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

• Time-to-disease progression [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]
• Objective response [ Designated as safety issue: No ]
• Adverse events as assessed by NCI CTCAE version 3.0 [ Designated as safety issue: Yes ]
• Association between biomarkers and antitumor activity/patient outcomes [ Designated as safety issue: No ]
• Relationships among the relevant mutations/activity indicators of biomarkers and clinical outcomes [ Designated as safety issue: No ]
• Correlations between molecular profiles and clinical outcomes for combinations and for individual agents within combinations [ Designated as safety issue: No ]
• Clinical outcomes for subsets of patients defined by the biomarker variables [ Designated as safety issue: No ]
• Quality of life as assessed by FACT-BR, EORTC QLQ-C15-PAL, and EORTC QLQ-BN20 questionnaires at baseline and courses 4, 6, 8, 10, and 12 [ Designated as safety issue: No ]

RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also make tumor cells more sensitive to radiation therapy. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This randomized phase I/II trial is studying the best dose of dasatinib and to see how well it works compared with a placebo when given together with radiation therapy and temozolomide in treating patients with newly diagnosed glioblastoma multiforme.

OBJECTIVES:

• To establish a maximum-tolerated dose of dasatinib combined with radiation and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I) (Phase I study closed to patient accrual on April 29, 2011 and has been completed)
• To determine the efficacy of dasatinib in combination with radiotherapy and concomitant adjuvant temozolomide, and compare it with the standard of care approach, consisting of radiotherapy and temozolomide, followed by adjuvant temozolomide in these patients. (Phase II) (Phase II study opened to patient accrualon August 5, 2011)
• To determine the relationship between tumor biomarkers and clinical outcome of patients treated with the dasatinib/radiotherapy/temozolomide combination. (Phase II)
• To evaluate potential mechanisms of therapy resistance in recurrent tumor samples obtained at the time of surgery for recurrent disease.
• To assess the impact of the addition of dasatinib to radiotherapy and temozolomide on the quality of life (QOL) of these patients, as assessed by FACT-Br, EORTC QLQ-C15-PAL, and EORTC QLQ-BN20. (Phase II)
• To compare the results of the two most commonly used QOL tools, FACT-Br and EORTC QLQ C15-PAL plus BN20 and validate the use of EORTC QLQ-C15-PAL plus BN20 in these patients.(Phase II)

OUTLINE: This is a multicenter, phase I dose-escalation study of dasatinib (Phase I study closed to patient accrual on April 29, 2011 and has been completed) followed by a randomized phase II study (Phase II study opened to patient accrual on August 5, 2011).

• Phase I:

  • Course 1: Patients receive oral dasatinib once daily and oral temozolomide once daily on days 1-42. Patients undergo external-beam radiotherapy (EBRT), including intensity-modulated radiotherapy, 5 days a week for 6 weeks.
  • Courses 2-7: Beginning 28-42 days after course 1, patients receive oral dasatinib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

• Phase II: Patients are stratified according to age (> 70 years vs ≤ 70 years). Patients are randomized to 1 of 2 treatment arms.

  • Arm I:

    • Course 1: Patients receive oral dasatinib once daily and oral temozolomide once daily on days 1-42. Patients undergo EBRT 5 days a week for 6 weeks.
    • Courses 2-7: Beginning 28-42 days after course 1, patients receive oral dasatinib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

  • Arm II:

    • Course 1: Patients receive oral placebo once daily on days 1-42 and temozolomide as in arm I. Patients also undergo EBRT as in arm I.
    • Courses 2-7: Beginning 28-42 days after course 1, patients receive oral placebo once daily on days 1-28 and temozolomide as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Tissue samples are collected for correlative studies.

Quality of life is assessed periodically using the FACT-Br, EORTC QLQ-C15-PAL v.1, and EORTC BN-20 questionnaires.

After completion of study therapy, patients are followed up every 6 months for 5 years.

• Drug: dasatinib
  Given orally
• Drug: temozolomide
  Given orally
• Other: placebo
  Given orally

• Experimental: Arm I (Phase II)
  Patients receive oral dasatinib once daily and oral temozolomide once daily on days 1-42. Patients undergo external-beam radiotherapy (EBRT), including intensity-modulated radiotherapy, 5 days a week for 6 weeks. Beginning 28-42 days after course 1, patients receive oral dasatinib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: dasatinib
  • Drug: temozolomide
• Active Comparator: Arm II (Phase II)
  Patients receive oral placebo once daily on days 1-42 and temozolomide as in arm I. Patients also undergo EBRT as in arm I. Beginning 28-42 days after course 1, patients receive oral placebo once daily on days 1-28 and temozolomide as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: temozolomide
  • Other: placebo

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)