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

Study ID
STU 032015-081

Study Sites

  • Clements University Hospital

Contact
Rafael Leon
214/648-1929
Rafael.Leon@UTSouthwestern.edu

Principal Investigator
Edward Pan, M.D.

Official Title

A Phase II/III Randomized Trial of Veliparib or Placebo in Combination With Adjuvant Temozolomide in Newly Diagnosed Glioblastoma With MGMT Promoter Hypermethylation

Brief Overview

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.

Description

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.

Eligibility

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
- 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