A multicenter phase Ib/II study of liposomal-irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) with nivolumab as second-line therapy for patients with advanced biliary tract cancer (BilT-03).
Authors: Sahai Vaibhav , Griffith Kent A. , Lin Bruce Shih-Li , Soares Heloisa P. , Chandana Sreenivasa R , Crysler Oxana V. , Enzler Thomas , Zalupski Mark 
Published: January 2022

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Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy and treatment beyond first-line platinum doublet remains largely investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells less sensitive to T cell-mediated lysis, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent anti-PD-1 antibody in BTC provide a rationale for combination chemoimmunotherapy. We conducted a multi-center, phase Ib/II, single-arm study to investigate the role of liposomal-irinotecan, 5FU and LV in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC after progression or intolerance of first-line systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. The limited phase Ib portion evaluated 10 pts to determine the recommended phase 2 dose (RP2D) based on the probability of dose-limiting toxicity (DLT) rate <30% during days 1-29. Study treatment included 5FU 2400 mg/m2 over 46 hrs, LV 400 mg/m2, liposomal-irinotecan 70 mg/m2 at dose level 0 along with nivolumab 240 mg every 2 wks for up to 2 yrs in absence of disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS) rate with an alternative and null hypothesis of 5.0 mo and 2.9 mo (two-sided alpha 0.05, power 80%), respectively. Secondary endpoints included best overall response rate (ORR) per immune related (ir)RECIST, median overall survival (OS), 75th percentile estimates of PFS and OS, and safety. Exploratory objectives include biomarker analysis using include targeted panel exome/transcriptome and immune cell subsets in tissue. Results: 30 eligible pts (60% men, 83% Caucasian) including 10 pts in phase Ib and 20 pts in phase II with a median age of 63.5 yrs (range 36-75) were enrolled across 4 US sites between June 2019 and July 2021. In phase Ib, one pt experienced DLT (grade 3 enterocolitis); RP2D was confirmed at dose level 0. All 30 pts were included in study reported outcomes with a median follow-up time of 10.7 mo. Median PFS was 4.2 mo (95% CI, 1.9-10.2) and failed to reject the null hypothesis. Median OS was 7.5 mo (95% CI, 5.8-21.4). The 75th percentile estimates for PFS and OS are 10.2 mo (95% CI, 5.4-NE) and 21.4 mo (95% CI, 7.8-21.4). ORR estimates and toxicity data are pending and will be presented at the meeting. Conclusions: The observed median PFS is insufficient to reject the null hypothesis. The 75th percentile estimates for PFS and OS are suggestive of prolonged benefit with chemoimmunotherapy in a small fraction of patients with BTC. Clinical trial information: NCT03785873.