{"doi":"10.1016/j.redox.2025.103895","title":"Phase IB trial of high dose ascorbic acid + nab-paclitaxel + cisplatin + gemcitabine in patients with untreated metastatic pancreatic cancer","abstract":"Preclinical studies suggest that cancer cells take up oxidized vitamin C (dehydroascorbate, DHA) via the GLUT1 transporter, leading to oxidative stress and glutathione depletion. This mechanism may offer a therapeutic strategy for KRAS-mutated cancers. This Phase IB trial evaluated high-dose intravenous ascorbic acid (AA) combined with nab-paclitaxel, cisplatin, and gemcitabine (NABPLAGEM) in patients with untreated metastatic pancreatic ductal adenocarcinoma (PDAC). Eligible patients (≥18 years, ECOG 0–1, measurable PDAC, adequate organ function) received AA (25, 37.5, or 56.25 g/m 2 twice weekly) plus NABPLAGEM on Days 1 and 8 of 21-day cycles. The primary endpoint was determining the maximum tolerated dose (MTD) of AA. Seventeen patients were enrolled (median age 63.9; 70.6% female; 82.4% white). No MTD was reached; AA up to 56.25 g/m 2 twice weekly was feasible. Patients on the lowest AA dose remained on treatment longer. Grade ≥3 treatment-related adverse events (TRAEs) included thrombocytopenia (82.4%), anemia (35.3%), neutropenia (29.4%), hypokalemia (29.4%), diarrhea (11.8%), and colitis (11.8%), with no significant differences between dose groups. Peak AA levels >20 mM were achieved in 57% of patients at the highest dose. Median progression-free survival (PFS) and overall survival (OS) were 7.1 and 14.2 months, respectively, with no significant differences by AA dose. Textural imaging showed decreased liver fat in 3 of 4 patients with baseline steatosis. High-dose AA with NABPLAGEM was tolerable in patients with advanced PDAC but did not improve disease response compared to historical data for chemotherapy alone. A separate study suggests AA may enhance gemcitabine and nab-paclitaxel efficacy without cisplatin. AA and cisplatin may have overlapping DNA-damaging effects, or differences in AA dosing frequency and exposure may influence outcomes - variables to consider in future trials. NCT03410030 • Pancreatic ductal adenocarcinoma tumors carry mutations in KRAS • KRAS mutations are associated with overexpression of the GLUT1 receptor • GLUT1 facilitates the uptake of ascorbic acid which can generate free radicals • Clinical trial, advanced pancreatic cancer, high dose ascorbic acid + chemotherapy","journal":"Redox Biology","year":2025,"id":579213,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9483,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT03410030"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1489840,"name":"S. Danielle. Legrand","orcid":null,"position":1,"is_corresponding":false},{"id":289280,"name":"Michael S. Gordon","orcid":"0000-0002-7679-9504","position":2,"is_corresponding":false},{"id":337069,"name":"Denise J. Roe","orcid":"0000-0001-6989-6579","position":3,"is_corresponding":false},{"id":513658,"name":"Betsy C. Wertheim","orcid":"0000-0003-3679-7405","position":4,"is_corresponding":false},{"id":252174,"name":"Kellen Olszewski","orcid":"0000-0001-9691-0831","position":5,"is_corresponding":false},{"id":108672,"name":"Joshua D. Rabinowitz","orcid":"0000-0002-1247-4727","position":6,"is_corresponding":false},{"id":80488,"name":"Ronald M. Evans","orcid":"0000-0002-9986-5965","position":7,"is_corresponding":false},{"id":80487,"name":"Michael Downes","orcid":"0000-0002-6351-9585","position":8,"is_corresponding":false},{"id":860816,"name":"Morgan Truitt","orcid":"0000-0001-7012-1228","position":9,"is_corresponding":false},{"id":633488,"name":"Ron Korn","orcid":null,"position":10,"is_corresponding":false},{"id":308164,"name":"Haiyong Han","orcid":"0000-0001-9031-9880","position":11,"is_corresponding":false},{"id":1489446,"name":"Max Miller","orcid":"0000-0002-4936-2243","position":12,"is_corresponding":false},{"id":323369,"name":"Michael T. Barrett","orcid":"0000-0002-5646-1530","position":13,"is_corresponding":false},{"id":1038318,"name":"David Propper","orcid":"0000-0002-4274-5460","position":14,"is_corresponding":false},{"id":87998,"name":"Daniel D. Von Hoff","orcid":"0000-0003-4723-7681","position":15,"is_corresponding":false},{"id":844157,"name":"Erkut Borazanci","orcid":"0000-0001-5136-5462","position":16,"is_corresponding":false},{"id":1431340,"name":"Gayle Jameson","orcid":"0000-0003-0987-5965","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41197185","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":[]}