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

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ClinicalTrials.gov Identifier: NCT03581292
Recruitment Status : Recruiting
First Posted : July 10, 2018
Last Update Posted : April 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Anaplastic Astrocytoma Glioblastoma Malignant Glioma Radiation: Radiation Therapy Drug: Temozolomide Drug: Veliparib Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 115 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 31, 2018
Estimated Primary Completion Date : October 29, 2024
Estimated Study Completion Date : October 29, 2024


Arm Intervention/treatment
Experimental: Treatment (veliparib, radiation therapy, temozolomide)

CHEMORADIOTHERAPY 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.

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation

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

Drug: Veliparib
Given PO
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888




Primary Outcome Measures :
  1. Event free survival (EFS) [ Time Frame: Up to 5.5 years ]
    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 :
  1. Objective response (OR) [ Time Frame: Up to 5.5 years ]
  2. Overall survival (OS) [ Time Frame: Up to 5.5 years ]

Other Outcome Measures:
  1. Biomarker analysis [ Time Frame: Up to 5.5 years ]
    Will provide a frequency table summarizing the number of patients with each aberration/alteration detected in germline and/or tumor samples. For longitudinal plasma samples used to assess circulating tumor deoxyribonucleic acid (DNA), will summarize the percentage of patients with samples as well as display/summarize any changes in molecular markers. When feasible we will explore the association of these aberrations with EFS/OS and objective response rates via Cox models and fisher exact tests, respectively. Will also explore associations between genetic variants and clinical/demographic variables including age, resection status, histology, etc. For analyses exploring associations of a large number of potential markers with clinical outcome, will utilize false discovery rate approaches in order to control family-wise error rate.



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT03581292


  Show 93 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Matthias A Karajannis Children's Oncology Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03581292     History of Changes
Other Study ID Numbers: NCI-2018-01361
NCI-2018-01361 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACNS1721 ( Other Identifier: Childrens Oncology Group )
ACNS1721 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: July 10, 2018    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: November 2018

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

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