The study will evaluate safety and efficacy in patients with:~Biliary tract carcinomas patients who have progressed on one prior line of gemcitabine and platinum-based chemotherapy in the metastatic setting.~Esophageal squamous cell carcinoma patients who have progressed on one prior line of platinum-based chemotherapy in the metastatic setting.~The trial is set up as 3 sub-studies.~Sub-study 1 includes biliary tract carcinoma patients and is composed of 2 investigational combination treatment arms (Sym021+Sym022 [Arm A] and Sym021+Sym023 [Arm B]).~Sub-study 2, includes biliary tract carcinoma patients and is composed of one investigational combination treatment arm:Sym021+Sym023+irinotecan. A safety lead- in phase is included to assess tolerability of the combination. A Study Safety Team will review clinical and laboratory safety data and will make decisions regarding the continued enrollment after the safety lead-in phase.~Sub-Study 3, includes esophageal squamous cell carcinoma patients and is composed of one investigational combination treatment arm: Sym021+Sym023+irinotecan. Dose of irinotecan in this arm will be selected based upon the safety lead in in sub-study 2 period.~August 2021 : Based upon results from a recent per protocol Interim Analysis (IA) it is has been decided as of 3rd of August 2021 to stop further enrollment into Sub-study 1 Arm A (Sym021+Sym022). Future patients will be allocated to either Sub-study 1 Arm B (Sym021+Sym023) or Sub-study 2 (Sym021+Sym023+irinotecan).
The study will evaluate the preliminary efficacy of 3 combinations (Sym021+Sym022, Sym021+Sym023 and Sym021+Sym023+irinotecan) in patients with biliary tract carcinomas (BTC) and with esophageal squamous cell carcinoma (ESCC) by assessing overall response rates (ORRs) per Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 The study will also evaluate the safety and tolerability profile of the 3 combinations