Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma
Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma
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 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 (BEV) 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.
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%

 -  White blood cell (WBC) count ≥ 3,000/mm^3

 -  Absolute neutrophil count (ANC) ≥ 1,500/mm^3

 -  Platelet count ≥ 100,000/mm^3

 -  Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)

 -  Serum glutamic oxaloacetic transaminase (SGOT) ≤ 3.0 times upper limit of normal (ULN)

 -  Serum glutamic pyruvic transaminase (SGPT) ≤ 3.0 times ULN

 -  Bilirubin ≤ 1.25 times ULN

 -  Creatinine < 1.7 mg/dL OR estimated glomerular filtration rate (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

 -  New York Heart Association (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 Centers for Disease Control and Prevention (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 positron emission tomography
 (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.