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Clinical Trial
. 2025 May 15;27(4):1092-1101.
doi: 10.1093/neuonc/noae247.

Phase 2 trial of veliparib, local irradiation, and temozolomide in patients with newly diagnosed high-grade glioma: a Children's Oncology Group study

Matthias A Karajannis  1 , Arzu Onar-Thomas  2 , Tong Lin  2 , Patricia A Baxter  3 , Daniel R Boué  4 , Bonnie L Cole  5 , Christine Fuller  6 , Sofia Haque  7 , Nada Jabado  8 , John T Lucas Jr  9 , Shannon M MacDonald  10 , Celeste Matsushima  11 , Namrata Patel  12 , Christopher R Pierson  4 , Mark M Souweidane  13   14 , Diana L Thomas  4 , Michael F Walsh  1 , Wafik Zaky  15 , Sarah E S Leary  16 , Amar Gajjar  17 , Maryam Fouladi  18 , Kenneth J Cohen  19
Affiliations
Clinical Trial

Phase 2 trial of veliparib, local irradiation, and temozolomide in patients with newly diagnosed high-grade glioma: a Children's Oncology Group study

Matthias A Karajannis et al. Neuro Oncol. .

Abstract

Background: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.

Methods: We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations, compared to patient-level data from historical cohorts with closely matching clinical and molecular features. Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant).

Results: Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year event-free survival (EFS) was 23% (standard error, SE = 9%) and the 1-year overall survival (OS) was 64% (SE = 10%). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year EFS was 57% (SE = 13%) and 1-year OS was 93% (SE = 0.7%).

Conclusions: Rapid central pathology review and molecular testing for eligibility were feasible. The protocol therapy including radiation, veliparib, and temozolomide was well tolerated but failed to improve outcomes compared to clinically and molecularly matched historical control cohorts treated with higher doses of alkylator chemotherapy.

Clinicaltrials.gov identifier: NCT03581292 (first posted: July 10, 2018).

Keywords: clinical trial; glioblastoma; high-grade glioma; temozolomide; veliparib.

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Conflict of interest statement

A.O.T. reports grants and contracts from Novocure, Apexigen, Senhwa, Novartis, Incyte, YmAbs, MimiVax, Pfizer, and Trevir, as well as Advisory Board participation for the Sunshine Project at Moffitt Cancer Center. C.F. reports payment for expert testimony from Carlton Fields, LLP and Greenberg Traurig, LLP. A.G. reports Data Safety Monitoring and Advisory Board participation for Day One Biopharmaceuticals and Bristol-Myers Squibb. S.M.M. reports support for attending meetings and travel from icotec Medical, Inc., as well as expert consultation and advice for Cleveland Clinic and Yale. M.M.S. reports grants and contracts from the American Cancer Society and St. Baldrick’s Foundation, support for attending meetings and travels from theChildren’s Brain Tumor Project, Advisory Board participation at IronMatt/The Matthew Larson Foundation and Brain Tumor Foundation, as well as leadership or fiduciary role at the NCI Brain Malignancy Steering Committee, Pediatric Brain Tumor Consortium, and Children’s Brain Tumor Project. M.F. reports serving as Chair of the CNS COG Committee and CONNECT Consortium. All other authors have no conflicts of interest related to this research to disclose.

References

    1. Jones C, Karajannis MA, Jones DTW, et al. Pediatric high-grade glioma: Biologically and clinically in need of new thinking. Neuro Oncol. 2017;19(2):153–161. - PMC - PubMed
    1. Cohen KJ, Pollack IF, Zhou T, et al. Temozolomide in the treatment of high-grade gliomas in children: A report from the Children’s Oncology Group. Neuro Oncol. 2011;13(3):317–323. - PMC - PubMed
    1. Jakacki RI, Cohen KJ, Buxton A, et al. Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: A report of the Children’s Oncology Group ACNS0423 study. Neuro Oncol. 2016;18(10):1442–1450. - PMC - PubMed
    1. Lulla RR, Buxton A, Krailo MD, et al. Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children’s Oncology Group Study. Neurooncol. Adv. 2024;6(1):vdae035. - PMC - PubMed
    1. Pollack IF, Boyett JM, Yates AJ, et al.; Children's Cancer Group. The influence of central review on outcome associations in childhood malignant gliomas: Results from the CCG-945 experience. Neuro Oncol. 2003;5(3):197–207. - PMC - PubMed

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