Neoadjuvant Gemcitabine and Cisplatin in Combination With Perioperative Pembrolizumab Versus Upfront Surgery for Patients With Primary Resectable and Borderline Resectable Perihilar and Distal Cholangiocarcinoma

NCT06923475 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: 2024-516898-72-00R-000724
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

Extrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive cancer with poor prognosis. ECCA can be further subcategorised in perihilar and distal cholangiocarcinoma (pCCA and dCCA). Surgical resection is the only potential cure, but only one-third of patients are eligible. Even among those deemed resectable, a significant portion (≈30%) experience disease progression before surgery, while another 30% are found unresectable during exploration. High recurrence rates and postoperative complications further limit survival, with 5-year overall survival ranging from 13% (R1 resection) to 40% (R0 resection). Given the long preoperative work-up period and lack of treatment during this phase, a neoadjuvant approach may improve outcomes by increasing R0 resections, reducing recurrence, and optimizing patient selection. This multicenter, randomized phase 2B/3 trial aims to assess whether neoadjuvant gemcitabine and cisplatin plus perioperative pembrolizumab improves event-free survival in patients with resectable and borderline resectable pCCA and dCCA.

Conditions

Extrahepatic Cholangiocarcinoma; Perihilar Cholangiocarcinoma; Distal Cholangiocarcinoma; Resectable; Borderline Resectable

Keywords

Extrahepatic cholangiocarcinoma; Perihilar Cholangiocarcinoma; Distal Cholangiocarcinoma; Resectable; Borderline resectable

Outcome Measures

Primary Outcomes (1)

• Event Free Survival

  An event is defined as the time from randomization to any progression of disease leading to unresectability, progression or recurrence of disease after surgery (all based on RECIST or pathology) or death from any cause.

  18 months

Secondary Outcomes (1)

• Overall Survival (OS)

  Median, 2-, 3-, 5- years OS

Study Arms (2)

Arm A

EXPERIMENTAL

Neoadjuvant gemcitabine plus cisplatin in combination with perioperative pembrolizumab (Intervention)

Drug: Pembrolizumab; Drug: Gemcitabine, Cisplatin

Arm B

NO INTERVENTION

Upfront surgery (Standard of care)

Interventions

Pembrolizumab DRUG

Patients will initiate with 2 sets of 3 cycles of neoadjuvant gemcitabine and cisplatin in combination with perioperative pembrolizumab (up to total of 1 year immunotherapy treatment)

Arm A

Gemcitabine, Cisplatin DRUG

Patients will initiate with 2 sets of 3 cycles of neoadjuvant gemcitabine and cisplatin in combination with perioperative pembrolizumab (up to total of 1 year immunotherapy treatment)

Arm A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed resectable or borderline resectable pCCA and dCCA. These are all the patients considered candidates for upfront surgical exploration, with intent to resect, as confirmed by local MDT and the study expert panel also taking into consideration endoscopic and radiological findings. In cases where drainage is not required, patients with a disease highly suspicious for extrahepatic cholangiocarcinoma, as determined by the expert MDT, may be included without histological proof to prevent unnecessary post-ERCP complications.
• Successful drainage, in case of clinical significant bile duct obstruction.
• Male/female participants who are at least 18 years of age on the day of signing informed consent.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.

You may not qualify if:

• Upfront "clearly" unresectable pCCA: circumferential unreconstructable vascular involvement of the FLR and/or insufficient FLR for potential radical resection. Insufficient FLR is defined as \<30% residual volume or a function \<2.7 min/m2. Patients considered borderline resectable but, by the discretion of the MDT, not a candidate for upfront exploration/resection, are considered ineligible for NEODISCO.
• Upfront clearly unresectable dCCA (following DPCG criteria).
• Patients with proven N2 lymph nodes (according to the AJCC 8th edition).
• PCCA eligible for liver transplantation.
• Intrahepatic cholangiocarcinoma with hilar involvement.
• Cancer suspicious for ampullary carcinoma (for instance involvement of papilla during endoscopy).
• Local recurrence following prior resection of eCCA (patients who develop local recurrence during the study are however not excluded).
• Patients with underlying liver diseases: PSC, untreated hepatitis, cirrhosis child-Pugh B, C.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Maastricht University Medical Center: collaborator
• UMC Utrecht: collaborator
• University Medical Center Groningen: collaborator
• Erasmus Medical Center: collaborator

Study Sites (1)

Amsterdam University Medical Center

Amsterdam, Netherlands

Location

MeSH Terms

Conditions

Cholangiocarcinoma; Klatskin Tumor

Interventions

pembrolizumab; Gemcitabine; Cisplatin

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Central Study Contacts

Johanna Wilmink, MD, PhD

CONTACT

+31-20-4444321; trialmedonc@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. J.W. Wilmink

Study Record Dates

• First Submitted: February 25, 2025
• First Posted: April 11, 2025
• Study Start: May 5, 2025
• Primary Completion (Estimated): November 6, 2028
• Study Completion (Estimated): November 6, 2028
• Last Updated: April 11, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

NL (1)