Symptoms and General Pathology

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Glioma

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Nervous System Neoplasms

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Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

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Brain Tumor, Adult

Anaplastic Astrocytoma

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Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Veliparib

Antineoplastic Agents, Alkylating

Alkylating Agents

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

ABT-888 20 mg x 21 days plus temozolomide 60 mg x 21 days

ABT-888 40 mg x 21 days plus temozolomide 60 mg x 21 days

ABT-888 20 mg x 21 days plus temozolomide 75 mg x 21 days

ABT-888 40 mg x 21 days plus temozolomide 75 mg x 21 days

ABT-888 40 mg x 5 days plus temozolomide 150 mg x 5 days

Temozolomide 60 mg/m2 x 21 days, with a 28-day cycle. Treatment will continue until progressive disease unless toxicity or the discretion of the treating physician precludes further therapy.

temozolomide 60 mg x 21 days

Temozolomide 75 mg/m2 x 21 days, with a 28-day cycle. Treatment will continue until progressive disease unless toxicity or the discretion of the treating physician precludes further therapy.

temozolomide 75 mg x 21 days

20 mg bid x 21 days, with a 28-day cycle. Treatment will continue until progressive disease unless toxicity or the discretion of the treating physician precludes further therapy.

ABT-888 20 mg x 21 days

40 mg bid x 21 days/28-day cycle. Treatment continues until progressive disease unless toxicity or the discretion of the treating physician preclude further therapy

ABT-888 40 mg x 21 days

150 mg/m2 x 5 days (up to 200 mg/m2 after 2nd cycle)\*, with a 28-day cycle; dose reduction to 125 mg/m2 if necessary. Treatment continues until progressive disease unless toxicity or the discretion of the treating physician preclude

Temozolomide 150 mg x 5 days

40 mg bid x 5 days/28-day cycle. Treatment continues until progressive disease unless toxicity or the discretion of the treating physician preclude

ABT-888 40 mg x 5 days

H. Ian Robins, MD, PhD

Mark R Gilbert, MD

Arnab Chakravarti, MD

RATIONALE: Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide. work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving veliparib together with temozolomide may kill more tumor cells.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of giving veliparib together with temozolomide and to see how well it works 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 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 (BEV) 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.

Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma

A Randomized Phase I/II Study of ABT-888 in Combination With Temozolomide in Recurrent (Temozolomide Resistant) Glioblastoma

Dose limiting toxicity (DLT) = any of the following events within 1st 8 weeks of treatment attributable to study drugs: Any grade (gr) 3/4 thrombocytopenia, gr 4 anemia, gr 3 neutropenia with fever (\>100.4). gr 4 neutropenia lasting \> 7 days; Any non-hematologic (NH) gr 3+ toxicity (TOX), excluding alopecia, despite maximal medical therapy (MLT); NH TOX such as rash, nausea, vomiting, diarrhea, mucositis, hypophosphatemia, and hypertension will only be considered DLTs if they remain gr 3+ despite MLT; 2nd occurrence of thromboembolism; Failure to recover from TOX (\<= gr 1) to be eligible for re-treatment with study drugs \<= 14 days of last dose of either drug; Any episode of non-infectious radiologically observed pneumonitis gr 2-4 any duration. Dose level will be considered acceptable if \<= 1 of the 1st 6 eligible patients experiences a DLT. If current level is considered acceptable, dose escalation occurs. Otherwise preceding acceptable dose level will be declared the MTD.

For patients with measureable disease after surgery: Progression defined as ≥ 25% increase in size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable/increased. Bevacizumab (BEV)-naïve group: p0= 15% as estimate of 6-mo. PFS \[null hypothesis (NH)\], p1= 30%, with a 15% absolute increase \[alternative hypothesis (AH)\]. Error rates of 10% alpha and 10% beta. If \<= 11 patients experience 6-month PFS of the first 53 analyzable patients, then do not reject the null hypothesis that the 6-month PFS rate of experimental arm is less than 15%; BEV-failure group: p0 = 2% as a conservative estimate of 6-month PFS \[NH\], p1 = 15%, with a 13% absolute increase \[AH\]. Using first 26 analyzable subjects for each experimental arm, there is \>= 90% power to detect \>= 15% increase at a significance level of 0.10, using a 1-sided binomial test. If \>= 2 patients (8%) are progression free at 6 mo., then claim this regimen to be promising in the patient group.

Response and progression will be evaluated using standard criteria for patients with malignant gliomas (Macdonald 1990). Partial response and complete response are centrally reviewed.

Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 6 months.

National Cancer Institute (NCI)

NRG Oncology

Radiation Therapy Oncology Group

Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.

Phase I: Dose Level 1

Phase I: Dose Level 2a

Phase I: Dose Level 2b

Phase I: Dose Level 3

ABT-888 40 mg x 5 days plus temozolomide 75 mg x 5 days

Phase II: Arm 1/BEV-NAIVE

Phase II: Arm 2/BEV-NAIVE

Phase II: Arm 1/BEV-FAILURE

Phase II: Arm 2/BEV-FAILURE

Total

Age, Continuous

Sex: Female, Male

Wendy Seiferheld, M.S.

Eligible patients who started study treatment

Phase 1: Maximum Tolerated Dose (MTD)

Randomized patients with measurable disease after surgery, at least one cycle of treatment, evaluable for 6 month PFS, and within the required sample size (i.e. the first 53 BEV-naive patients and the first 26 BEV-failure patients- the number of patients will be less than sample size if not enough patients meet the criteria).

Phase II: 6-month Progression-free Survival (PFS) Rate for Patients With Measurable Disease After Surgery

Eligible patients with at least one cycle of treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma	NCT01026493	Brain and Centr...	temozolomide 60... temozolomide 75... ABT-888 20 mg x... ABT-888 40 mg x... Temozolomide 15... ABT-888 40 mg x...	18 Years - 120 Years	Radiation Therapy Oncology Group
Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma	NCT01026493	Brain and Centr...	temozolomide 60... temozolomide 75... ABT-888 20 mg x... ABT-888 40 mg x... Temozolomide 15... ABT-888 40 mg x...	18 Years - 120 Years	Radiation Therapy Oncology Group

Spots Global Cancer Trial Database for temozolomide 75 mg x 21 days