Devimistat With Gemcitabine and Cisplatin Advances to Phase 2 in Biliary Tract Cancer

Following the successful completion of the phase 1b analysis, the study of devimistat in combination with gemcitabine and cisplatin in biliary tract cancer has moved on to phase 2.

The phase 1b BilT-04 study of devimistat (CPI-613) in combination with gemcitabine and cisplatin to treat patients with biliary tract cancer has been completed and is moving forward to phase 2, according to a press release from Rafael Pharmaceuticals, Inc.1

Phase 1b investigated the incidence of dose-limiting toxicity in patients with biliary tract cancer treated with devimistat in combination with gemcitabine and cisplatin. The purpose behind this end point was to determine the maximum-tolerated dose of devimistat using the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Twenty patients were included in the phase 1b portion of the study.2

“The phase 1b part of the trial has successfully identified the recommended phase 2 dose of CPI-613 when given in combination with gemcitabine and cisplatin in this patient population. The 2:1 randomized phase 2 part of the trial has already started enrolling patients and will now determine the efficacy of devimistat at this maximum tolerated dose in combination with gemcitabine and cisplatin as compared with the combination chemotherapy alone,” said Vaibhav Sahai, MBBS, MS, primary investigator and medical oncologist at the University of Michigan Rogel Cancer Center, in the press release.

Prior research has shown a 26% objective response rate (ORR) with the combination of gemcitabine and cisplatin in this patient population. Further, the chemotherapy doublet can achieve a median overall survival (OS) of 11.7 months. Taken together with devimistat’s mechanism of action as an inhibitor of the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle, investigators hypothesized that the addition of devimistat to gemcitabine and cisplatin will improve both responses and survival.3

BilT-04 is 80% powered to detect either a 25% ORR or 43% ORR with a one-sided alpha of 0.05 to determine the efficacy of therapy in the devimistat arm. To test the theory, approximately 78 patients with biliary tract cancer will be included in the study with the primary end point of ORR and secondary end points of progression-free survival, OS, and the incidence of toxicities. Exploratory end points including molecular makers of response and resistance are also being assessed in phase 2.

In the devimistat arm, patients will be dosed at either 500 mg/m2, 1000 mg/m2, 1500 mg/m2, and 2000 mg/m2 via intravenous infusion on days 1 and 8 every 21 days. Gemcitabine 1000 mg/m2 is administered along with cisplatin 25 mg/m2 on the same dosing schedule as devimistat in both the experimental and control arms.

To be eligible for the study, patients aged 18 years or older must have pathologically or cytologically confirmed carcinoma of the biliary tract, which may include intra-hepatic, extra-hepatic or gallbladder cancer. All patients must have radiographically measurable disease per RECIST v.1.1, and ECOG performance status of 0 or 1, adequate organ function and tissue available for biopsy. Inclusion in the study is not granted to individuals who have received prior systemic therapy, or those who prior radiation, chemoembolization, radioembolization or other local ablative therapies or hepatic resection if completed less than 4 weeks before the study.2

Patients are automatically excluded from the study if they have a history of brain metastasis, had major surgery within 4 weeks of enrollment, have an active secondary malignancy, infection, psychiatric illness, are pregnant or breastfeeding, have active heart disease, QTcF interval >480 msec, or are hypertensive to the any drug used in the study.

BilT-04 is actively recruiting patients who meet the requirements at treatment centers in Arizona, Illinois, Michigan, New Jersey, Ohio, Tennessee, Texas, Washington, and Wisconsin.

“We are extremely excited and gratified to have completed phase 1b and to be able to advance to the next phase (phase 2),” said Sanjeev Luther, president and CEO of Rafael Pharmaceuticals, in a press release. “Advanced biliary tract cancer is a rare and aggressive cancer with a 5-year survival rate of less than 5%, and the continuation of the trial aligns with our mission to help patients with significant unmet medical needs.”


1. Rafael pharmaceuticals announces the successful completion of phase 1b clinical trial and initiates phase 2 for CPI-613® (devimistat) in combination with gemcitabine and cisplatin in patients with biliary tract cancer. News release. August 25, 2021. Accessed August 30, 2021.

2. Gemcitabine and cisplatin with or without CPI-613 as first line therapy for patients with advanced unresectable biliary tract cancer (BilT-04). Accessed August 30, 2021.

3. Sahai V, Chang AE, Crysler OV, et al. A multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin with or without CPI-613 as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-04). J Clin Oncol. 2021; 39(suppl 15). doi: 10.1200/JCO.2021.39.15_suppl.TPS4158