Clinical Trials /

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

NCT02152982

Description:

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.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-00616
  • SECONDARY ID: NCI-2014-00616
  • SECONDARY ID: A071102
  • SECONDARY ID: CALGB-A071102
  • SECONDARY ID: A071102
  • SECONDARY ID: A071102
  • SECONDARY ID: P50CA108961
  • SECONDARY ID: U10CA180821
  • SECONDARY ID: U10CA031946
  • NCT ID: NCT02152982

Conditions

  • Glioblastoma
  • Gliosarcoma

Interventions

DrugSynonymsArms
TemozolomideCCRG-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, TemomedacArm I (temozolomide, veliparib)
VeliparibABT-888, PARP-1 inhibitor ABT-888Arm I (temozolomide, veliparib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (temozolomide, veliparib)ExperimentalPatients 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.
  • Temozolomide
  • Veliparib
Arm II (temozolomide, placebo)Placebo ComparatorPatients 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.
  • Temozolomide

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From study registration to the date of death due to any cause, assessed up to 10 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Interaction with Optune device
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Change in quality of life (QOL), measured by the fatigue/uniscale tool
Time Frame:Baseline to up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 2, 2018