A phase I open-label, dose-escalation study of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.

Abstract

323 Background: IV ascorbic acid (vit c) is a prodrug for steady state formation of ascorbate radical (Asc·-) in the extracellular space resulting in sustained production of H2O2 leading to selective killing of tumor cells by a pro-oxidative mechanism. In preclinical models of panc cancer pharmacologic concentrations of Asc·- with gem resulted in a synergistic cytotoxic response. We conducted a Phase I dose escalation study of IV ascorbic acid with gem plus erlotinib chemo as first line therapy in panc cancer. Methods: Patients with adv panc cancer were enrolled using a standard 3+3+3 design to assess the safety and pharmacology of IV vit c in combo with gem and erlotinib. Cohort 1 received 50 g IV vit c and subsequent cohorts were escalated by 25 g to a final dose of 100 g. Pts were given 3 infusions of vit c per week on separate days for 8 w (1 cycle). IV gem was given on day 1 (1000 mg/m2) and weekly for 7 w followed by a rest week. Oral erlotinib (100 mg) was given daily for 8 w. Trt continued until disease progression or toxicity. Steady state ascorbate PK was assessed in cohorts 2 and 3. AEs were determined using NCI CTCAE v3.0. Tumor responses were assessed per RECIST. Results: Of 14 pts enrolled, 9 or 3 per cohort completed the study. Median age was 64 years. 5 pts did not complete trt (2 discontinued, 3 died). 9 pts completed at least 24 ascorbic acid trts and 1 cycle of gem/erlotinib therapy. There were 24 AEs. These included 15 non-serious AEs and 8 SAEs. The most frequent AEs were grade 1/2 thrombocytopenia. Other grade 1/2 events included anemia, hyperglycemia, abd discomfort, ascites and infection. SAEs: 2 grade 3 heme, 1 grade 3 GI, 1 grade 3 infectious and 2 grade 4 thrombosis. Plasma asc levels were 25.3 - 31.9 mm/L for pts receiving the 100g dose. 8 of the 9 pts had a reduction in the panc primary with 1 pt having no change at 8 w. For non-target lesions, 2 had PD and 7 had SD per RECIST. Conclusions: Overall safety data do not reveal AEs other than those expected in patients with metastatic panc cancer and/or treatment with gem and erlotinib. Addition of IV ascorbic acid did not increase toxicity. Preliminary efficacy results are encouraging. A phase II study is planned.