Phase 1b/2 results of a multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin +/- devimistat as first-line therapy for patients with advanced biliary tract cancer (BilT-04).

4116 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis despite systemic chemotherapy. Until recently, gemcitabine (G) and cisplatin (C) was a standard first-line systemic therapy with overall response rates (ORR) of 26% and 18.7%, median progression-free survival (PFS) of 8.0 and 5.7 months (mo), and median overall survival (OS) of 11.7 mo and 11.5 mo in the phase (Ph) 3 ABC-02 and TOPAZ-1 trials, respectively. CPI-613/Devimistat (D) is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic acid (TCA) cycle, preferentially within the mitochondria of cancer cells augmenting chemotherapeutic cytotoxicity. Methods: This investigator-initiated, multi-institutional Ph 1b/2 trial across 10 sites in the US investigated the combination of G 1000 mg/m 2 , C 25 mg/m 2 and D (dose levels: (-1) 500, (1) 1000, (2) 1500 and (3) 2000 mg/m 2 ) (GCD) on days 1 and 8 every 21 days in pts with previously untreated advanced BTC. The recommended Ph 2 dose (RP2D) from the Ph1 b portion was 2000 mg/m 2 (n=20 pts; TiTE-CRM methodology). The primary endpoint of the Ph 2 portion (n=48-58 pts; 2:1 randomization with Bayesian control arm) was to determine the best ORR in the GCD arm with an alternative hypothesis of 38% (null of 21.1% with 80% power and two-sided alpha of 0.05). GC arm efficacy estimates were to be compared to the null hypothesis to confirm reasonable comparison. Secondary endpoints included evaluation of median PFS and OS, and safety. Exploratory objectives include targeted exome/ transcriptomic analysis of tissue, and metabolomic analysis of plasma (pre-, on- and post-treatment). Clinical trial information: NCT04203160. Results: 75 pts were enrolled (20 Ph1b GCD, 37 Ph 2 GCD arm and 18 Ph 2 GC arm) between Jun 2020 to Mar 2023; median age 67 years (range 33-84), ECOG PS 0/1 (36/35), women (49%), Caucasian (88%), intrahepatic/hilar/distal cholangiocarcinoma and gallbladder (48/9/4/7), and metastatic/locally advanced stage (52/17). For the Ph 2 primary endpoint of ORR, 63 pts were evaluable (GCD at RP2D + GC with follow-up scans or clinical progression). ORR in the GCD was 15/50 (30%; 95% CI 17.9-44.6). ORR in GC arm was 6/13 (46.2%; 95% CI 19.2-74.9) and not different than historical estimate/null hypothesis. In the intention-to-treat analysis (n=75), median PFS and OS of pts treated with GCD (n=57) and GC arms (n=18) were 8.7 mo (95% CI 6.3-12.6) and 8.6 mo (4.0-NE), and 16.3 mo (11.3-21.5) and 22.2 mo (6.5-NE), respectively. Conclusions: The combination of GCD did not meet the primary endpoint of increased ORR. GCD was well tolerated, however, and demonstrated encouraging PFS and especially OS as compared to historical estimates in this Ph 1b/2 trial. Targeted exome/ transcriptome and plasma metabolome analyses are ongoing. Clinical trial information: NCT04203160 .