A Phase II/III Randomized Trial of Veliparib or Placebo in Combination With Adjuvant Temozolomide in Newly Diagnosed Glioblastoma With MGMT Promoter Hypermethylation
A Phase II/III Randomized Trial of Veliparib or Placebo in Combination With Adjuvant Temozolomide in Newly Diagnosed Glioblastoma With MGMT Promoter Hypermethylation
This randomized phase II/III trial studies how well temozolomide and veliparib work compared to temozolomide alone in treating patients with newly diagnosed glioblastoma multiforme. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether temozolomide is more effective with or without veliparib in treating glioblastoma multiforme.
PRIMARY OBJECTIVE:
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.
CORRELATIVE SCIENCE 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 placebo PO twice daily (BID) on days 1-7. Treatment repeats every 28 days for 6 cycles in the absence of disease progression (confirmed progression) or unacceptable toxicity.
ARM II: Patients receive temozolomide as in Arm I and veliparib PO BID on days 1-7. Treatment repeats every 28 days for 6 cycles 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:
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:
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:
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:
No Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS
Burbank, California 91505, United States
Sacramento, California 95817, United States
Deerfield Beach, Florida 33442, United States
Miami, Florida 33136, United States
Highland Park, Illinois 60035, United States
Grand Rapids, Michigan 49503, United States
Saint Joseph, Michigan 49085, United States
Saint Joseph, Michigan 49085, United States
Lebanon, New Hampshire 03756, United States
New Brunswick, New Jersey 08903, United States
Harrisburg, Pennsylvania 17109, United States
Houston, Texas 77030, United States
Madison, Wisconsin 53792, United States
Sturgeon Bay, Wisconsin 54235-1495, United States
Summit, Wisconsin 53066, United States