SUMMARY
Intrahepatic cholangiocarcinoma (IHC) is a subtype of biliary tract adenocarcinoma with a poor prognosis and
rising incidence. SEER data recently documented an average 4.4% rise over the past decade. Similarly, an
analysis spanning 18 years reported a 7% annual increase in incidence, the highest of any biliary tract subtype.
Both studies highlight the abysmal survival of patients with IHC, the latter reporting a median of approximately 6
months. Most patients with IHC have unresectable disease at diagnosis, and even those few fortunate enough
to undergo resection recur commonly. For these patients, treatment options are limited, with systemic
chemotherapy representing the standard, and in most cases, the only approach. Combination therapy with
gemcitabine (GEM) and a platinum agent is the current gold standard, but its benefit is limited, offering a median
overall survival of approximately 12 months. Recently, our group completed a phase II single-arm study of
regional chemotherapy using continuous infusion hepatic arterial (HAI) floxuridine (FUDR) combined with GEM
and oxaliplatin (OX). The median overall survival was 25 months, with four patients responding sufficiently to
undergo resection. Based on these promising results, the primary goal of this proposal is to establish the efficacy
of HAI FUDR added to the most active systemic regimen (GEM/OX) for the treatment of unresectable IHC in a
multi-center randomized phase II study, with the primary endpoint of progression-free survival.
Further improvements in the management of IHC have been hindered in large part by a poor understanding of
the biology of the disease. IHC is among the most genomically heterogeneous solid tumor, resulting from the
wide array of risk factors and multiple potential cells of origin. Significant heterogeneity has been shown not only
from patient to patient, but even within the same tumor. This feature has precluded precise characterization of
molecular pathogenesis, made it difficult to identify effective targeted therapies, and results in inaccurate
assessment of the mutational landscape when based on a single biopsy. The proposed clinical trial provides an
ideal opportunity to address these gaps. We will evaluate intratumoral heterogeneity (ITH) using targeted exome
sequencing of multiple tumor biopsies and cell-free DNA (cfDNA) from a large cohort of patients and use these
findings to stratify patients with respect to response and survival. For the subset of patients that progress while
enrolled in the trial, we will obtain tumor biopsies and blood at the time of progression to elucidate mechanism(s)
of treatment resistance by tumor DNA and cfDNA sequencing. Using these same samples, we will establish
patient-derived organoid models for functional evaluation of genetic predictors of treatment response. Finally,
we will use radiogenomics, or the merger of quantitative imaging with molecular analyses, to explore non-
invasive stratification of patients based on mutational patterns and to quantify the degree of heterogeneity. Using
an integrated analysis approach, these studies will provide a foundation for multimodal risk stratification for IHC.
