Temozolomide With or Without Veliparib in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

PRIMARY OBJECTIVES:

I. Test whether the experimental combination of ABT-888 (veliparib) combined with TMZ
(temozolomide), compared to the control of placebo combined with TMZ, significantly extends
overall survival in newly diagnosed glioblastoma multiforme (GBM) patients with tumor MGMT
promoter hypermethylation.

SECONDARY OBJECTIVES:

I. Test whether the experimental treatment significantly extends progression-free survival.

II. Test whether the experimental treatment improves objective tumor response. III. Test
whether the experimental treatment is associated with significantly greater rates of grade 3
or higher adverse events.

TERTIARY OBJECTIVES:

I. Evaluate the utility of dynamic susceptibility contrast (DSC) and diffusion weighted
imaging (DWI) magnetic resonance imaging (MRI) techniques in defining time to progression in
the setting of a large multi-institutional clinical trial.

II. Test the concordance between site-determined MGMT methylation status and central
laboratory determination of MGMT status in cases with local testing.

III. Evaluate whether genetic or epigenetic alterations in deoxyribonucleic acid (DNA) repair
or replication genes are associated with overall survival, progression-free survival, and
objective tumor response.

IV. Test whether polymorphisms in MGMT, PARP1, or other DNA repair proteins, are associated
with overall survival, progression-free survival, objective tumor response, or rates of grade
3 or higher adverse events.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5 and veliparib PO
twice daily (BID) on days 1-7. Treatment repeats every 28 days for 6 courses in the absence
of disease progression (confirmed progression) or unacceptable toxicity.

ARM II: Patients receive temozolomide as in Arm I and placebo PO BID on days 1-7. Treatment
repeats every 28 days for 6 courses in the absence of disease progression (confirmed
progression) or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years,
every 6 months for 2 years.

Inclusion Criteria:

- Histologic documentation: newly diagnosed World Health Organization (WHO) grade IV
intracranial glioblastoma or gliosarcoma; 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

- Sufficient tissue available for central pathology review and MGMT methylation status
evaluation

- Patients who have had a local MGMT testing that is unmethylated are not allowed to
participate

- Tumor MGMT promoter hypermethylation determined by central testing at MD Anderson

- Confirmation by central pathology review of WHO grade IV glioblastoma or gliosarcoma

- Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 14 days prior to study
registration)

- Platelets >= 100,000 cells/mm^3 (within 14 days prior to study registration)

- Creatinine =< 1.5 x upper limit of normal (ULN) (within 14 days prior to study
registration)

- Bilirubin =< 1.5 x ULN (within 14 days prior to study registration; unless patient has
Gilbert's disease)

- Alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to study registration)

- Aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to study
registration)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Measurable disease or non-measurable disease; extent of resection: patients with
complete resection, partial resection, or biopsy are eligible

- Progression: patients deemed to have progressive disease based on clinical
deterioration after chemoradiation or radiographic progression outside of the
radiation field are not eligible; patients deemed to have pseudoprogression are
eligible

- Prior treatment:

- Must have completed standard radiotherapy and concomitant TMZ therapy as defined
and determined by the study oncologist

- Besides concomitant TMZ with radiation, no other therapy (neo-adjuvant or
adjuvant) can be given prior to study registration, including chemotherapy (also
including Gliadel/carmustine [BCNU] wafers), biologics, immunotherapy, radiation
therapy; the only exception is the Optune device (NovoTTF-100A), which may be
started any time after end of radiation therapy up through the initiation of
Cycle 1; intent to use Optune must be declared at registration for stratification

- No prior allogeneic bone marrow transplant or double umbilical cord blood
transplantation

- Not pregnant and not nursing; females of childbearing potential must have negative
urine or serum pregnancy test within 7 days of registration but before start of
treatment; a female of childbearing potential is a sexually mature female who:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months)

- Concomitant medications: patients receiving anticoagulation should be on stable dose 2
weeks prior to registration

- Comorbid conditions: patients are unable to participate due to the following:

- Generalized or partial seizure disorder that is uncontrolled at the time of
registration; the definition of controlled generalized seizures is patients must
be on a stable dose of anti-seizure medication and without generalized seizures
for at least 10 days prior to registration; the definition of controlled partial
seizures is patients must be on a stable dose of anti-seizure medication for at
least 10 days prior to registration; patients with occasional breakthrough
partial seizures are allowed at treating physician's discretion

- Grade 3 or 4 thromboembolic disease within 6 months (mo) of registration

- Known history of prolonged QT syndrome

- No history of major surgery =< 14 days prior to registration

- Patients must have adequate organ and marrow function measured within 28 days prior to
administration of ABT-888 as defined below:

- >= 10.0 g/dL hemoglobin (Hb) with no blood transfusion in the past 28 days

- No Patients with treatment-related acute myeloid leukemia (AML)
(t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS