Veliparib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600 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 BRAFV600 Mutations

Summary:

This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations. Poly adenosine diphosphate (ADP) ribose polymerases (PARPs) are proteins that help repair DNA mutations. PARP inhibitors, such as veliparib, can keep PARP from working, so tumour cells can't repair themselves, and they may stop growing. Radiation therapy uses high energy x-rays to kill tumour cells and shrink tumours. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumour 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 patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations compared to radiation therapy and temozolomide alone.

Trial Description

Primary Outcome:

• Event free survival (EFS)

• Objective response
• Overall survival (OS)

PRIMARY OBJECTIVES:

• To determine whether veliparib (ABT-888), when added to radiation therapy (RT) and temozolomide, is efficacious for the treatment of patients with newly-diagnosed high-grade glioma (HGG) whose tumours' molecular profile are wild-type for H3 K27M, BRAF, and IDH1/2.
• To determine whether veliparib (ABT-888), when added to RT and temozolomide, is efficacious for the treatment of patients with newly-diagnosed HGG whose tumours' molecular profile are wild-type for H3 K27M and BRAF and harbor an IDH1/2 mutation.

·         EXPLORATORY OBJECTIVES:

• To explore associations of genomic, transcriptomic, and/or epigenetic alterations of the tumours with treatment response and outcome.
• To explore the extent to which patients with BRCA1/2 gene alterations and other deoxyribonucleic acid (DNA) damaged genes display tumour 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.
• 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).
• To explore constitutional imprinting abnormalities associated with EP300 and IGF2 in peripheral blood from patients with HGGs.

OUTLINE:

CHEMORADIOTHERAPY PHASE: Patients 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, patients receive veliparib PO BID and temozolomide PO once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, and then once yearly for years 4-10.

View this trial on ClinicalTrials.gov