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

  • STATUS
    Recruiting
  • End date
    Oct 29, 2024
  • participants needed
    115
  • sponsor
    National Cancer Institute (NCI)
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Updated on 17 January 2021
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Investigator
Steven K. Bergstrom
Primary Contact
Kaiser Permanente-Oakland (9.6 mi away) Contact
+105 other location
platelet count
cancer
x-rays
MRI
glomerular filtration rate
epilepsy
neutrophil count
immunohistochemistry
tumor cells
blood transfusion
seizure
glioblastoma multiforme
temozolomide
astrocytoma
malignant glioma
anaplastic astrocytoma
astrocytoma, anaplastic

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 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.

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, 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.

Details
Treatment radiation therapy, Temozolomide, Veliparib
Clinical Study IdentifierNCT03581292
SponsorNational Cancer Institute (NCI)
Last Modified on17 January 2021

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Eligibility

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Inclusion Criteria

Is your age between 3 yrs and 25 yrs?
Gender: Male or Female
Do you have any of these conditions: Gliomas or Glioma or BRAF V600 Wild Type or Glioblastoma Multiforme or Astrocytoma or H3 K27M Negative?
Do you have any of these conditions: Glioblastoma Multiforme or H3 K27M Negative or BRAF V600 Wild Type or astrocytoma, anaplastic or Glioma or anaplastic astrocytoma or Gliomas or malign...?
Do you have any of these conditions: anaplastic astrocytoma or BRAF V600 Wild Type or glioblastoma or Gliomas or Astrocytoma or Glioma or malignant glioma or Glioblastoma Multiforme or H3...?
Do you have any of these conditions: High Grade Glioma or anaplastic astrocytoma or malignant glioma or Glioblastoma Multiforme or H3 K27M Negative or BRAF V600 Wild Type or astrocytoma, ...?
Do you have any of these conditions: High Grade Glioma or astrocytoma, anaplastic or Astrocytoma or anaplastic astrocytoma or malignant glioma or Glioma or H3 K27M Negative or BRAF V600 W...?
Do you have any of these conditions: Glioblastoma Multiforme or High Grade Glioma or anaplastic astrocytoma or Astrocytoma or glioblastoma or malignant glioma or astrocytoma, anaplastic o...?
Do you have any of these conditions: H3 K27M Negative or Glioma or High Grade Glioma or BRAF V600 Wild Type or Astrocytoma or glioblastoma or Gliomas or malignant glioma or Glioblastoma M...?
Do you have any of these conditions: malignant glioma or High Grade Glioma or astrocytoma, anaplastic or H3 K27M Negative or anaplastic astrocytoma or Gliomas or Glioblastoma Multiforme o...?
Do you have any of these conditions: anaplastic astrocytoma or Gliomas or malignant glioma or High Grade Glioma or glioblastoma or H3 K27M Negative or BRAF V600 Wild Type or astrocytoma, ...?
Do you have any of these conditions: Glioma or anaplastic astrocytoma or glioblastoma or Astrocytoma or BRAF V600 Wild Type or H3 K27M Negative or astrocytoma, anaplastic or Gliomas or Gl...?
Do you have any of these conditions: BRAF V600 Wild Type or Glioblastoma Multiforme or High Grade Glioma or H3 K27M Negative or astrocytoma, anaplastic or Astrocytoma or anaplastic astroc...?
Do you have any of these conditions: Gliomas or Glioma or astrocytoma, anaplastic or anaplastic astrocytoma or Astrocytoma or BRAF V600 Wild Type or malignant glioma or High Grade Glioma ...?
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)
to < 6 years: 0.8 (male and female) maximum serum creatinine (mg/dL)
to < 10 years: 1 (male and female) maximum serum creatinine (mg/dL)
to < 13 years: 1.2 (male and female) maximum serum creatinine (mg/dL)
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
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