Phase I/II and window-of-opportunity study of pamiparib and metronomic temozolomide for recurrent isocitrate dehydrogenase mutant gliomas
Recommended Citation
Schiff D, Ye X, Li J, Ellingson BM, Wen PY, Walbert T, Campian J, Burt Nabors L, Ozer BH, Desai A, Omuro A, Desideri S, Danda N, Grossman S, and Bindra RS. Phase I/II and Window-of-Opportunity Study of Pamiparib and Metronomic Temozolomide for Recurrent IDH Mutant Gliomas. Neuro Oncol 2025;28(2):485-494.
Document Type
Article
Publication Date
2-1-2026
Publication Title
Neuro Oncol
Keywords
Humans, Temozolomide, Female, Glioma, Isocitrate Dehydrogenase, Middle Aged, Male, Brain Neoplasms, Adult, Neoplasm Recurrence, Local, Mutation, Antineoplastic Combined Chemotherapy Protocols, Aged, Maximum Tolerated Dose, Administration, Metronomic, Prognosis, Follow-Up Studies, Young Adult, Survival Rate, Antineoplastic Agents, Alkylating
Abstract
BACKGROUND: Preclinical studies demonstrate activity of poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors in isocitrate dehydrogenase (IDH) mutant gliomas. We investigated safety, tolerability, pharmacokinetics, and efficacy of the PARP inhibitor pamiparib in conjunction with metronomic low-dose temozolomide in patients with recurrent IDH mutant (IDHmt) gliomas in a multicenter Phase I/II/window of opportunity study.
METHODS: Patients received pamiparib in conjunction with daily temozolomide. Following Phase I determination of maximum tolerated dose (MTD), we enrolled 2 patient cohorts (Arm A, multiple prior chemotherapy regimens; Arm B, single prior regimen) in a 2-stage design. Exploratory cohorts examined grade 4 IDHmt patients and intratumoral pharmacokinetics of pamiparib. The primary endpoint was objective radiographic response (ORR) by RANO criteria.
RESULTS: Sixty-six subjects were enrolled. We established pamiparib 60 mg twice daily with temozolomide 20 mg daily as the phase II dose. In non-enhancing and enhancing tumor, pamiparib exhibited an unbound tumor/plasma ratio of 0.92 and 0.98, respectively. 0/15 Arm A and 1/24 Arm B patients achieved a centrally confirmed partial response. Median progression-free survival for Arm A was 5.9 months (95% CI, 1.2-14.8 months), and for Arm B was 9.7 months (95% CI, 5.7-21.7 months). Grade 3+ anemia and neutropenia affected 24% and 33% of patients, respectively. Twenty-two of 66 patients (33.3%) discontinued study treatment for reasons other than tumor progression.
CONCLUSIONS: Pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors. While some patients achieved prolonged progression-free survival, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial and impacted long-term tolerability.
Medical Subject Headings
Humans; Temozolomide; Female; Glioma; Isocitrate Dehydrogenase; Middle Aged; Male; Brain Neoplasms; Adult; Neoplasm Recurrence, Local; Mutation; Antineoplastic Combined Chemotherapy Protocols; Aged; Maximum Tolerated Dose; Administration, Metronomic; Prognosis; Follow-Up Studies; Young Adult; Survival Rate; Antineoplastic Agents, Alkylating
PubMed ID
41099363
ePublication
ePub ahead of print
Volume
28
Issue
2
First Page
485
Last Page
494
