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

NCT ID: NCT06923475

Last Updated: 2025-04-11

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-05-05
• Study Completion Date: 2028-11-06

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A

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

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: 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)

Gemcitabine, Cisplatin

Intervention Type: 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 B

Upfront surgery (Standard of care)

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Pembrolizumab

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)

Intervention Type: DRUG

Gemcitabine, Cisplatin

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)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.
• MidCCA inclusion in the NEODISCO-trial will be permitted and will be included according to the proposed type of resection.
• 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.

Exclusion Criteria

• 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.
• Previous malignancy unless no evidence of disease, or diagnosed more than 3 years before diagnosis of eCCA, or with a life expectancy of more than 5 years from date of inclusion.
• 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Maastricht University Medical Center

OTHER

Sponsor Role: collaborator

UMC Utrecht

OTHER

Sponsor Role: collaborator

University Medical Center Groningen

OTHER

Sponsor Role: collaborator

Erasmus Medical Center

OTHER

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

Trial Office Medical Oncology VUmc

Prof. Dr. J.W. Wilmink

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Amsterdam University Medical Center

Amsterdam, , Netherlands

Countries

Netherlands

Central Contacts

Johanna Wilmink, MD, PhD

Role: CONTACT

trialmedonc@amsterdamumc.nl

+31-20-4444321

Facility Contacts

Britte ten Haaft, MD

Role: primary

b.tenhaaft@amsterdamumc.nl

+31-20-4444321

Other Identifiers

R-000724

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

2024-516898-72-00

Identifier Type: -

Identifier Source: org_study_id