GemCis with or without CPI-613 as First-Line Therapy for Patients with Advanced BTCs: The BilT-04 Study

September 2022, Vol 3, No 3

Patients with advanced biliary tract cancers (BTCs) have a poor prognosis despite systemic chemotherapy. Gemcitabine/cisplatin (GemCis) is the standard first-line systemic therapy for BTCs; however, median overall survival was only 11.7 months. CPI-613 (devimistat) is a stable intermediate of a lipoate analog that is a specific inhibitor of key enzymes of the tricarboxylic cycle within the mitochondria of cancer cells, leading to increased chemotherapeutic cytotoxicity. To improve efficacy outcomes, an ongoing investigator-initiated, multi-institutional, phase 1b/2 trial (BilT-04) is evaluating the addition of CPI-613 to the standard GemCis backbone in patients with previously untreated advanced BTCs. Results of the phase 1b portion of the study were reported at the 2022 ASCO annual meeting.

The primary objective of the phase 1b portion was to determine the recommended phase 2 dose (RP2D). Patients received combination GemCis (gemcitabine 1000 mg/m2, cisplatin 25 mg/m2) plus CPI-613 at various dose levels on days 1 and 8 every 21 days; the phase 1b dose levels of CPI-613 were 500 mg/m2 (dose level –1), 1000 mg/m2 (dose level 1), 1500 mg/m2 (dose level 2), and 2000 mg/m2 (dose level 3).

A total of 20 patients were included in this analysis. Of these, 1 patient each was assigned to dose levels –1 and 1, 2 patients to dose level 2, and 16 patients to dose level 3. The median age of the study population was 65 years (range, 43-75 years); 55% were men, 85% were Caucasian, 45% had ECOG performance status 0, and 75% had metastatic disease. Of the 20 patients, 9 had a diagnosis of intrahepatic cholangiocarcinoma (CCA), 5 had hilar CCA, 2 had distal CCA, and 3 had gallbladder cancer.

A dose-limiting toxicity of grade 2 creatinine elevation was reported in only 1 patient at dose level 3 (2000 mg/m2), so the RP2D for CPI-613 was established as 2000 mg/m2. In the total population of phase 1b, the objective response rate was 45%, including 1 complete response and 7 partial responses. Median progression-free survival was 14.9 months (95% confidence interval, 7.4-16.0), with 7 patients still on treatment. Overall survival was not yet estimable, with 15 patients still alive. Treatment-related serious adverse events were reported in 4 patients, including grade 3 febrile neutropenia (n = 2) and infection (n = 2).

Based on results of the phase 1b portion of the BilT-04 study, Sahai and colleagues concluded that the combination of CPI-613 plus GemCis was well-tolerated and that “CPI-613 in combination with gemcitabine and cisplatin may be active in this malignancy.” The randomized phase 2 portion of the trial is accruing patients at 10 sites, with enrollment expected to be completed in the third quarter of 2022.

Source: Sahai V, Zhen DB, Crysler OV, et al. Phase 1b results of a multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin +/- CPI-613 as first-line therapy for patients with advanced biliary tract cancer (BilT-04). Abstract 4094.

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