Table 1 Objectives and endpoints of the TRITICC trial

1. Objectives

 1.1 Primary Objectives

  • To assess the efficacy of a combination therapy of FTD/TPI and Irinotecan in patients with advanced, non resectable or metastatic cholangio- and gallbladder carcinoma after failure to respond to a previous gemcitabine treatment.

 1.2 Secondary Objectives

  • To determine efficacy and safety of the treatment concept

  • To determine health-related quality of life (HR-QoL)

  • To determine translational observations (circulating miRNAs and lncRNAs, concentrations of inflammatory cytokines, gut microbiome analysis)

2. Endpoints

 2.1 Primary Endpoint

  • Median progression free survival (PFS) assessed by the local investigator

 2.2 Secondary Endpoints

 Efficacy

  • Progression-free survival rate @ 4 months defined as the proportion of patients with non-progressive disease 4 months after inclusion by intention to treat analysis

  • Median overall survival

  • Proportion of patients with an objective response according to RECIST 1.1

 Safety

  • Type, frequency and severity of adverse events with severity according to NCI CTCAE version

 Health-Related Quality of Life

  • HR-QoL according to EORTC QLQ-C30 and the EQ-5D-5L

Translational part

  • cfDNA exome sequencing: a panel of 28 mutations (e.g. IDH1, IDH2, SMAD4) that are specific for BTC will be recapitulated in patient’s serum by using cfDNA exome sequencing.

  • Circulating miRNAs and lncRNAs: Alterations in serum miRNAs as prognostic markers will be analysed using array based techniques in representative patients and significantly altered miRNAs will be validated using qPCR in the whole cohort of patients.

  • Concentrations of inflammatory cytokines: A panel of inflammatory cytokines will be analyzed using FACS bead technology in the serum of patients. This panel will include analysis of Osteopontin, suPAR, APRIL, TWEAK, TRAIL, CCL1, 2, 5, and CXCR1, 2, 5, 9)

  • Gut microbiome analysis: By using high-throughput sequencing of bacterial 16S RNA a complete and unbiased analysis of the gut microbiota will be performed in each individual patient. Both the baseline composition and alterations during therapy will be correlated with PFS and response to therapy.