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

• ClinicalTrials.gov Identifier: NCT02152982
• Recruitment Status: Active, not recruiting
• First Posted: June 2, 2014
• Last Update Posted: June 18, 2020
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: May 27, 2014
• First Posted Date: June 2, 2014
• Last Update Posted Date: June 18, 2020
• Actual Study Start Date: December 15, 2014
• Estimated Primary Completion Date: January 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 20, 2015)

Overall survival (OS) [ Time Frame: From study registration to the date of death due to any cause, assessed up to 10 years ]

The distribution of OS for each arm will be estimated using the Kaplan-Meier method and compared with a stratified logrank test. Stratified Cox proportional hazard models will be used to estimate the hazard ratio for the treatment effect.

Original Primary Outcome Measures (submitted: May 29, 2014)

Overall survival (OS) [ Time Frame: From study registration to the date of death due to any cause, assessed up to 5 years ]

The distribution of OS for each arm will be estimated using the Kaplan-Meier method, and will be compared using Cox models.

Current Secondary Outcome Measures (submitted: June 22, 2018)

• Interaction with Optune device [ Time Frame: Up to 5 years ]
  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.
• Progression-free survival (PFS) [ Time Frame: From study registration to the date of first observation of disease progression or death due to any cause (whichever comes first), assessed up to 10 years ]
  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.
• Objective tumor response, defined as complete response or partial response as specified in the Revised Assessment in Neuro-Oncology criteria [ Time Frame: Up to 5 years ]
  An objective tumor response will be evaluated for each patient and the tumor response rate will be summarized for each arm and compared using the Chi-square test.
• 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) [ Time Frame: Up to 5 years ]
  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.
• Change in quality of life (QOL), measured by the fatigue/uniscale tool [ Time Frame: Baseline to up to 5 years ]
  The fatigue/uniscale tool will be used as a measure of QOL. Potential differences in fatigue levels of patients treated on the two different arms will be evaluated. Changes in this measure will be evaluated over the course of treatment for both arms and will be compared using a two-sample t-test at each timepoint. Will also compute a normalized area under the curve (AUC) for the values of each patient over time and compare the mean AUCs for patients on the two arms.

Original Secondary Outcome Measures (submitted: May 29, 2014)

• Progression-free survival (PFS) [ Time Frame: From study registration to the date of first observation of disease progression or death due to any cause (whichever comes first), assessed up to 5 years ]
  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.
• Objective tumor response, defined as complete response or partial response as specified in the Revised Assessment in Neuro-Oncology criteria [ Time Frame: Up to 5 years ]
  An objective tumor response will be evaluated for each patient and the tumor response rate will be summarized for each arm and compared using the Chi-square test.
• 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 [ Time Frame: Up to 5 years ]
  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.

Current Other Pre-specified Outcome Measures (submitted: November 5, 2014)

MGMT status [ Time Frame: Baseline ]

The concordance between site-determined MGMT methylation status and central laboratory determination of MGMT status will be analyzed using the Chi-Square test of proportions and 95% confidence intervals for the proportion of tests in disagreement with the local site.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Temozolomide With or Without Veliparib in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
• 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 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 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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Glioblastoma
• Gliosarcoma

Intervention

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Placebo Administration
  Given PO
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Drug: Temozolomide
  Given PO
  Other Names:

  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac
  • TMZ
• Drug: Veliparib
  Given PO
  Other Names:

  • ABT-888
  • PARP-1 inhibitor ABT-888

Study Arms

• Experimental: Arm I (temozolomide, veliparib)
  Patients receive temozolomide PO QD on days 1-5 and veliparib 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.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Quality-of-Life Assessment
  • Drug: Temozolomide
  • Drug: Veliparib
• Placebo Comparator: Arm II (temozolomide, placebo)
  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.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Placebo Administration
  • Other: Quality-of-Life Assessment
  • Drug: Temozolomide

• Publications *: Gupta SK, Kizilbash SH, Carlson BL, Mladek AC, Boakye-Agyeman F, Bakken KK, Pokorny JL, Schroeder MA, Decker PA, Cen L, Eckel-Passow JE, Sarkar G, Ballman KV, Reid JM, Jenkins RB, Verhaak RG, Sulman EP, Kitange GJ, Sarkaria JN. Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma. J Natl Cancer Inst. 2015 Nov 27;108(5). pii: djv369. doi: 10.1093/jnci/djv369. Print 2016 May.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: November 5, 2014): 440
• Original Estimated Enrollment (submitted: May 29, 2014): 400
• Study Completion Date: Not Provided
• Estimated Primary Completion Date: January 14, 2021 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT02152982
• Other Study ID Numbers: NCI-2014-00616; NCI-2014-00616 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); A071102; CALGB-A071102; A071102 ( Other Identifier: Alliance for Clinical Trials in Oncology ); A071102 ( Other Identifier: CTEP ); P50CA108961 ( U.S. NIH Grant/Contract ); U10CA180821 ( U.S. NIH Grant/Contract ); U10CA031946 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jann N Sarkaria; Alliance for Clinical Trials in Oncology

• PRS Account: National Cancer Institute (NCI)
• Verification Date: May 2020