Dasatinib or Placebo, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

This trial includes a phase I dose-escalation study and a double-blind randomized phase II
trial for patients with newly diagnosed glioblastoma multiforme (GBM). Phase I will be a
cohort of 3 dose-escalation trial of dasatinib in combination with radiation and concomitant
temozolomide. Patients receive concomitant chemotherapy and radiation therapy for cycle one.
Patients receive adjuvant chemotherapy 28-42 days post cycle one treatment. Patients receive
only dasatinib post cycle 8 treatment until progressive disease, unacceptable adverse events
or refusal.

Phase II will be a randomized trial with two treatment arms. Patients will be randomized at
the time of registration at a ratio of 1:2 respectively to either standard therapy arm
(continuous daily placebo prior, during and after standard radiotherapy/temozolomide followed
by temozolomide. For more information please see the Arms section. The primary objectives are
listed below.

Primary Objectives:

1. To establish a maximum tolerated dose of dasatinib combined with radiation and
temozolomide in this patient population (Phase I)

2. To determine the efficacy of dasatinib in combination with radiotherapy and concomitant
and adjuvant temozolomide in patients with newly diagnosed glioblastoma, and compare it
with the standard of care approach in the treatment of these patients consisting of
radiotherapy and temozolomide, followed by adjuvant temozolomide (Phase II)

Patients are followed for 5 years post treatment. The study permanently closed to accrual on
January 31, 2014.

Pre-registration Inclusion Criteria:

1. Central Pathology Review - Central pathology review submission. This review is mandatory
prior to registration to confirm eligibility.

Registration Inclusion Criteria:

1. Age ≥ 18 years

2. Histological Confirmation of Glioblastoma - Histologically confirmed newly diagnosed
glioblastoma (GBM) (grade 4 astrocytoma) as determined by pre-registration central
pathology review. Note: GBM with oligodendroglial features are not permitted in this
study if they are 1p19q codeleted. Sites submitting GBM with oligodendroglial features
will be asked to provide results of 1p/19q codeletion status.

3. Measurable or Evaluable Disease - Measurable or evaluable disease by gadolinium MRI or
contrast CT scan. Note: Patients who have had a gross total resection are eligible on
the basis of evaluable disease.

4. ECOG Performance Status 0, 1 or 2.

5. Required Laboratory Values:

The following laboratory values obtained ≤ 14 days prior to registration.

- Absolute neutrophil count (ANC) ≥ 1500/mm3

- Platelet count ≥ 100,000/mm3

- Hemoglobin > 9.0 g/dL

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

- SGOT (AST) ≤ 2.5 x ULN

- Creatinine ≤ 1.5 x ULN

6. Required INR Value: The following INR value obtained ≤ 28 days prior to registration

- INR ≤ 1.5

7. Urine or Serum Pregnancy Test - Negative urine or serum pregnancy test done ≤ 7 days
prior to registration, for women of childbearing potential only.

8. Written Informed Consent - Patient must provide written informed consent.

9. Return to Enrolling Institution - Patient must be willing to return to Alliance
enrolling institution for follow-up.

10. Tissue Samples - Patient must be willing to provide tissue samples for research
purposes.

11. Patient must be willing to provide tissue samples for research purposes.

12. Required Antibiotic Prophylaxis - Patient must be willing to comply with antibiotic
prophylaxis with trimethoprim/sulfamethoxazole, pentamidine or dapsone.

13. Grapefruit and Grapefruit Juice - Patient must be willing to abstain from eating
grapefruit or drinking grapefruit juice for the duration of the study treatment.

14. Ability to Swallow - Patient must have the ability to take oral medication (dasatinib
must be swallowed whole).

15. Quality of Life (QOL) Questionnaires - Phase II patients only: Patients must be
willing and able to complete QOL questionnaires independently or with the help of a
caregiver.

16. Other Anti-Tumor Drug Therapies - Patient must be willing to forego other cytotoxic
and non-cytotoxic drug therapy against the tumor while being treated with dasatinib
and temozolomide.

Registration Exclusion Criteria:

1. Pregnancy, Nursing and Required Contraception - Any of the following because this
study involves an investigational agent whose genotoxic, mutagenic and teratogenic
effects on the developing fetus and newborn are unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception throughout study treatment and for at least 12 weeks after study
drug is stopped.

2. Prior Radiotherapy or Chemotherapy for Any CNS Neoplasm - Received any prior
radiotherapy or chemotherapy for any CNS neoplasm (hormones, vitamins and growth
factors are not considered chemotherapy for the purposes of this study.

3. Prior Surgery for Any CNS Neoplasm - Prior surgeries for any CNS neoplasms, other than
surgery related to the current GBM diagnosis. Note: If Gliadel wafers are placed at
time of primary resection, this would be considered prior therapy and patient would be
ineligible.

4. Concurrent Illness or Disease - Co-morbid systemic illnesses or other severe
concurrent disease which, 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:

- History of bleeding diathesis

- Current use of chronic systemic anticoagulation therapy that cannot be
discontinued (antiplatelet agents, Aspirin)

- Current chronic use of NSAIDs which cannot be discontinued

5. Pleural or Pericardial Effusions - Pleural or pericardial effusion of any grade.

6. Immunocompromised Status - Immunocompromised patients (other than that related to the
use of corticosteroids) and patients known to be HIV positive and currently receiving
antiretroviral therapy. Note: Patients known to be HIV positive, but without clinical
evidence of an immunocompromised state, are eligible for this trial.

7. Uncontrolled Intercurrent Illness - 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.

8. Other Investigational Agents - Receiving any other investigational agent which would
be considered as a treatment for the primary neoplasm.

9. Other Active Malignancies - Other active malignancy ≤ 5 years prior to registration.

Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. Note: If
there is a history of prior malignancy, they must not be receiving other specific
treatment other than hormonal therapy for their cancer.

10. History of Cardiac or Metabolic Conditions:

- Myocardial infarction ≤ 6 months, or congestive heart failure requiring use of
ongoing maintenance therapy for life-threatening ventricular arrhythmias

- Diagnosed congenital long QT syndrome

- Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)

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

- Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to
dasatinib administration.

11. Clinically Significant Cardiovascular Disease - 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)

Note: 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 ECG to rule out QTc prolongation. The
patient may be referred to a cardiologist at the discretion of the principal
investigator.

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

12. Congestive Heart Failure - New York Heart Association classification ≥ Class II
Congestive Heart Failure.

13. Prohibited or Restricted Concomitant Treatments - Currently taking one of the
following medications:

- Enzyme inducing anti-convulsants (EIACs) Note: To be eligible, patient must be
switched to non-EIAC medications ≥7 days prior to registration. See protocol for
a list of EIAC and non-EIAC medications.

- Potent inhibitors of CYP3A4 which cannot be discontinued. See protocol for a list
of medications known to inhibit CYP3A4.

- Medications known to prolong QT interval which cannot be discontinued or
switched. See Appendix II for a list of medications which are known to prolong
the QT interval.

- Medications that may possibly prolong QT interval and produce a QTc that is ≥ 60
msec or a QTcF that is ≥ 450 msec. See Appendix II for a list of medications that
may possibly prolong QTc.

- St. John's Wort

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

14. Allergy to Antibiotic Prophylaxis Medications - Severe allergy to sulfa medications
and dapsone and pentamidine.