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Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01026493
Recruitment Status : Completed
First Posted : December 4, 2009
Results First Posted : July 2, 2017
Last Update Posted : July 2, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: temozolomide 60 mg x 21 days Drug: temozolomide 75 mg x 21 days Drug: ABT-888 20 mg x 21 days Drug: ABT-888 40 mg x 21 days Drug: Temozolomide 150 mg x 5 days Drug: ABT-888 40 mg x 5 days Phase 1 Phase 2

Detailed Description:

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.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 257 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase I/II Study of ABT-888 in Combination With Temozolomide in Recurrent (Temozolomide Resistant) Glioblastoma
Study Start Date : July 2010
Primary Completion Date : May 2014
Study Completion Date : December 2016


Arms and Interventions

Arm Intervention/treatment
Experimental: Phase I: Dose Level 1
ABT-888 20 mg x 21 days plus temozolomide 60 mg x 21 days
Drug: temozolomide 60 mg x 21 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.
Other Names:
  • Temodar
  • Temodal
  • Temcad
Drug: ABT-888 20 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.
Other Name: Veliparib
Experimental: Phase I: Dose Level 2a
ABT-888 40 mg x 21 days plus temozolomide 60 mg x 21 days
Drug: temozolomide 60 mg x 21 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.
Other Names:
  • Temodar
  • Temodal
  • Temcad
Drug: ABT-888 40 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
Other Name: Veliparib
Experimental: Phase I: Dose Level 2b
ABT-888 20 mg x 21 days plus temozolomide 75 mg x 21 days
Drug: temozolomide 75 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.
Other Names:
  • Temodar
  • Temodal
  • Temcad
Drug: ABT-888 20 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.
Other Name: Veliparib
Experimental: Phase I: Dose Level 3
ABT-888 40 mg x 21 days plus temozolomide 75 mg x 21 days
Drug: temozolomide 75 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.
Other Names:
  • Temodar
  • Temodal
  • Temcad
Drug: ABT-888 40 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
Other Name: Veliparib
Experimental: Phase II: Arm 1/BEV-NAIVE
ABT-888 40 mg x 21 days plus temozolomide 75 mg x 21 days
Drug: temozolomide 75 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.
Other Names:
  • Temodar
  • Temodal
  • Temcad
Drug: ABT-888 40 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
Other Name: Veliparib
Experimental: Phase II: Arm 2/BEV-NAIVE
ABT-888 40 mg x 5 days plus temozolomide 150 mg x 5 days
Drug: Temozolomide 150 mg x 5 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
Other Names:
  • Temodar
  • Temcad
  • Temodal
Drug: ABT-888 40 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
Other Name: Veliparib
Experimental: Phase II: Arm 1/BEV-FAILURE
ABT-888 40 mg x 21 days plus temozolomide 75 mg x 21 days
Drug: temozolomide 75 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.
Other Names:
  • Temodar
  • Temodal
  • Temcad
Drug: ABT-888 40 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
Other Name: Veliparib
Experimental: Phase II: Arm 2/BEV-FAILURE
ABT-888 40 mg x 5 days plus temozolomide 150 mg x 5 days
Drug: Temozolomide 150 mg x 5 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
Other Names:
  • Temodar
  • Temcad
  • Temodal
Drug: ABT-888 40 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
Other Name: Veliparib


Outcome Measures

Primary Outcome Measures :
  1. Phase 1: Maximum Tolerated Dose (MTD) [ Time Frame: Start of treatment to 8 weeks. ]
    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.

  2. Phase II: 6-month Progression-free Survival (PFS) Rate for Patients With Measurable Disease After Surgery [ Time Frame: Randomization to 6 months. ]
    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.


Secondary Outcome Measures :
  1. Phase II: Objective Response (Partial and Complete Response) Rate for Patients With Measurable Disease After Surgery [ Time Frame: Analysis occurs after all patients have been on study for at 6 months. (Patients are followed from randomization to death or study termination whichever occurs first.) ]
    Response and progression will be evaluated using standard criteria for patients with malignant gliomas (Macdonald 1990). Partial response and complete response are centrally reviewed.

  2. Phase II: Overall Survival (OS) [ Time Frame: Analysis occurs after all patients have been on study for at 6 months. (Patients are followed from randomization to death or study termination whichever occurs first.) ]
    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.


Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 120 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of 1 of the following:

    • Any intracranial high-grade glioma (phase I*)
    • Glioblastoma or gliosarcoma (phase II*)
  • Patients whose original histology was low-grade glioma are eligible provided they were subsequently diagnosed with glioblastoma or gliosarcoma
  • Unequivocal radiographic evidence for tumor progression by MRI within 14 days prior to registration and with a stable or decreasing dose of steroids at least 5 days prior to scanning OR recent resection (registration within 30 days of resection) as long as all of the following conditions are met:

    • Patients must have recovered from the effects of surgery
    • Residual disease following resection of recurrent glioblastoma is not mandated for eligibility into the study; to best assess the extent of residual disease post-operatively, a post-operative MRI scan should be performed within 28 days prior to registration and within 96 hours post surgery (although 24 hours would be optimum)
    • Prior radiation is required for the phase I* arm
    • Patients must have completed a course of radiation therapy and at least 2 consecutive adjuvant cycles of temozolomide (phase II*)
    • A stable or decreasing dose of steroids at least 5 days prior to scanning is not mandated for patients who had a recent resection
  • No evidence of acute (i.e., new and active) intratumoral hemorrhage on MRI

    • Patients with MRI demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection) are eligible Note: *Phase I was closed and phase II was opened on 3/6/12.

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 70-100%
  • White blood cell (WBC) count ≥ 3,000/mm^3
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
  • Serum glutamic oxaloacetic transaminase (SGOT) ≤ 3.0 times upper limit of normal (ULN)
  • Serum glutamic pyruvic transaminase (SGPT) ≤ 3.0 times ULN
  • Bilirubin ≤ 1.25 times ULN
  • Creatinine < 1.7 mg/dL OR estimated glomerular filtration rate (GFR) ≥ 30 mL/min
  • Urine protein:creatinine ratio ≤ 0.5 OR urine protein < 1,000 mg by 24-hour urine collection**
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
  • Able to undergo brain MRI scans with IV gadolinium
  • Able to swallow oral medications
  • Patients with a history of seizure, or new onset of seizures, should be clinically controlled with no seizures for at least 14 days prior to registration
  • No other prior invasive malignancy (except for nonmelanomatous skin cancer or carcinoma in situ of the cervix) unless the patient has been disease-free and off therapy for that disease for ≥ 3 years
  • No severe, active comorbidity, including any of the following:

    • Transmural myocardial infarction or unstable angina within the past 6 months
    • Evidence of recent myocardial infarction or ischemia as indicated by S-T elevations of ≥ 2 mm on EKG performed within the past 14 days
    • New York Heart Association (NYHA) class II-IV congestive heart failure requiring hospitalization within the past 12 months
    • Stroke or transient ischemic attack within the past 6 months
    • Cerebral vascular accident within the past 6 months
    • Serious and inadequately controlled cardiac arrhythmia
    • Clinically significant peripheral vascular disease
    • Evidence of bleeding diathesis or coagulopathy
    • Serious non-healing would, ulcer, or bone fracture
    • Abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within the past 28 days
    • Significant traumatic injury within the past 28 days
    • Acute bacterial or fungal infection requiring IV antibiotics at the time of study registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 14 days
    • AIDS based upon current Centers for Disease Control and Prevention (CDC) definition (HIV testing is not required)
  • No condition that would impair the ability to swallow pills (e.g., GI tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease)
  • No disease that would obscure toxicity or dangerously alter drug metabolism
  • Not on dialysis
  • No history of chronic hepatitis B or C Note: **Required for patients who received prior bevacizumab and developed known clinically significant nephrotic syndrome during treatment and whose baseline values have not returned to normal.

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from the toxic effects of prior therapy
  • Prior interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery allowed provided there is confirmation of progressive disease by positron emission tomography (PET) scan, thallium scan, MRI spectroscopy, perfusion MRI, or surgical documentation
  • No more than 3 prior treatment regimens (phase I*)
  • No more than 2 prior treatment regimens for recurrent glioblastoma/gliosarcoma (phase II*)
  • More than 28 days since prior major surgical procedure or open biopsy (with the exception of craniotomy)
  • At least 28 days since prior investigational agents or cytotoxic agents (42 days for nitrosoureas, 21 days for procarbazine, and 14 days for vincristine)
  • At least 14 days since prior non-cytotoxic agents (e.g., bevacizumab, interferon, tamoxifen, thalidomide, isotretinoin, or tyrosine kinase inhibitors)
  • No concurrent highly-active antiretroviral therapy
  • No concurrent herbal products of unknown constitution
  • No concurrent major surgical procedures Note: *Phase I was closed and phase II was opened on 3/6/12.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01026493


Locations
United States, California
Rebecca and John Moores UCSD Cancer Center
La Jolla, California, United States, 92093-0658
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
United States, Hawaii
Leeward Radiation Oncology
'Ewa Beach, Hawaii, United States, 96706
Cancer Research Center of Hawaii
Honolulu, Hawaii, United States, 96813
Queen's Cancer Institute at Queen's Medical Center
Honolulu, Hawaii, United States, 96813
Hawaii Medical Center - East
Honolulu, Hawaii, United States, 96817
United States, Illinois
University of Chicago Cancer Research Center
Chicago, Illinois, United States, 60637-1470
United States, Kansas
CCOP - Kansas City
Prairie Village, Kansas, United States, 66208
United States, Kentucky
Central Baptist Hospital
Lexington, Kentucky, United States, 40503-9985
Louisville Oncology at Norton Cancer Institute - Louisville
Louisville, Kentucky, United States, 40202
United States, Mississippi
Regional Cancer Center at Singing River Hospital
Pascagoula, Mississippi, United States, 39581
United States, Nevada
Renown Institute for Cancer at Renown Regional Medical Center
Reno, Nevada, United States, 89502
United States, New Hampshire
Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756-0002
United States, New Jersey
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
New Brunswick, New Jersey, United States, 08903
United States, New York
Highland Hospital of Rochester
Rochester, New York, United States, 14620
James P. Wilmot Cancer Center at University of Rochester Medical Center
Rochester, New York, United States, 14642
United States, Oregon
Legacy Good Samaritan Hospital & Comprehensive Cancer Center
Portland, Oregon, United States, 97210
Sponsors and Collaborators
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
NRG Oncology
Investigators
Principal Investigator: H. Ian Robins, MD, PhD University of Wisconsin, Madison
Principal Investigator: Mark R Gilbert, MD National Cancer Institute/National Institutes of Health
Study Chair: Arnab Chakravarti, MD Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Ohio State University Medical School
More Information

Responsible Party: Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier: NCT01026493     History of Changes
Other Study ID Numbers: RTOG-0929
CDR0000660545
First Posted: December 4, 2009    Key Record Dates
Results First Posted: July 2, 2017
Last Update Posted: July 2, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Radiation Therapy Oncology Group:
adult giant cell glioblastoma
adult glioblastoma
adult gliosarcoma
recurrent adult brain tumor
adult anaplastic astrocytoma
adult anaplastic ependymoma
adult anaplastic oligodendroglioma
adult brain stem glioma
adult mixed glioma
adult pineal gland astrocytoma

Additional relevant MeSH terms:
Glioblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Temozolomide
Dacarbazine
Veliparib
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors