Abstract CT080: A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic ductal adenocarcinoma
Authors: Kamgar Mandana , Khan Husain Yar , Aboukameel Amro , Bannoura Sahar F. , Chung Brian Y. , Szabo Aniko , Li Yiwei , Hallak Mohammed Najeeb Al , Philip Philip A. , George Ben , Christians Kathleen K. , Evans Douglas B. , Tsai Susan , Erickson Beth , Goldberg John M. , Azmi Asfar S. , Hall William A. 
Published: April 2024

Abstract
Background: Local tumor progression is a cause of significant mortality and morbidity in patients (pts) with inoperable pancreatic ductal adenocarcinoma (PDAC). Effective approaches to achieve durable local control are urgently needed. Metabolic reprogramming and enhanced mitochondrial function are known contributors to chemo- and radio-resistance in PDAC. CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in combination with gemcitabine and radiation (gem-RT). We initiated a phase I study (NCT05325281) to determine the maximum tolerated dose (MTD) of CPI-613 when used with gem-RT. Here, we present the results from the first cohort of this study.
Methods: Adult pts with inoperable PDAC that, by institutional multidisciplinary review, were considered to benefit from definitive local control of the primary tumor were eligible for the study. CPI-613 was administered once weekly by intravenous infusion over ~ 2 hours at a starting dose of 500 mg/m2 and dose-escalated using a Bayesian optimal interval design. Gemcitabine was given once weekly at 400 mg/m2 and RT at 45-54 Gray (Gy) in 25-30 fractions.
Results: By Jan 7, 2024, six pts were enrolled, and five completed the treatment and dose-limiting toxicity (DLT) period.
Table 1 describes the characteristics of these five pts. As CPI-613 was not associated with any additional toxicities, specifically cytopenia(s), after the first two pts, the study protocol was amended to allow CPI-613 to be administered on weeks gemcitabine was held for cytopenia(s). The study, therefore, enrolled five pts in the first cohort. All pts received ≥ 16 weeks of systemic chemotherapy with at least stable disease per imaging prior to enrollment. None of the pts experienced DLTs. All treatment-related toxicities were expected from gem-RT, unrelated to CPI-613, and manageable. The trial is currently enrolling pts in the second cohort (CPI-613 dose of 1000 mg/m2).
Conclusions: CPI-613 combined with gem-RT was safe and well tolerated at a dose of 500 mg/m2. Recruitment to the study is ongoing to determine the MTD of CPI-613 in combination with gem-RT.
Table 1. Characteristic of Patients Sex Race Age ECOG Stage Prior chemotherapy Chemotherapy duration (weeks) M W 67 1 LA FFX 16 M W 64 1 LA GnP 35 M W 73 1 BR* GnP 16 M B 71 1 LA GnP 27 M W 80 1 Oligometastatic** GnP 18 * Medically inoperable ** Two lung metastases treated with stereotactic body radiation therapy (SBRT); BR: Borderline resectable; B: Black; FFX: FOLFIRINOX; GnP: Gemcitabine/Nab-paclitaxel; LA: Locally advanced. M: Male; W: White
Citation Format: Mandana Kamgar, Husain Yar Khan, Amro Aboukameel, Sahar F. Bannoura, Brian Y. Chung, Aniko Szabo, Yiwei Li, Mohammed Najeeb Al Hallak, Philip A. Philip, Ben George, Kathleen K. Christians, Douglas B. Evans, Susan Tsai, Beth Erickson, John M. Goldberg, Asfar S. Azmi, William A. Hall. A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT080.