be discontinued

- No other active malignancy ≤ 5 years prior to registration

- Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

- If there is a history of prior malignancy, they must not be receiving other
specific treatment (other than hormonal therapy) for their cancer

- No severe allergy to sulfa medications and dapsone

- Able to tolerate either intravenous or inhaled dapsone

- Able to take oral medication

- Willingness to abstain from eating grapefruit or drinking grapefruit juice for the
duration of the study treatment

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- See Patient Characteristics

- At least 5 days since prior and no concurrent St. John wort

- No prior radiotherapy or chemotherapy for any CNS neoplasm (hormones, vitamins, and
growth factors are not considered chemotherapy for the purposes of this study)

- At least 7 days, but < 42 days, since prior stereotactic biopsy

- At least 14 days, but < 42 days, since prior open craniotomy

- Willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor
while being treated with dasatinib and temozolomide

- No other concurrent investigational agent considered as treatment for the primary
neoplasm

- Must not be currently taking any of the following medications:

- Enzyme-inducing anticonvulsants (EIACs)

- To be eligible, patient must be switched to non-EIAC medications ≥ 7 days
prior to registration

- Potent inhibitors of CYP3A4 that cannot be discontinued

- Medications that may possibly prolong QT interval and produce a QTc that is ≥ 60
msec or a QTcF that is ≥ 450 msec

- H2 blockers or proton pump inhibitors (PPIs), such as famotidine (Pepcid) and
omeprazole (Prilosec) respectively, that cannot be discontinued or switched to
locally acting agents, such as Maalox, Mylanta, or TUMS

- No concurrent treatment immunosuppressive agent, except corticosteroids

- No concurrent other anticancer agents

- No concurrent prophylactic leukocyte growth factors (e.g., filgrastim [G-CSF] and
sargramostim [GM-CSF])

- No concurrent live vaccines

- No concurrent therapeutic anticoagulation with warfarin

- No concurrent ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs)