2108 - CPI-613 (Devimistat) in Combination with Chemoradiation in Patients with Pancreatic Ductal Adenocarcinoma (PDAC): Results of the Phase I Clinical Trial

03:00pm - 04:00pm ET

Poster Hall - Exhibit Hall A

Screen: 31

POSTER

Presenter(s)

Mandana Kamgar, MD - Medical College of Wisconsin, Milwaukee, WI

M. Kamgar¹, H. Y. Khan², A. Aboukameel², S. K. Low¹, S. Bannoura², B. Y. Chung¹, A. Szabo¹, M. R. Farazi¹, M. N. Al Hallak², P. A. Philip^2,3, B. George⁴, K. Christians¹, D. B. Evans⁵, S. Tsai⁶, B. A. Erickson¹, J. M. Goldberg⁷, A. Azmi², and W. A. Hall¹; ¹Medical College of Wisconsin, Milwaukee, WI, ²Karmanos Cancer Institute, Detroit, MI, ³Henry Ford Health System, Detroit, MI, ⁴Mayo Clinic Comprehensive Cancer Center, Rochester, MN, ⁵Medical College of Wisconsin Department of Surgery, Milwaukee, WI, ⁶The James Gastrointestinal and Colorectal Cancer Center, Columbus, OH, ⁷Cornerstone Pharmaceuticals, Cranbury, NJ

Purpose/Objective(s):

In PDAC, local tumor progression is a major cause of patient morbidity and mortality. Metabolic reprogramming and heightened mitochondrial activity are known contributors to chemo- and radio-resistance. Devimistat, a lipoic acid analog, selectively targets and inhibits the Krebs cycle within cancer cells and demonstrated a synergistic effect when paired with gemcitabine and radiation (GemRT) in preclinical models. Given these findings, we performed a single-center, open-label, phase I prospective study to test the hypothesis that devimistat can be safely used in combination with standard of care GemRT.

Materials/Methods:

Adult patients with inoperable PDAC that, by institutional multidisciplinary review, were considered to benefit from definitive local control of the primary tumor and were not considered suitable candidates for ablative doses of radiation, due to tumor anatomy or medical condition, were included. All patients received = 16 weeks of systemic chemotherapy with at least stable disease per imaging, prior to enrollment in the study. Devimistat was administered once weekly by intravenous infusion over approximately 2 hours at a starting dose of 500 mg/m2, and the dose was escalated using a Bayesian optimal interval design. Gemcitabine was given once weekly at a 400 mg/m2 dosage and intensity-modulated radiation therapy as 45-54 Gy in 25-30 fractions, with up to five fractions given per week. The primary objective was to determine the maximum tolerated dose (MTD) of devimistat when used concomitantly with GemRT.

Results:

Between November 2022 and March 2024, 8 patients were enrolled in the study. The median age at enrollment was 71 (minimum of 60; maximum of 80), and 6 (75%) were male. Five patients were enrolled in cohort 1 (500 mg/m2), with the other 3 in cohort 2 (1000 mg/m2). All patients finished treatment on the study per protocol. None of the patients experienced dose-limiting toxicities. All treatment-related toxicities were expected from GemRT (grade 3+ per CTCAE v5.0: 8 [100%] lymphopenia, 3 [38%] thrombocytopenia, 1 [11%] anemia, 1 [11%] leukopenia, and 1 [11%] hypokalemia), were unrelated to the CPI-613, and were manageable. The MTD of devimistat in combination with GemRT could not be determined in our study, as the study was terminated early because the manufacturer ceased drug production. Median progression-free survival (PFS) was 9.2 months and median local PFS was 16 months.

Conclusion:

The combination of devimistat and GemRT was well tolerated. The extent to which devimistat contributed to the local control of disease remains unclear, but the combination resulted in remarkable local control of disease. The results of the secondary endpoint, patient-related quality of life, and the exploratory endpoint, changes in plasma metabolomics after devimistat-GemRT, will be presented at the meeting.