Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma

• Dose-limiting toxicity (Phase I) [ Designated as safety issue: Yes ]
• 6-month progression-free survival rate (Phase II) [ Designated as safety issue: No ]

• Treatment-related toxicity as measured by the NCI CTCAE version 4.0 [ Designated as safety issue: Yes ]
• Objective response (partial and complete response) rate (Phase II) [ Designated as safety issue: No ]
• Overall survival (Phase II) [ Designated as safety issue: No ]

• Treatment-related toxicity as measured by the CTEP Active Version of the CTCAE [ Designated as safety issue: Yes ]
• Objective response (partial and complete response) rate (Phase II) [ Designated as safety issue: No ]
• Overall survival (Phase II) [ Designated as safety issue: No ]

RATIONALE: Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving veliparib together with temozolomide may kill more tumor cells.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of giving veliparib together with temozolomide and to see how well it works in treating patients with recurrent glioblastoma.

OBJECTIVES:

Primary

• To define the maximum-tolerated dose of the combination of temozolomide and veliparib in patients with recurrent glioblastoma previously or not treated with temozolomide. (Phase I*)
• To determine the efficacy of the combination of temozolomide and veliparib (using a 5-day vs 21-day schedule) as measured by the 6-month progression-free survival rate in patients with recurrent glioblastoma previously treated with temozolomide. (Phase II*)

Secondary

• To characterize the safety profile of the combination of temozolomide and veliparib. (Phase I*)
• To determine the adverse event profile and tolerability of the combination of temozolomide and veliparib (using a 5-day vs 21-day schedule) in patients with recurrent glioblastoma. (Phase II*)
• To determine the efficacy of the combination of temozolomide and veliparib (using a 5-day vs 21-day schedule) as measured by objective response in patients with measurable disease. (Phase II*)
• To determine the overall survival of patients with measurable disease treated with the combination of temozolomide and veliparib (using a 5-day vs 21-day schedule). (Phase II*) NOTE: *Phase I was closed and phase II was opened on 3/6/12.

OUTLINE: This is a multicenter, phase I* dose-escalation study followed by a phase II* randomized study. Patients enrolled in the phase II portion are stratified according to bevacizumab status (bevacizumab-naive vs bevacizumab-failure), age (< 50 years vs ≥ 50 years), Karnofsky performance status (70-80% vs 90-100%), and recent resection (yes vs no/biopsy only).

• Phase I:* Patients receive oral temozolomide once daily and oral veliparib twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

• Phase II:* Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive temozolomide and veliparib as in phase I.
  • Arm II: Patients receive oral temozolomide once daily and oral veliparib twice daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 1 year, every 26 weeks for 2 years, and then annually thereafter.

NOTE: *Phase I was closed and phase II was opened on 3/6/12.

PROJECTED ACCRUAL: A total of 240 patients (28 for phase I* and 212 for phase II*) will be accrued for this study.

NOTE: *Phase I was closed and phase II was opened on 3/6/12.

• Drug: temozolomide
  Given orally
• Drug: veliparib
  Given orally

• Experimental: Arm I (phase II)
  Patients receive oral temozolomide once daily and oral veliparib twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: temozolomide
  • Drug: veliparib
• Experimental: Arm II (phase II)
  Patients receive oral temozolomide once daily and oral veliparib twice daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: temozolomide
  • Drug: veliparib

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

  • Any intracranial high-grade glioma (phase I*)
  • Glioblastoma or gliosarcoma (phase II*)
• Patients whose original histology was low-grade glioma are eligible provided they were subsequently diagnosed with glioblastoma or gliosarcoma

• Unequivocal radiographic evidence for tumor progression by MRI within 14 days prior to registration and with a stable or decreasing dose of steroids at least 5 days prior to scanning OR recent resection (registration within 30 days of resection) as long as all of the following conditions are met:

  • Patients must have recovered from the effects of surgery
  • Residual disease following resection of recurrent glioblastoma is not mandated for eligibility into the study; to best assess the extent of residual disease post-operatively, a post-operative MRI scan should be performed within 28 days prior to registration and within 96 hours post surgery (although 24 hours would be optimum)
  • Prior radiation is required for the phase I* arm
  • Patients must have completed a course of radiation therapy and at least 2 consecutive adjuvant cycles of temozolomide (phase II*)
  • A stable or decreasing dose of steroids at least 5 days prior to scanning is not mandated for patients who had a recent resection

• No evidence of acute (i.e., new and active) intratumoral hemorrhage on MRI

  • Patients with MRI demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection) are eligible NOTE: *Phase I was closed and phase II was opened on 3/6/12.

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• WBC ≥ 3,000/mm^3
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
• SGOT ≤ 3.0 times upper limit of normal (ULN)
• SGPT ≤ 3.0 times ULN
• Bilirubin ≤ 1.25 times ULN
• Creatinine < 1.7 mg/dL OR estimated GFR ≥ 30 mL/min
• Urine protein:creatinine ratio ≤ 0.5 OR urine protein < 1,000 mg by 24-hour urine collection**
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
• Able to undergo brain MRI scans with IV gadolinium
• Able to swallow oral medications
• Patients with a history of seizure, or new onset of seizures, should be clinically controlled with no seizures for at least 14 days prior to registration
• No other prior invasive malignancy (except for nonmelanomatous skin cancer or carcinoma in situ of the cervix) unless the patient has been disease-free and off therapy for that disease for ≥ 3 years

• No severe, active comorbidity, including any of the following:

  • Transmural myocardial infarction or unstable angina within the past 6 months
  • Evidence of recent myocardial infarction or ischemia as indicated by S-T elevations of ≥ 2 mm on EKG performed within the past 14 days
  • NYHA class II-IV congestive heart failure requiring hospitalization within the past 12 months
  • Stroke or transient ischemic attack within the past 6 months
  • Cerebral vascular accident within the past 6 months
  • Serious and inadequately controlled cardiac arrhythmia
  • Clinically significant peripheral vascular disease
  • Evidence of bleeding diathesis or coagulopathy
  • Serious non-healing would, ulcer, or bone fracture
  • Abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within the past 28 days
  • Significant traumatic injury within the past 28 days
  • Acute bacterial or fungal infection requiring IV antibiotics at the time of study registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 14 days
  • AIDS based upon current CDC definition (HIV testing is not required)
• No condition that would impair the ability to swallow pills (e.g., GI tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease)
• No disease that would obscure toxicity or dangerously alter drug metabolism
• Not on dialysis
• No history of chronic hepatitis B or C NOTE: **Required for patients who received prior bevacizumab and developed known clinically significant nephrotic syndrome during treatment and whose baseline values have not returned to normal.

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from the toxic effects of prior therapy
• Prior interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery allowed provided there is confirmation of progressive disease by PET scan, thallium scan, MRI spectroscopy, perfusion MRI, or surgical documentation
• No more than 3 prior treatment regimens (phase I*)
• No more than 2 prior treatment regimens for recurrent glioblastoma/gliosarcoma (phase II*)
• More than 28 days since prior major surgical procedure or open biopsy (with the exception of craniotomy)
• At least 28 days since prior investigational agents or cytotoxic agents (42 days for nitrosoureas, 21 days for procarbazine, and 14 days for vincristine)
• At least 14 days since prior non-cytotoxic agents (e.g., bevacizumab, interferon, tamoxifen, thalidomide, isotretinoin, or tyrosine kinase inhibitors)
• No concurrent highly-active antiretroviral therapy
• No concurrent herbal products of unknown constitution
• No concurrent major surgical procedures NOTE: *Phase I was closed and phase II was opened on 3/6/12.