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

• ClinicalTrials.gov Identifier: NCT03581292
• Recruitment Status: Active, not recruiting
• First Posted: July 10, 2018
• Results First Posted: April 23, 2024
• Last Update Posted: May 20, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: July 4, 2018
• First Posted Date: July 10, 2018
• Results First Submitted Date: February 22, 2024
• Results First Posted Date: April 23, 2024
• Last Update Posted Date: May 20, 2024
• Actual Study Start Date: November 6, 2018
• Actual Primary Completion Date: March 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 28, 2024)

Event Free Survival (EFS) [ Time Frame: Up to 2 years ]

Compare event free survival to historical data for each stratum. Analysis will be based on a 2-sample, 1 sided logrank test. EFS is measured from time of enrollment to the date of first documented progression, second malignancy, or date of death from any cause, whichever comes first. Subjects who do not have any event will be censored at the last follow-up date.

Original Primary Outcome Measures (submitted: July 4, 2018)

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.

Current Secondary Outcome Measures (submitted: March 28, 2024)

• Objective Response [ Time Frame: Anytime during treatment (up to 1 year from enrollment) ]
  Estimate the objective response rate in patients with measurable disease. The 95% confidence interval will be calculated by Clopper-Pearson method. Objective responses are defined as patients who achieved complete response or partial response anytime during treatment. Tumor response criteria are determined by changes in size using the longest tumor dimension, and its perpendicular. Either T1, T2 weighted/FLAIR images are used - whichever gives the best estimate of tumor size. Complete Response (CR): Disappearance of all target lesions; Partial response (PR): >=50% decrease in the sum of the products of the two perpendicular diameters of target lesions, compared to baseline measurement. Objective Response = CR + PR.
• Overall Survival (OS) [ Time Frame: Up to 2 years ]
  The Kaplan-Meier method will be used to estimate the 2-year overall survival for each stratum. OS is measured from time of enrollment to the date of death from any cause. Subjects who do not have any event will be censored at the last follow-up date.

Original Secondary Outcome Measures (submitted: July 4, 2018)

• Objective response (OR) [ Time Frame: Up to 5.5 years ]
• Overall survival (OS) [ Time Frame: Up to 5.5 years ]

Current Other Pre-specified Outcome Measures (submitted: February 22, 2024)

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, 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.

Original Other Pre-specified Outcome Measures (submitted: July 4, 2018)

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.

Descriptive Information

• Brief Title: 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
• Brief 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.

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, 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Anaplastic Astrocytoma
• Glioblastoma
• Malignant Glioma

Intervention

• Radiation: Radiation Therapy
  Undergo radiation therapy
  Other Names:

  • Cancer Radiotherapy
  • Energy Type
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
• Drug: Temozolomide
  Given PO
  Other Names:

  • CCRG-81045
  • Gliotem
  • 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
  • Temizole
  • Temodal
  • Temodar
  • Temomedac
  • TMZ
• Drug: Veliparib
  Given PO
  Other Names:

  • ABT-888
  • PARP-1 inhibitor ABT-888

Study Arms

Experimental: Treatment (radiation therapy, veliparib, temozolomide)

CHEMORADIOTHERAPY PHASE: Patients 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, patients receive veliparib PO BID and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.

Interventions:

• Radiation: Radiation Therapy
• Drug: Temozolomide
• Drug: Veliparib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 19, 2023): 38
• Original Estimated Enrollment (submitted: July 4, 2018): 115
• Estimated Study Completion Date: September 22, 2024
• Actual Primary Completion Date: March 31, 2023 (Final data collection date for primary outcome measure)

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

  • Please note Stratum 1 was closed to accrual on January 24, 2020
• 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 glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
• 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 surgery (Day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years to 25 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, New Zealand, Puerto Rico, United States

Administrative Information

• NCT Number: NCT03581292
• Other Study ID Numbers: NCI-2018-01361; NCI-2018-01361 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ACNS1721 ( Other Identifier: Children's Oncology Group ); ACNS1721 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Matthias A Karajannis; Children's Oncology Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: January 2024