Clinical Trials /

Veliparib, Radiation Therapy, and Temozolomide in Treating Participants With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600E Mutations

NCT03581292

Description:

This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating participants with newly diagnosed malignant glioma without H3 K27M or BRAFV600E mutations. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. 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. Giving veliparib, radiation therapy, and temozolomide may work better in treating participants with newly diagnosed malignant glioma without H3 K27M or BRAFV600E mutations.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Veliparib, Radiation Therapy, and Temozolomide in Treating Participants With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600E Mutations
  • Official Title: A Phase 2 Study of Veliparib (ABT-888) and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients With Newly Diagnosed High-Grade Glioma (HGG) Without H3 K27M or BRAFV600E Mutations

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01361
  • SECONDARY ID: NCI-2018-01361
  • SECONDARY ID: ACNS1721
  • SECONDARY ID: ACNS1721
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03581292

Conditions

  • Anaplastic Astrocytoma
  • Glioblastoma
  • Malignant Glioma

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, TemomedacTreatment (veliparib, radiation therapy, temozolomide)
VeliparibABT-888, PARP-1 inhibitor ABT-888Treatment (veliparib, radiation therapy, temozolomide)

Purpose

This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating participants with newly diagnosed malignant glioma without H3 K27M or BRAFV600E mutations. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. 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. Giving veliparib, radiation therapy, and temozolomide may work better in treating participants with newly diagnosed malignant glioma without H3 K27M or BRAFV600E mutations.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine whether veliparib (ABT-888), when added to radiotherapy (RT) and
      temozolomide, is efficacious for the treatment of patients with newly-diagnosed high-grade
      glioma (HGG) whose tumors' molecular profile are wild-type for H3 K27M, BRAFV600E, and
      IDH1/2.

      II. To determine whether veliparib (ABT-888), when added to RT and temozolomide, is
      efficacious for the treatment of patients with newly-diagnosed HGG whose tumors' molecular
      profile are wild-type for H3 K27M and BRAFV600E and harbor an IDH1/2 mutation.

      SECONDARY OBJECTIVES:

      I. To explore associations of genomic, transcriptomic, and/or epigenetic alterations of the
      tumors with treatment response and outcome.

      II. To explore the extent to which patients with BRCA1/2 gene alterations and other
      deoxyribonucleic acid (DNA) damaged genes display tumor genomic features consistent with
      homologous repair deficiency (HRD), including large scale state transitions (LSTs),
      mutational signature 3, and an enrichment for deletions flanked by sequences of (micro)
      homology.

      III. To explore the burden of high, moderate, and low penetrant germline alterations in HRD
      genes (such as BRCA1, BRCA2, PALB2, Fanconi complex genes, ATM, CHEK2, RAD51B/C/D), mis-match
      repair genes (such as MLH1, MSH2, MSH6, PMS2, EPCAM), and energy metabolism genes (such as
      SDHA, SDHB, SDHC, SDHAF2, SDHD, IDH1, IDH2, and FH).

      IV. To explore constitutional imprinting abnormalities associated with EP300 and IGF2 in
      peripheral blood from patients with HGGs.

      OUTLINE:

      CHEMORADIOTHERAPY PHASE: Participants receive veliparib orally (PO) twice daily (BID) and
      undergo 30 daily fractions of radiation therapy 5 days per week for 6-7 weeks in the absence
      of disease progression or unacceptable toxicity.

      MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after chemoradiotherapy phase, participants
      receive veliparib PO BID and temozolomide PO once daily (QD) on days 1-5. Treatment repeats
      every 28 days for up to 10 courses in the absence of disease progression or unacceptable
      toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (veliparib, radiation therapy, temozolomide)ExperimentalCHEMORADIOTHERAPY PHASE: Participants receive veliparib PO BID and undergo 30 daily fractions of radiation therapy 5 days per week for 6-7 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after chemoradiotherapy phase, participants receive veliparib PO BID and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.
  • Temozolomide
  • Veliparib

Eligibility Criteria

        Inclusion Criteria:

          -  Stratum 1 (IDH wild-type): Patients must be >= 3 years of age and =< 21 years of age
             at the time of enrollment

          -  Stratum 2 (IDH mutant): Patients must be >= 3 years of age and =< 25 years of age at
             the time of enrollment

          -  Patients must have eligibility confirmed by rapid central pathology and central
             molecular screening reviews performed on APEC14B1:

               -  Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma

               -  Negative results for H3 K27M by immunohistochemistry (IHC)

               -  Negative results for BRAFV600E mutation by next-generation sequencing (NGS)

          -  Patients must have histological verification of diagnosis. Patients with M+ disease
             (defined as evidence of neuraxis dissemination) are not eligible. Cerebrospinal fluid
             (CSF) cytology is not required but may be obtained if clinically indicated prior to
             study enrollment. If cytology is positive, the patient would be considered to have
             metastatic disease and would, therefore, be ineligible

          -  Pre-operative and post-operative brain magnetic resonance imaging (MRI) with and
             without contrast must be obtained. The requirement for a post-operative MRI is waived
             for patients who undergo biopsy only. A spine MRI is not required, but may be obtained
             if clinically indicated. If the spine MRI is positive, the patient would be considered
             to have M+ disease (defined as neuraxis dissemination) and would be ineligible

          -  Patients must have a performance status of >= 50 by Lansky or Karnofsky, corresponding
             to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for
             patients > 16 years of age and Lansky for patients =< 16 years of age. Patients who
             are unable to walk because of paralysis, but are up in a wheelchair will be considered
             ambulatory for the purposes of assessing the performance score

          -  Peripheral absolute neutrophil count (ANC) >= 1,000/uL

          -  Platelet count >= 100,000/uL (transfusion independent)

          -  Hemoglobin >= 8.0 gm/dL (can be transfused)

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

               -  3 to < 6 years: 0.8 (male and female) maximum serum creatinine (mg/dL)

               -  6 to < 10 years: 1 (male and female) maximum serum creatinine (mg/dL)

               -  10 to < 13 years: 1.2 (male and female) maximum serum creatinine (mg/dL)

               -  13 to < 16 years: 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL)

               -  >= 16 years: 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

          -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
             serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
             upper limit of normal (ULN) for age

          -  Patients with seizure disorder may be enrolled if seizures are well-controlled (i.e.,
             patients must not have required rescue medications for uncontrolled seizures within 14
             days prior to enrollment)

          -  Patients must be enrolled and protocol therapy must be projected to begin no later
             than 31 days after definitive diagnostic surgery (Day 0)

          -  All patients and/or their parents or legal guardians must sign a written informed
             consent

          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
             (NCI) requirements for human studies must be met

        Exclusion Criteria:

          -  Patients with the following histologies:

               -  Diffuse astrocytoma (grade 2)

               -  Oligodendrogliomas (any grade)

               -  Pleomorphic xanthoastrocytoma (PXA, any grade)

          -  Patients with primary tumor location of brainstem or spinal cord

          -  Patients with M+ disease (defined as neuraxis dissemination either by imaging or by
             cytology)

          -  Patients must not have received any prior tumor-directed therapy including radiation
             therapy, chemotherapy (tumor-directed therapy), molecularly targeted agents, or
             immunotherapy for the treatment of HGG other than surgical intervention

          -  Lumbar CSF cytology is not required, but may be performed if clinically indicated
             prior to study enrollment. If lumbar CSF cytology is positive, the patient is
             considered to have M+ disease and is ineligible

               -  Note: False positive cytology can occur within 10 days of surgery

          -  Patients with gliomatosis cerebri type 1 or 2

          -  Patients who are not able to receive protocol specified radiation therapy

          -  Patients must not be currently receiving other anti-cancer agents

          -  Patients with known constitutional mismatch repair deficiency syndrome
             (CMMR-D)/biallelic mismatch repair deficiency (bMMRD)

          -  Female patients who are pregnant are ineligible due to risks of fetal and teratogenic
             adverse events as seen in animal/human studies

          -  Lactating females are not eligible unless they have agreed not to breastfeed their
             infants

          -  Female patients of childbearing potential are not eligible unless a negative pregnancy
             test result has been obtained

          -  Sexually active patients of reproductive potential are not eligible unless they have
             agreed to use an effective contraceptive method for the duration of their study
             participation and for 4 months after the last dose of veliparib
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event free survival (EFS)
Time Frame:Up to 5.5 years
Safety Issue:
Description:Analysis will be based on a 2-sample, 1 sided logrank test. For each stratum will also consider Cox models that incorporate known prognostic factors as feasible including resection status (gross total resection [GTR] versus [vs.] < GTR) and tumor grade (grade 3 vs. 4), spinal primaries vs. others, etc. to ensure that these variables do not have undue influence on the overall outcome. For patients with measurable disease at baseline, will also report the objective response rate.

Secondary Outcome Measures

Measure:Objective response (OR)
Time Frame:Up to 5.5 years
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:Up to 5.5 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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