Phase IB trial of high dose ascorbic acid + nab-paclitaxel + cisplatin + gemcitabine in patients with untreated metastatic pancreatic cancer

Background 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). Methods Eligible patients (≥18 years, ECOG 0–1, measurable PDAC, adequate organ function) received AA (25, 37.5, or 56.25 g/m² 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. Results Seventeen patients were enrolled (median age 63.9; 70.6 % female; 82.4 % white). No MTD was reached; AA up to 56.25 g/m² 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. Conclusion 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. Trial registration NCT03410030.