Neuro-oncology · 2026
Phase I/II and window-of-opportunity study of pamiparib and metronomic temozolomide for recurrent isocitrate dehydrogenase mutant gliomas.
СтатьяКлиническое исследование I фазыКлиническое исследование II фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Schiff David, Ye Xiaobu, Li Jing, Ellingson Benjamin M, Wen Patrick Y, Walbert Tobias, Campian Jian, Nabors Louis B, Ozer Byram H, Desai Arati, Omuro Antonio, Desideri Serena, Danda Neeraja, Grossman Stuart, Bindra Ranjit S
Аннотация
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.
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.
Предметные рубрики MeSH
HumansTemozolomideFemaleGliomaIsocitrate DehydrogenaseMiddle AgedMaleBrain NeoplasmsAdultNeoplasm Recurrence, LocalMutationAntineoplastic Combined Chemotherapy ProtocolsAgedMaximum Tolerated DoseAdministration, MetronomicPrognosisFollow-Up StudiesYoung AdultSurvival RateAntineoplastic Agents, Alkylating