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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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 veliparib 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 placebo 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.

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

Conditions
-----------------
Glioblastoma, Gliosarcoma

Intervention / Treatment
-----------------
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration
* Other: Quality-of-Life Assessment
* Drug: Temozolomide
* Drug: Veliparib


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (temozolomide, veliparib)<br>Patients receive temozolomide PO QD on days 1-5 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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|
| Placebo Comparator: Arm II (temozolomide, placebo)<br>Patients receive temozolomide as in Arm I and placebo 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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The distribution of OS for each arm will be estimated using the Kaplan-Meier method and compared with a stratified logrank test. | 83 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interaction With Optune Device | Cox proportional hazards model will be used to evaluate whether there is a potential interaction between the treatment arm and the Optune device. If an interaction is detected, separate analyses of treatment effect (using Cox models) will be done for patients treated with the Optune device and patients who were not treated with the Optune device. | 5 years | 
| Progression-free Survival (PFS) | The distribution of PFS for each arm will be estimated using the Kaplan-Meier method, and be compared using Cox proportional hazard models with all stratification factors adjusted. Progression (PD): Defined by any of the following: > 25% increase in sum of products of perpendicular diameters of enhancing lesions, compared with the smallest tumor measurement obtained either at baseline or best response Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after therapy initiation (stable doses of steroids include patient not on steroids) not caused by comorbid events Any new lesion Clear clinical deterioration not attributable to other causes apart from tumor or change in corticosteroid dose Failure to return for evaluation as a result of death or deteriorating condition Clear progression of non-measurable disease | 83 months | 
| Objective Tumor Response | Defined as complete response (CR) or partial response (PR) as specified in the Revised Assessment in Neuro-Oncology criteria. An objective tumor response will be evaluated for each patient and the tumor response count will be summarized for each arm and compared using the Chi-square test. For CR, all of the following must be true: disappearance of all enhancing measurable and non-measurable disease; no new enhancing lesions; stable or improved non-enhancing lesions; patients must be off corticosteroids; stable or improved clinically A PR requires all of the following: > 50% decrease in sum of products of perpendicular diameters of all measurable enhancing lesions compared with baseline; no progression of non-measurable disease; no new lesions; stable or improved non-enhancing lesions on same or lower dose of corticosteroids compared with baseline scan; steroid dose should be same or lower compared with baseline scan; stable or improved clinically | 5 years | 
| Overall Adverse Event Rates for Grade 3 or Higher Adverse Events | Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5 beginning April 1, 2018). The overall adverse event rates for grade 3 or higher adverse events will be summarized and be compared using Chi-Square or Fisher's Exact tests between treatment arms. The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. Treatment-related adverse events will be tabulated for each arm. | 5 years |