{"doi":"10.1093/noajnl/vdad087","title":"Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas","abstract":"Abstract 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.","journal":"Neuro-Oncology Advances","year":2023,"id":364239,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1119462,"name":"M. Kelly Nicholas","orcid":null,"position":1,"is_corresponding":false},{"id":844442,"name":"Richard A. Peterson","orcid":"0000-0002-0431-6913","position":2,"is_corresponding":false},{"id":1119035,"name":"Stefania Maraka","orcid":"0000-0001-5617-3320","position":3,"is_corresponding":false},{"id":1119036,"name":"Li Liu","orcid":"0000-0003-2681-8487","position":4,"is_corresponding":false},{"id":1099266,"name":"James H. Fischer","orcid":"0000-0001-5570-7562","position":5,"is_corresponding":false},{"id":273500,"name":"Jeffrey S. Wefel","orcid":"0000-0003-3584-023X","position":6,"is_corresponding":false},{"id":612795,"name":"Timothy M. Fan","orcid":"0000-0003-2510-7050","position":7,"is_corresponding":false},{"id":396878,"name":"Tracy D. Vannorsdall","orcid":"0000-0003-3103-1371","position":8,"is_corresponding":false},{"id":1119463,"name":"Meredith Jones Russell","orcid":null,"position":9,"is_corresponding":false},{"id":1119037,"name":"Michaella Iacoboni","orcid":"0009-0005-9514-2486","position":10,"is_corresponding":false},{"id":689874,"name":"Theodore M. Tarasow","orcid":"0000-0003-0784-1219","position":11,"is_corresponding":false},{"id":313454,"name":"Paul J. Hergenrother","orcid":"0000-0001-9018-3581","position":12,"is_corresponding":false},{"id":328529,"name":"Arkadiusz Z. Dudek","orcid":"0000-0002-9114-8945","position":13,"is_corresponding":false},{"id":911286,"name":"Oana C. Danciu","orcid":"0000-0003-4487-9136","position":14,"is_corresponding":false},{"id":62902,"name":"Matthias Holdhoff","orcid":"0000-0002-3285-3484","position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":null,"created_at":"2026-07-19T01:14:36.728255Z","pmid":"37554223","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}