Abstract B27: A phase Ib/II trial of high-dose (HD) ascorbic acid (AA) + paclitaxel protein bound (PP) + cisplatin (C) + gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (MPC)
Authors: Jameson Gayle S. , Borazanci Erkut H. , Rabinowitz Joshua , Ansaldo Karen , LeGrand Sarah , Propper David , Snyder Courtney , Gordon Michael , Roe Denise , Hoff Daniel D. Von 
Published: March 2020

Abstract
Introduction: Based on the unmet medical need in MPC, its high frequency of Ras mutations, and prior work combining PP + C + G demonstrating an objective response rate of 70.5% in 24 pts with MPC with a median survival of 16.4 mos (J Clin Oncol 2017;35 [suppl 4S; abstract 341]), we are exploring the addition of HD AA to PP + C + G (#NCT03410030).
Background: Increasing evidence suggests that HD AA (vitamin C) can decrease the growth of aggressive tumors, including Ras-mutant tumors, by inducing oxidative stress (Chen et al., PNAS 2008; Yun et al., Science 2015; Shoenfeld et al., Cancer Cell 2017). Despite the potential to produce toxic radicals, high-dose AA has generally been well tolerated in animals and humans, including in combination with chemotherapy.
Methods: This phase Ib/II trial uses a 3 + 3 dose escalation of AA. Eligibility criteria include pts with previously untreated stage IV MPC, ECOG 0-1, and measurable disease. Excluded are pts with a G6PD deficiency, history of renal oxalate stones, and need of frequent capillary blood glucose monitoring as AA causes false low readings. Doses are PP 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2 on days 1 and 8 of each 21-day cycle. AA infusions are given on days 1, 3, 8, 10, 15, and 17 every 21 days. We plan on studying up to 4 dose levels of AA including 25, 37.5, 56.25, and 75 gm/m2, seeking to determine the recommended phase 2 dose (RP2D). Tissue analysis is being done on pre- and optional post-treatment tumor biopsies. Primary objective(s): phase Ib—to determine the maximum tolerated dose (MTD) and RP2D of AA with PP + C + G; phase II—to determine the efficacy (disease control rate of CR+ PR+ SD x 18 weeks) of the combination at the RP2D in pts with MPC. Exploratory objectives include quantitative textural analysis, correlation between peak plasma levels of AA and treatment response, and potential biomarkers in the tumor. Planned sample size is up to 24 pts in phase Ib and up to 21 pts in phase II.
Results: As of 6/23/19, 9 pts have been treated. Grade (gr) ≥ 3 treatment-related adverse events are thrombocytopenia, gr 3 (44%), gr 4 (11%) with no serious bleeding events; neutropenia gr 3 (22%); anemia gr 3 (22%); hypokalemia gr 3 (22%); diarrhea gr 3 (11%); hypomagnesemia gr 3 (11%); and hypophosphatemia gr 3 (11%). In the 7 response-evaluable pts (baseline and ≥ 1 follow-up CT scan), all pts have experienced a disease response to therapy with substantial decrease in tumor size and decline in tumor markers. It is too early in the trial to determine complete and partial response rates.
Conclusion: Through the first two dose levels of AA we have observed good tolerability and preliminary evidence of high levels of antitumor activity. Dose escalation is continuing. (Supported by SU2C, Cancer Research UK, Lustgarten Foundation & Destroy Pancreatic Cancer.)
Citation Format: Gayle S. Jameson, Erkut H. Borazanci, Joshua Rabinowitz, Karen Ansaldo, Sarah LeGrand, David Propper, Courtney Snyder, Michael Gordon, Denise Roe, Daniel D. Von Hoff. A phase Ib/II trial of high-dose (HD) ascorbic acid (AA) + paclitaxel protein bound (PP) + cisplatin (C) + gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (MPC) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B27.