Neoadjuvant gemcitabine and cisplatin in combination with perioperative pembrolizumab versus upfront surgery for patients with primary resectable and borderline resectable perihilar and distal cholangiocarcinoma (NEODISCO): A Multicentre Phase 2B/3 Randomised Controlled Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Amsterdam UMC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Apr 2026 → ongoing

Decision date (initial)

2025-11-21

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the event free survival in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.

Secondary objectives 12

1. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the overall survival in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
2. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the locoregional failure free interval in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
3. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the distant metastasis free interval in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
4. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the resection rate in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
5. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the R0 rate in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
6. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the postoperative complications in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
7. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the postoperative moratality (30 and 90 days) in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
8. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab is safe (evaluated by reporting adverse events) in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
9. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the quality of life in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
10. To determine whether neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab improves the serum tumor markers in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
11. To determine the clinical and pathological response rate after neoadjuvant treatment with gemcitabine and cisplatin plus perioperative pembrolizumab in patients with resectable and borderline resectable perihilar and distal cholangiocarcinoma.
12. To assess the expression of biomarkers. This includes (but is not limited to) analysis of circulating tumor DNA (ctDNA) extracted from plasma of patients at five time points in the intervention arm (baseline, after 3 neoadjuvant cycles of interventional treatment, after 6 neoadjuvant cycles of intervention treatment, after 3 adjuvant cycles of interventional treatment and 6 months after surgery) and three time points in the control arm (baseline, 3 months follow-up and 6 months follow-up).

Conditions and MedDRA coding

Perihilar cholangiocarcinoma, distal cholangiocarcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Histologically or cytologically confirmed resectable or borderline resectable perihilar or distal cholangiocarcinoma
2. Successful drainage in case of clinical significant bile duct obstruction
3. MidCCA inclusion in the NEODISCO-trial will be permitted and will be included according to the proposed type of resection.
4. Male/female participants who are at least 18 years of age on the day of signing informed consent
5. The participant provides written informed consent for the trial
6. 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
7. A male participant must agree to use a contraception as detailed in Appendix 2 of this protocol during the treatment period and for at least 18 weeks after the last dose of study treatment and refrain from donating sperm during this period.
8. A female participant is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least one of the following conditions applies: Is NOT a woman of childbearing potential (WOCBP) as defined in Appendix 5 OR IS a WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 18 weeks after the last dose of study treatment.
9. Have a history of Hepatitis B or C. See Table 3 for management of Hepatitis B/flare and Hepatitis C exacerbations/relapse.
10. Known HIV-positive participants or as determined after screening, should be co-managed by a HIV specialist and the investigator during the study, including monitoring of HIV viral load, CD4+ T-cell count, and additional supportive care measures. HIV-infected participants must have well-controlled HIV on ART, defined as: a. Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening b. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening c. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months d. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study e. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers)
11. Have adequate organ function as defined in the following table (Table 2). Specimens must be collected within 10 days prior to the start of study intervention.

Exclusion criteria 30

1. 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
2. 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).
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
4. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
5. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS diseases permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.
6. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. See section 5.5 for information on COVID-19 vaccines.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
8. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
10. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)
11. Has an active infection requiring systemic therapy.
12. Upfront clearly unresectable dCCA.
13. Has not adequately recovered from major surgery or has ongoing surgical complications.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
15. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
16. Fertile women (< 1 year after last menstruation) and procreative men not willing or able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile)
17. Has had an allogenic tissue/solid organ transplant.
18. Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study.
19. Patients with proven N2 lymph nodes (according to the AJCC 8th edition).
20. Distant metastasis clear on imaging or otherwise confirmed by percutaneous biopsy.
21. PCCA eligible for liver transplantation.
22. Intrahepatic cholangiocarcinoma with hilar involvement.
23. Cancer suspicious for ampullary carcinoma (for instance involvement of papilla during endoscopy).
24. Local recurrence following prior resection of eCCA (patients who develop local recurrence during the study are however not excluded).
25. 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.
26. Patients with underlying liver diseases: PSC, untreated hepatitis, cirrhosis child-Pugh B, C.
27. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
28. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
29. Presence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent.
30. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event free survival

Secondary endpoints 16

1. Overall survival
2. Locoregional failure free interval
3. Distant metastasis-free interval
4. Resection rate
5. Radical resection rate
6. Postoperative complications (30 and 90 days)
7. Postoperative moratlity (30 and 90 days)
8. (Serious) adverse events
9. Toxicity (CTCAE V5.0)
10. QoL: EORTC QLQ-C30
11. QoL: EQ-5D
12. Clinical response rate (using RECIST)
13. Lymf node status: nodes 8, 9, 12A and 12P will be resected and examined by the pathologist to determine the N status.
14. Serum CA 19-9 and CEA response: defined as the change in CA 19-9 levels after 3 and 6 cycles neoadjuvant, and during follow up after surgery, relative to baseline
15. Pathologic complete and partial response: assessed using the CAP (College of American Pathologists) pancreas protocol.
16. Expression of biomarkers: including but not limited to analysis of circulation tumor DNA

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Amsterdam UMC

Sponsor organisation

Stichting Amsterdam UMC

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Stichting Amsterdam UMC

Contact name

Prof. Dr. J.W. Wilmink

Public contact point

Organisation

Stichting Amsterdam UMC

Contact name

Prof. Dr. J.W. Wilmink

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications