In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT163-CT163
Abstract:
Background Increasing evidence suggests that 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. The reason for the cancer-specific toxicity of AA is incompletely understood. One possibility is that AA targets cancer cells due to their having larger labile iron pools. Another is that cancer cells selectively take up the oxidized form of AA, dehydroascorbate, via the GLUT1 glucose transporter, causing glutathione (GSH) depletion, intracellular ascorbate accumulation, inactivation of glyceraldehyde 3-phosphate dehydrogenase, and energetic crisis selectively in glycolytic, GLUT1-expressing cancer cells. Based on the unmet medical need in MPC, its high frequency of Ras mutations, and prior work combing PP + C + G showing promising results in 24 pts with MPC with a response rate of 70.5%, median survival 16.4 mos, [J Clin Oncol 35, 2017 (suppl 4S; abstract 341)], here we are exploring the addition of AA to PP + C + G. Methods This Phase Ib/II pilot trial utilizes a 3 + 3 design for dose escalation of AA. Primary objective(s): Phase Ib - to determine the maximum tolerated dose (MTD) of AA with PP + C + G; phase II - to determine the preliminary efficacy (disease control rate of CR+ PR+ SD x 18 weeks) of the combination with AA at MTD in pts with MPC. Exploratory objectives include analysis of tumor texture on radiologic scans as an imaging biomarker for response, biologic, pathologic and outcome measures; correlation between peak plasma levels of AA and response to treatment; potential biomarkers in the tumor including tumor immune cell infiltration, stromal activation, stem cell enumeration; changes in numbers of circulating tumor stem cells and macrophage lineage changes. #NCT03410030 Eligibility criteria include stage IV MPC, no prior treatment for MPC, ECOG 0 -1, and measurable disease. Excluded are pts with a G6PD deficiency, history of renal oxalate stones, or need of frequent capillary blood glucose monitoring as AA causes false low readings. Planned sample size is up to 24 pts in Phase Ib, up to 21 pts in Phase II. Doses are PP 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2 on days 1 & 8 of a 21 day cycle. AA infusions are given on days 1, 3, 8, 10, 15, and 17 of a 21-day cycle. The AA dose for phase II will be determined in the Phase 1b study based on tolerability of AA at 25, 37.5, 56.25 or 75 gm/m2. Tumor tissue analysis will be done on pre and optional post treatment tumor biopsies. Trial opened to enrollment 4/2018. As of 1/2019, 5 pts have been treated in the AA 25 gm/m2 cohort. Supported by SU2C, Cancer Research UK, Lustgarten Foundation & Destroy Pancreatic Cancer Citation Format: Gayle S. Jameson, Erkut H. Borazanci, Joshua D. Rabinowitz, David Propper, Karen Ansaldo, Denise J. Roe, Daniel D. Von Hoff. A Phase Ib/II trial of high dose ascorbic acid (AA) + paclitaxel protein bound (PP) + cisplatin (C) + gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (MPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT163.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-CT163
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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