Veliparib and Temozolomide 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.

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.