Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

Keywords: cholangiocarcinoma; clinical trials; co-clinical trials; precision medicine; targeted therapy.

Figure 1

The conventional drug development process versus co-clinical trials. The different phases of clinical trials in the conventional drug development process take approximately 10–20 years for regulatory approval of the candidate drugs. Preclinical studies with animal models and clinical trials are conducted concurrently in co-clinical trials. The real-time data integration between the two parallel studies can accurately stratify patients into resistant or sensitive subtypes. The patients classified into resistant subtypes can be tested for enrolment in other existing clinical trials. The patient cohorts of the sensitive phenotype are then recruited to the trial with the animal study conducted in parallel. This will improve trial outcomes for candidate drugs and therefore encourage regulatory approval.

Figure 2

Schematics of co-clinical trials to expedite drug and research development in cholangiocarcinoma (CCA). In this proposed system, the patient is enrolled in the study after being diagnosed with CCA. Post-surgical resection, the CCA tissue is implanted in patient-derived-xenograft (PDX) models and derived into primary cell lines. If the tumor is unresectable, the molecular diagnosis of biopsies will enable researchers to design genetically engineered mouse models (GEMMs) and edited cell line models specific to the patients’ gene signature. The non-animal models are used for molecular profiling and initial drug screening with candidate drugs as monotherapy or in combination with other therapies. The animal models are then treated with prospective treatment protocol based on the initial drug screening. The treatment regime in the patient trials is then adjusted based on the real-time data integration from the animal studies, ensuring that each individual patient always receives optimal care.