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Updated: Jul 19, 2025
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with
Matthias Holdhoff1, M Kelly Nicholas2, Richard A Peterson3
1Department of Oncology, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
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 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 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.
Insights
Procaspase-activating compound-1 (PAC-1) combined with temozolomide (TMZ) showed good tolerability in recurrent high-grade astrocytoma patients. Further dose escalation is recommended before efficacy studies.
Area of Science:
- Neuro-oncology
- Translational oncology
- Clinical pharmacology
Background:
- Procaspase-3 (PC-3) is overexpressed in gliomas, making targeted activation a potential therapeutic strategy.
- Combining PC-3 activation with chemotherapy like temozolomide (TMZ) shows preclinical promise for high-grade gliomas.
- This study evaluated the safety and tolerability of procaspase-activating compound-1 (PAC-1) with TMZ in recurrent high-grade astrocytomas.
Purpose of the Study:
- To determine the safety and tolerability of PAC-1 in combination with TMZ.
- To assess dose-limiting toxicities and neurocognitive function (NCF) during treatment.
- To establish a recommended dose for future efficacy studies.
Main Methods:
- A modified-Fibonacci dose-escalation 3+3 design was employed.
- PAC-1 was administered orally at escalating doses (DL1=375 mg) on days 1-21, with TMZ (150 mg/m²/5 days) per 28-day cycle.
- Dose-limiting toxicity and NCF were monitored throughout the study.
Main Results:
- Eighteen patients (13 GBM, IDH-wild type) were enrolled; dose escalation stopped at DL3 (PAC-1, 625 mg) due to funding.
- The combination was generally well tolerated up to 625 mg PAC-1; Grade 3 toxicities included elevated liver transaminases and headache.
- Two partial responses were noted in GBM patients with methylated MGMT promoter; NCF showed no clear dose-related decline.
Conclusions:
- The combination of PAC-1 and TMZ is well-tolerated in recurrent high-grade astrocytomas up to 625 mg PAC-1 daily.
- The maximum tolerated dose was not reached, suggesting potential for higher doses.
- Further dose escalation of PAC-1 with TMZ is recommended prior to efficacy trials.
