A phase II trial of trifluridine/tipiracil plus oxaliplatin in patients with advanced or metastatic biliary tract cancer following first-line therapy.

Abstract

TPS4258 Background: Biliary tract cancers (BTCs) comprising of intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer are aggressive and difficult cancers to treat. Most patients present with metastatic or unresectable disease, and systemic therapy is the only therapeutic option. Treatment options are highly limited after progressing on first line therapy with median survival of 6 months. We demonstrated encouraging activity with single agent trifluridine/tipiracil (FTD/TPI) and FTD/TPI plus irinotecan in separate phase 2 trials in patients with refractory BTCs after multiple lines of therapies (NCT03278106 and NCT04072445). Disease control rate (DCR) of 50% was reported with the combination therapy and median OS was 9.1 months. Prior studies have suggested oxaliplatin-based therapy may be more effective than irinotecan-based therapy in BTC. Thus, FTD/TPI plus oxaliplatin may be an active regimen in patients with advanced BTCs. Methods: This is a phase II trial evaluating FTD/TPI plus oxaliplatin as second line treatment in patients with advanced BTCs and disease progression on standard of care gemcitabine-based combination therapy. Key inclusion criteria are pathologically confirmed BTC, ECOG performance status 0 or 1, prior gemcitabine-based combination therapy, adequate organ function, signed informed consent. Key exclusion criteria include > 1 prior line of systemic therapy for advanced disease (adjuvant therapy not counted) and active autoimmune disease requiring systemic therapy. Participants will be enrolled at Case Comprehensive Cancer Center sites and receive a dose of FTD/TPI of 25 mg/m 2 twice daily on days 1-5 and oxaliplatin 85 mg/m 2 on day 1 of a 14-day cycle until disease progression, intolerable toxicities, or patient declines to continue study. Primary endpoint is DCR, defined as proportion of patients achieving responses or stable disease with trial treatment. The trial is a Simon 2-stage optimal design with a significance level of 0.05 and 80% power. We estimate a DCR of 0.62 compared to historical control of 0.33 in second line setting. If ≤2 patients have disease control out of the first 6 patients enrolled, then regimen will be considered ineffective. If > 3 patients have disease control, then the study will proceed to stage 2. During stage 2, an additional 18 patients will be enrolled for 24 total evaluable patients. If > 12 patients of the 24 evaluable patients have disease control, then the trial will be considered a success and a larger trial will be planned. Secondary endpoints are grade and duration of adverse events, ORR, PFS, OS. Correlative studies are circulating DNA and oral and fecal samples for microbiome testing. The study is supported by the National Comprehensive Cancer Network (NCCN) through a grant provided by Taiho Oncology. Neither NCCN nor Taiho are the sponsor. Clinical trial information: NCT07146646 .