Abstract PO-015: A phase Ib/II trial of high dose ascorbic acid (AA) + paclitaxel protein bound (PP) + cisplatin (C) + gemcitabine (G) in patients (pts) with previously untreated metastatic pancreatic cancer (MPC)
Authors: Jameson Gayle S. , Borazanci Erkut H. , Von Hoff Daniel D. , Rabinowitz Joshua D. , Gordon Michael S. , LeGrand Sarah D. , Snyder Courtney , Ansaldo Karen , Roe Denise J. , Han Haiyong 
Published: November 2021

Abstract
Background: Increasing evidence suggests that high concentrations of AA (vitamin C) can decrease the growth of aggressive tumors, including Ras-mutant tumors. Based on the unmet need in MPC, its high frequency of Ras mutations, and prior work combining PP +C +G in pts with MPC (response rate of 70.5%, median survival 16.4 mos), we explored the addition of AA to that regimen. Pre and post treatment biopsies for biomarkers and digital spacial profiling are also being performed. Methods: This pilot trial utilized a 3 + 3 design for dose escalation of AA. Eligibility criteria included untreated stage IV MPC, ECOG 0-1, and measurable disease. Excluded were pts with a G6PD deficiency, renal oxalate stones, or need of capillary blood glucose monitoring as AA causes false low readings. The primary objective of the phase 1b was to determine the maximum tolerated dose (MTD) of AA in combination with PP +C +G in pts with MPC. Exploratory objectives included analysis of tumor texture on radiologic scans as an imaging biomarker for response; correlation between peak plasma levels of AA and response to treatment; potential biomarkers in the tumor including tumor immune cell infiltration, stromal activation, stem call enumeration; change in numbers of circulating tumor stem cells and macrophage lineage changes. Results: As of 7/2021, the phase Ib enrollment in this study has been completed. Six pts were treated in the cohort of AA 25 gm/m2, 4 pts at AA 37.5 gm/m2, and 7 pts at 56.25 gm/m2. The majority of all reported AEs were grades 1-2. The most common AEs related to study treatment were: platelet count decrease (70.6%), diarrhea (70.6%), hypomagnesemia (52.9%), dysgeusia (47.1%), peripheral sensory neuropathy (47.1%), nausea (35.3%), fatigue (35.3%), neutrophil count decreased (35.3%), and hypokalemia (35.3%). Of the 17 pts enrolled, 15 were evaluable. Response by RECIST 1.1 is 11 PR (73.3%), 2 SD (13.3%), 2 PD (13.3%). Evaluation of median PFS and OS is ongoing. Conclusions: This study has a high response rate of 73%. Most pts in all AA dosing cohorts experienced a brisk response to therapy. AA did not appear to add toxicities compared to historical AE data of PP +C +G and was well tolerated in all dose cohorts. The MTD of AA was not reached in the 56.25 gm/m2 cohort. The protocol allowed for an additional dose escalation of AA to 75 gm/m2. However, all pts in the 56.25 gm/m2 cohort achieved our goal of peak plasma AA levels of &gt; 20 mM so the study was closed to enrollment. Quality of life measures, tumor tissue and blood sample analyses are underway. Supported by SU2C, Cancer Research UK, Lustgarten Foundation, Destroy Pancreatic Cancer & the Young family.
Citation Format: Gayle S. Jameson, Erkut H. Borazanci, Daniel D. Von Hoff, Joshua D. Rabinowitz, Michael S. Gordon, Sarah D. LeGrand, Courtney Snyder, Karen Ansaldo, Denise J. Roe, Haiyong Han. A phase Ib/II trial of high dose ascorbic acid (AA) + paclitaxel protein bound (PP) + cisplatin (C) + gemcitabine (G) in patients (pts) with previously untreated metastatic pancreatic cancer (MPC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-015.