Phase I dose escalation study of procaspase-activating compound-1 (PAC-1) in combination with temozolomide in patients with recurrent high-grade astrocytomas

Matthias Holdhoff, M Kelly Nicholas, Richard a Peterson, Stefania Maraka, Li C. Liu, James H Fischer, Jeffrey S Wefel, Timothy M Fan, Tracy Vannorsdall, Meredith Russell, Michaella Iacoboni, Theodore M Tarasow, Paul J Hergenrother, Arkadiusz Z Dudek, Oana C Danciu

Research output: Contribution to journalArticlepeer-review


Background: Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-Activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. Methods: A modified-Fibonacci dose-escalation 3a+a3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1a=a375 mg) on days 1-21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Results: Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Conclusions: Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

Original languageEnglish (US)
Article numbervdad087
JournalNeuro-Oncology Advances
Issue number1
StatePublished - 2023


  • PAC-1
  • recurrence
  • temozolomide
  • astrocytoma
  • glioblastoma
  • Procaspase activating compound 1
  • Procaspase-Activating compound-1

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Surgery


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