Veliparib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600 Mutations
Veliparib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600 Mutations
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
 tumor cells can't repair themselves, and they may stop growing. 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 patients with newly diagnosed
 malignant glioma without H3 K27M or BRAFV600 mutations compared to radiation therapy and
 temozolomide alone.
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, BRAF, 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 BRAF and harbor an IDH1/2 mutation.

 EXPLORATORY 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: 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.
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 BRAFV600 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 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

 -  Peripheral absolute neutrophil count (ANC) >= 1,000/uL (within 7 days prior to
 enrollment)

 -  Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
 enrollment)

 -  Hemoglobin >= 8.0 gm/dL (can be transfused) (within 7 days prior to enrollment)

 -  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 (within 7 days
 prior to enrollment):

 -  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 (within 7 days prior to
 enrollment)

 -  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 (within 7 days prior to enrollment)

 -  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 with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic
 syndrome (MDS) or with features suggestive of AML/MDS

 -  Prior allogenic bone marrow transplant or double umbilical cord blood transplantation

 -  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 and/or
 corticosteroids

 -  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 6 months after the last dose of protocol-specified chemotherapy