Intrahepatic CholangiocarcinomaNCT06140134
Liver Transplantation in Intrahepatic Cholangiocarcinoma
An observational study of Intrahepatic Cholangiocarcinoma and Cholangiocarcinoma, Intrahepatic, run by Rutgers, The State University of New Jersey at 2 sites in United States.
Trial summary
The aim of the current study is to determine the potential efficacy of liver transplantation in the form of patients' overall survival (OS) after neoadjuvant systemic therapy in patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) in comparison to patients… Read more about this study
- Who is it for?
- Ages 18 to 89 years
- Conditions the study is for
- Intrahepatic Cholangiocarcinoma, Cholangiocarcinoma, Intrahepatic
- What is being tested?
- Liver Transplant
- Type of treatment
- Surgery or procedure
- How many people
- 30 participants
- Where
- 2 sitesUnited States
- Study dates
- 15 Dec 2023to Nov 2029
- How long will I take part?
- 5 Years
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 89 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic chemotherapy with a radiographic disease stability or regression.
Who may be able to join
- Age ≥18 years of age on the day of consenting to the study.
- Patients must have histologically confirmed diagnosis of locally advanced intrahepatic cholangiocarcinoma
- Confirmed diagnosis of locally advanced unresectable iCCA with no vascular invasion, lymph node, or extrahepatic disease.
- Unresectable disease based on tumor location or underlying liver disease
- Patients must have ≥ 6 months of disease stability or tumor regression on neoadjuvant therapy. In cases in which patients had received second-line therapy, disease must also have been controlled for ≥ 6 months on that regimen.
- Patients who had previous surgical resection for iCCA are eligible if surgery occurred more than 6 months prior to listing, and patients have had ≥ 6 months of disease stability or response on therapy.
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- ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A).
- Patients must have organ and marrow function acceptable for liver transplantation per institutional protocol:
- If history of chronic hepatitis B virus (HBV) infection, viral load should be undetectable on suppressive therapy.
- If history of chronic hepatitis C virus (HCV) infection, patients should have undetectable HCV viral load.
- Women of child-bearing years must have contraception plan in place from the time of study enrollment until at least one year following liver transplant.
- Ability to understand and the willingness to sign a written informed consent document
- Meets all other medical and psychosocial criteria for liver transplant
- Demonstrate ability to comply with study procedures
Who cannot join
- Age <18 years of age on the day of consenting to the study.
- Patients who have extrahepatic metastases, lymph node involvement, invasion or encasement of major hepatic vascular structures, perforation of the visceral peritoneum, invasion of extrahepatic structures, invasion of perihilar fat, periductular invasion, concurrent hepatoma or mixed hepatocellular cholangiocarcinoma.
- Concurrent severe and/or uncontrolled concurrent illness including, but not limited to, ongoing or active infection, acute fulminant liver failure, symptomatic congestive heart failure, unstable angina pectoris, severe uncorrected coronary artery disease, severe cerebrovascular disease, severe pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements and that would exclude the patient from eligibility for liver transplantation per institutional protocol.
- Prior solid organ or bone marrow transplant
- Dependent on ≥2 IV inotropic support to maintain hemodynamics
- Previous (within the past 5 years) or concurrent presence of other cancer, except non-melanoma skin cancer and in situ carcinomas.
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- Eastern Cooperative Oncology Group (ECOG) Performance Status Scale score >1 (Karnofsky <70%, see Appendix A).
- Unable to understand and sign a written informed consent document
- Untreated viral hepatitis
- Pregnant or breast-feeding women
- HIV-infected patients
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Angenie Preval, PA contact
United States2 sites, 2 recruiting
- Recruiting
Rutgers New Jersey Medical School
Newark, New Jersey, 07103
Keri E Lunsford, MD, PhD, keri.lunsford@rutgers.edu
- Recruiting
University Hospital
Newark, New Jersey, 07103
Keri E Lunsford, MD, PhD, keri.lunsford@rutgers.edu
Keri E Lunsford, MD, PhD
About this study
Official title: A Single-Arm Nonrandomized Phase II Study of Liver Transplantation in Locally Advanced Unresectable Non-Metastatic Intrahepatic Cholangiocarcinoma Treated With Neoadjuvant Systemic Therapy
The aim of the current study is to determine the potential efficacy of liver transplantation in the form of patients' overall survival (OS) after neoadjuvant systemic therapy in patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) in comparison to patients historically treated with chemotherapy alone.
Read the detailed description
Research Significance:
Cholangiocarcinoma, which arises from biliary epithelium, can be anatomically subdivided into distal, hilar, and intrahepatic subgroups. Intrahepatic cholangiocarcinoma (iCCA) constitutes the second most common primary liver cancer after hepatocellular carcinoma, with a rising incidence but without parallel advances in treatment or patient outcome. At present, surgical resection is the only widely accepted potentially curative therapy for iCCA; however, 5-year survival rates for resectable disease are less than 25%. This high mortality is attributed to high tumor recurrence. Two-thirds of patients who undergo curative-intent resection for iCCA suffer from postoperative disease recurrence, most commonly in the remnant liver, followed by the peritoneum and abdominal lymph nodes. Approximately 83% of recurrences occur within the first 2 years after resection, suggesting inadequate local tumor control with resection in this highly infiltrative cancer.
Liver transplantation for intrahepatic cholangiocarcinoma:
While liver transplantation has been previously investigated for unresectable iCCA, the outcomes have been poor in comparison to the results for hepatocellular carcinoma, with 18-25% OS and RFS after 5 years; however, most studies evaluated patients with either incidental iCCA or iCCA misdiagnosed prior to transplant as hepatocellular carcinoma (HCC). Thus, iCCA is considered by most centers to be a formal contraindication to liver transplantation.
Neoadjuvant therapy with subsequent liver transplantation for perihilar cholangiocarcinoma:
Similar to iCCA, liver transplantation outcomes for perihilar cholangiocarcinoma were initially poor; however, an analysis of the United Network of Organ Sharing (UNOS) database found a significant survival benefit for patients with perihilar cholangiocarcinoma who received pre-transplant neoadjuvant systemic therapy compared with patients who transplanted for incident disease. Subsequently, several studies reported improved survival for hilar cholangiocarcinoma treated with neoadjuvant chemoradiation followed by liver transplantation. A multicenter study reported a 65% 5-year survival rate; liver transplantation has thus become the preferred treatment for patients with locally advanced unresectable hilar cholangiocarcinoma. Response to neoadjuvant therapy probably offers a means to select patients with hilar cholangiocarcinoma who might benefit from transplantation.
Neoadjuvant therapy with subsequent liver transplantation for intrahepatic cholangiocarcinoma (iCCA):
The published literature regarding liver transplantation (LT) for iCCA is mostly limited to incidental or misdiagnosed tumors identified on pathology, with most patients not receiving neoadjuvant therapy. Retrospective analysis including a small cohort of patients receiving neoadjuvant therapy showed that pre-transplant therapy appeared to decrease disease recurrence; however, reports did not distinguish between hilar cholangiocarcinoma and iCCA. In 2016, a multi-center, international, retrospective study investigated outcomes of liver transplantation in 48 iCCA patients who had not received neoadjuvant chemotherapy or locoregional therapy. In that study, 5-year OS was 65% for iCCA ≤2 cm and 45% for advanced larger lesions. Survival outcomes for locally advanced iCCA were worse, but patients having received pre-transplant neoadjuvant therapy in this series were excluded. The effect of neoadjuvant chemotherapy in patients with larger and multifocal tumors remains largely undefined. In 2020, another multicenter study compared the outcomes of patients with cirrhosis undergoing liver transplantation or liver resection who had iCCA or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The retrospective study analyzed a total of 49 LT and 26 liver resected patients with cirrhosis and histologically confirmed iCCA/ cHCC-CCA ≤5 cm. Results suggested that liver transplanted patients had a significantly lower tumor recurrence (diameter of largest nodule and tumor differentiation were independently predictive) and had a significantly higher 5-year recurrence-free survival. The effects of liver transplantation may provide a benefit for highly selected patients with cirrhosis and unresectable iCCA/cHCC-CCA with specific tumor dimensions. These findings suggests that liver transplantation might be a viable option for small, solitary iCCA in the absence of pre-transplant therapy or with locoregional therapy alone.
A subset of patients with iCCA experienced sustained response to neoadjuvant therapy, and it has been postulated that response duration might be an appropriate surrogate marker for the selection of patients for liver transplantation. Through the Methodist-MD Anderson Joint Cholangiocarcinoma Collaborative Committee, a recent prospective case-series of 6 patients with locally advanced unresectable iCCA without extrahepatic disease or vascular involvement was performed. Patients treated with neoadjuvant systemic chemotherapy with a minimum of 6 months radiographic disease stability or regression received liver transplantation. The median post-transplant follow-up duration was 36 months (range; 29-51). The OS rate was 100% (95% Confidence interval [CI]; 100-100) at 1-year, 83·3% (95% CI; 27·3-97·5) at 3 years, and 83·3% (95% CI; 27·3-97·5) at 5 years. Three patients developed post-transplant recurrence at a median of 7·6 months with 50% (95% CI; 11·1-80·4) RFS at 1-, 3-, and 5-years. Since publication, an additional 5 patients have been transplanted, and all patients have been followed for an additional 24 months. More recent data indicates a 5-year OS of 79.5% with RFS of 42.4%. In regards to recurrence, 4 of 5 occurred within 12 months of transplant. Retrospective evaluation of the pre-transplant imaging demonstrated evidence of pre-transplant extrahepatic disease. More stringent patient selection, such as the addition of a PET-CT scan, would likely avoid early recurrence in the majority of patients. Adverse events have been reported, including grade 3 postoperative ileus in one patient and grade 4 acute kidney injury requiring temporary dialysis in another patient. Both adverse events were among those commonly occurring with liver transplantation for any indication. No post-operative complications could be directly related to this protocol. Therefore, the investigators anticipate that selected patients with locally advanced non-metastatic iCCA who show pre-transplant disease stability on neoadjuvant therapy might benefit from liver transplantation.
Research Design and Methods:
This is a single-center phase II study. Patients with locally advanced unresectable iCCA with no evidence of vascular invasion or extrahepatic disease who have at least 6 months of disease stability or regression on neoadjuvant systemic therapy will be enrolled. Eligible patients who also meet center-specific medical criteria for transplant listing will be listed in the United Network of Organ Sharing (UNOS) national registry. When a decision is made to list the patient, the patient will be assigned a subject identification number. All organ offers will be received as per UNOS regulations. When a matching donor liver becomes available, the inclusion and exclusion criteria will be re-verified.
- Being tested
- Liver Transplant
- Keywords
- liver transplantation, neoadjuvant systemic therapy, intrahepatic cholangiocarcinoma, iCCA, locally advanced non-metastatic iCCA, non-metastatic intrahepatic cholangiocarcinoma, liver transplant, unresectable intrahepatic cholangiocarcinoma, locally advanced intrahepatic cholangiocarcinoma
- Medical subject headings
- Cholangiocarcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Liver TransplantProcedure or surgery
Also called Orthotopic liver transplantation
Whole liver allotransplantation will be performed for patients on the liver transplant waiting list
| Study group | Role | What they receive |
|---|---|---|
| Intrahepatic cholangiocarcinoma listed for liver transplant | Listed patients enrolled with diagnosis of intrahepatic cholangiocarcinoma will be enrolled on an intent to treat basis with comparison between patients receiving transplant versus those who expire or are removed from the waitlist. Receives: Procedure: Liver Transplant |
What is being measured
The primary outcome is the main question the study is designed to answer.
5-year Overall Survival Rate (ORS)
5-year ORS is the length of time that patients diagnosed with locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic therapy followed by liver transplant (LT) are still alive post-LT.
Measured: 5 years from the time of transplant or until death of patient, whichever came first
Secondary outcomes (3)
Recurrence-free survival (RFS)
RFS is the length of time from liver transplantation (LT) to the time of disease recurrence, time of patient death, or time of study completion for patients with locally advanced non-metastatic intrahepatic cholangiocarcinoma treated with neoadjuvant systemic therapy followed by liver transplantation.
Measured: From date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years
Intent-to-treat Overall Survival Rate (ITT ORS)
ITT ORS is the length of time that patients diagnosed with locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic therapy and waitlisted for liver transplant for iCCA are still alive after being waitlisted for liver transplantation.
Measured: 5 years from time of waitlist or until death of patient, whichever came first
Post-liver transplant functional assessments to identify postoperative complications, short-term morbidities, and long-term morbidities
All serious adverse events will be followed and documented, including bleeding requiring re-operation, hepatic artery or portal vein thrombosis, bile duct leak, bile duct stricture, primary non-function of the transplant liver, need for re-transplant of the liver.
Measured: From date of emergence of a post-transplant adverse event until the date the adverse event is designated as resolved by investigator or its effect on patient's condition stabilizes, whichever came first, assessed up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2023
- Study start15 Dec 2023
- Primary completionNov 2028 (estimated)
- Study completionNov 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (30)Papers the sponsor has linked to this study.
- Other trials for Intrahepatic CholangiocarcinomaStudies of the same condition, open and under way.
- More trials run by Rutgers, The State University of New JerseyThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 30 participants (estimated)
- Target duration
- 5 Years
Sponsor and investigators
- Lead sponsor
- Rutgers, The State University of New Jersey
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Keri E. Lunsford, Rutgers, The State University of New Jersey
- Investigators
- Keri E Lunsford, MD, PhD, Principal investigator, Rutgers University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06140134
- Sponsor's protocol ID
- Pro2021000973
- Status last verified
- Mar 2026
- First submitted
- 2 Oct 2023
- Last updated
- 20 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results reported in this study after deidentification (text, tables, figures and appendices)
Publications
Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, Lind GE, Folseraas T, Forbes SJ, Fouassier L, Geier A, Calvisi DF, Mertens JC, Trauner M, Benedetti A, Maroni L, Vaquero J, Macias RI, Raggi C, Perugorria MJ, Gaudio E, Boberg KM, Marin JJ, Alvaro D. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016 May;13(5):261-80. doi: 10.1038/nrgastro.2016.51. Epub 2016 Apr 20.
PubMed 27095655Spolverato G, Kim Y, Ejaz A, Alexandrescu S, Marques H, Aldrighetti L, Gamblin TC, Pulitano C, Bauer TW, Shen F, Sandroussi C, Poultsides G, Maithel SK, Pawlik TM. Conditional Probability of Long-term Survival After Liver Resection for Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis of 535 Patients. JAMA Surg. 2015 Jun;150(6):538-45. doi: 10.1001/jamasurg.2015.0219.
PubMed 25831462Benson AB 3rd, Abrams TA, Ben-Josef E, Bloomston PM, Botha JF, Clary BM, Covey A, Curley SA, D'Angelica MI, Davila R, Ensminger WD, Gibbs JF, Laheru D, Malafa MP, Marrero J, Meranze SG, Mulvihill SJ, Park JO, Posey JA, Sachdev J, Salem R, Sigurdson ER, Sofocleous C, Vauthey JN, Venook AP, Goff LW, Yen Y, Zhu AX. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw. 2009 Apr;7(4):350-91. doi: 10.6004/jnccn.2009.0027. No abstract available.
PubMed 19406039Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D'Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O'Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008 Jul;248(1):84-96. doi: 10.1097/SLA.0b013e318176c4d3.
PubMed 18580211Hyder O, Hatzaras I, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L, Ferrone CR, Zhu AX, Bauer TW, Walters DM, Groeschl R, Gamblin TC, Marsh JW, Nguyen KT, Turley R, Popescu I, Hubert C, Meyer S, Choti MA, Gigot JF, Mentha G, Pawlik TM. Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery. 2013 Jun;153(6):811-8. doi: 10.1016/j.surg.2012.12.005. Epub 2013 Mar 15.
PubMed 23499016Tabrizian P, Jibara G, Hechtman JF, Franssen B, Labow DM, Schwartz ME, Thung SN, Sarpel U. Outcomes following resection of intrahepatic cholangiocarcinoma. HPB (Oxford). 2015 Apr;17(4):344-51. doi: 10.1111/hpb.12359. Epub 2014 Nov 14.
PubMed 25395176Wang Y, Li J, Xia Y, Gong R, Wang K, Yan Z, Wan X, Liu G, Wu D, Shi L, Lau W, Wu M, Shen F. Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J Clin Oncol. 2013 Mar 20;31(9):1188-95. doi: 10.1200/JCO.2012.41.5984. Epub 2013 Jan 28.
PubMed 23358969Doussot A, Gonen M, Wiggers JK, Groot-Koerkamp B, DeMatteo RP, Fuks D, Allen PJ, Farges O, Kingham TP, Regimbeau JM, D'Angelica MI, Azoulay D, Jarnagin WR. Recurrence Patterns and Disease-Free Survival after Resection of Intrahepatic Cholangiocarcinoma: Preoperative and Postoperative Prognostic Models. J Am Coll Surg. 2016 Sep;223(3):493-505.e2. doi: 10.1016/j.jamcollsurg.2016.05.019. Epub 2016 Jun 11.
PubMed 27296525Gupta R, Gupta J. Strategies to improve survival of patients with intrahepatic cholangiocarcinoma undergoing liver transplantation. Hepatology. 2017 May;65(5):1777-1778. doi: 10.1002/hep.28994. Epub 2017 Feb 3. No abstract available.
PubMed 27997682Rana A, Hong JC. Orthotopic liver transplantation in combination with neoadjuvant therapy: a new paradigm in the treatment of unresectable intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. 2012 May;28(3):258-65. doi: 10.1097/MOG.0b013e32835168db.
PubMed 22333563Sapisochin G, Facciuto M, Rubbia-Brandt L, Marti J, Mehta N, Yao FY, Vibert E, Cherqui D, Grant DR, Hernandez-Alejandro R, Dale CH, Cucchetti A, Pinna A, Hwang S, Lee SG, Agopian VG, Busuttil RW, Rizvi S, Heimbach JK, Montenovo M, Reyes J, Cesaretti M, Soubrane O, Reichman T, Seal J, Kim PT, Klintmalm G, Sposito C, Mazzaferro V, Dutkowski P, Clavien PA, Toso C, Majno P, Kneteman N, Saunders C, Bruix J; iCCA International Consortium. Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment. Hepatology. 2016 Oct;64(4):1178-88. doi: 10.1002/hep.28744. Epub 2016 Aug 24.
PubMed 27481548Goldstein RM, Stone M, Tillery GW, Senzer N, Levy M, Husberg BS, Gonwa T, Klintmalm G. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg. 1993 Dec;166(6):768-71; discussion 771-2. doi: 10.1016/s0002-9610(05)80696-8.
PubMed 8273866Pichlmayr R, Weimann A, Oldhafer KJ, Schlitt HJ, Klempnauer J, Bornscheuer A, Chavan A, Schmoll E, Lang H, Tusch G, et al. Role of liver transplantation in the treatment of unresectable liver cancer. World J Surg. 1995 Nov-Dec;19(6):807-13. doi: 10.1007/BF00299775.
PubMed 8553670Becker NS, Rodriguez JA, Barshes NR, O'Mahony CA, Goss JA, Aloia TA. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg. 2008 Jan;12(1):117-22. doi: 10.1007/s11605-007-0335-4. Epub 2007 Oct 26.
PubMed 17963015Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, Botha JF, Mezrich JD, Chapman WC, Schwartz JJ, Hong JC, Emond JC, Jeon H, Rosen CB, Gores GJ, Heimbach JK. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012 Jul;143(1):88-98.e3; quiz e14. doi: 10.1053/j.gastro.2012.04.008. Epub 2012 Apr 12.
PubMed 22504095
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single-Arm Nonrandomized Phase II Study of Liver Transplantation in Locally Advanced Unresectable Non-Metastatic Intrahepatic Cholangiocarcinoma Treated With Neoadjuvant Systemic Therapy
- ClinicalTrials.gov ID
- NCT06140134
- Acronym / sponsor ID
- Pro2021000973
- Keywords
- liver transplantation, neoadjuvant systemic therapy, intrahepatic cholangiocarcinoma, iCCA, locally advanced non-metastatic iCCA, non-metastatic intrahepatic cholangiocarcinoma, liver transplant, unresectable intrahepatic cholangiocarcinoma
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Rutgers, The State University of New JerseyUniversity, hospital or other
- Study start
- 15 Dec 2023 (actual)
- Primary completion
- Nov 2028 (estimated)
- Study completion
- Nov 2029 (estimated)
- First posted
- 18 Nov 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of the current study is to determine the potential efficacy of liver transplantation in the form of patients' overall survival (OS) after neoadjuvant systemic therapy in patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) in comparison to patients historically treated with chemotherapy alone.
Detailed description
Research Significance:
Cholangiocarcinoma, which arises from biliary epithelium, can be anatomically subdivided into distal, hilar, and intrahepatic subgroups. Intrahepatic cholangiocarcinoma (iCCA) constitutes the second most common primary liver cancer after hepatocellular carcinoma, with a rising incidence but without parallel advances in treatment or patient outcome. At present, surgical resection is the only widely accepted potentially curative therapy for iCCA; however, 5-year survival rates for resectable disease are less than 25%. This high mortality is attributed to high tumor recurrence. Two-thirds of patients who undergo curative-intent resection for iCCA suffer from postoperative disease recurrence, most commonly in the remnant liver, followed by the peritoneum and abdominal lymph nodes. Approximately 83% of recurrences occur within the first 2 years after resection, suggesting inadequate local tumor control with resection in this highly infiltrative cancer.
Liver transplantation for intrahepatic cholangiocarcinoma:
While liver transplantation has been previously investigated for unresectable iCCA, the outcomes have been poor in comparison to the results for hepatocellular carcinoma, with 18-25% OS and RFS after 5 years; however, most studies evaluated patients with either incidental iCCA or iCCA misdiagnosed prior to transplant as hepatocellular carcinoma (HCC). Thus, iCCA is considered by most centers to be a formal contraindication to liver transplantation.
Neoadjuvant therapy with subsequent liver transplantation for perihilar cholangiocarcinoma:
Similar to iCCA, liver transplantation outcomes for perihilar cholangiocarcinoma were initially poor; however, an analysis of the United Network of Organ Sharing (UNOS) database found a significant survival benefit for patients with perihilar cholangiocarcinoma who received pre-transplant neoadjuvant systemic therapy compared with patients who transplanted for incident disease. Subsequently, several studies reported improved survival for hilar cholangiocarcinoma treated with neoadjuvant chemoradiation followed by liver transplantation. A multicenter study reported a 65% 5-year survival rate; liver transplantation has thus become the preferred treatment for patients with locally advanced unresectable hilar cholangiocarcinoma. Response to neoadjuvant therapy probably offers a means to select patients with hilar cholangiocarcinoma who might benefit from transplantation.
Neoadjuvant therapy with subsequent liver transplantation for intrahepatic cholangiocarcinoma (iCCA):
The published literature regarding liver transplantation (LT) for iCCA is mostly limited to incidental or misdiagnosed tumors identified on pathology, with most patients not receiving neoadjuvant therapy. Retrospective analysis including a small cohort of patients receiving neoadjuvant therapy showed that pre-transplant therapy appeared to decrease disease recurrence; however, reports did not distinguish between hilar cholangiocarcinoma and iCCA. In 2016, a multi-center, international, retrospective study investigated outcomes of liver transplantation in 48 iCCA patients who had not received neoadjuvant chemotherapy or locoregional therapy. In that study, 5-year OS was 65% for iCCA ≤2 cm and 45% for advanced larger lesions. Survival outcomes for locally advanced iCCA were worse, but patients having received pre-transplant neoadjuvant therapy in this series were excluded. The effect of neoadjuvant chemotherapy in patients with larger and multifocal tumors remains largely undefined. In 2020, another multicenter study compared the outcomes of patients with cirrhosis undergoing liver transplantation or liver resection who had iCCA or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The retrospective study analyzed a total of 49 LT and 26 liver resected patients with cirrhosis and histologically confirmed iCCA/ cHCC-CCA ≤5 cm. Results suggested that liver transplanted patients had a significantly lower tumor recurrence (diameter of largest nodule and tumor differentiation were independently predictive) and had a significantly higher 5-year recurrence-free survival. The effects of liver transplantation may provide a benefit for highly selected patients with cirrhosis and unresectable iCCA/cHCC-CCA with specific tumor dimensions. These findings suggests that liver transplantation might be a viable option for small, solitary iCCA in the absence of pre-transplant therapy or with locoregional therapy alone.
A subset of patients with iCCA experienced sustained response to neoadjuvant therapy, and it has been postulated that response duration might be an appropriate surrogate marker for the selection of patients for liver transplantation. Through the Methodist-MD Anderson Joint Cholangiocarcinoma Collaborative Committee, a recent prospective case-series of 6 patients with locally advanced unresectable iCCA without extrahepatic disease or vascular involvement was performed. Patients treated with neoadjuvant systemic chemotherapy with a minimum of 6 months radiographic disease stability or regression received liver transplantation. The median post-transplant follow-up duration was 36 months (range; 29-51). The OS rate was 100% (95% Confidence interval [CI]; 100-100) at 1-year, 83·3% (95% CI; 27·3-97·5) at 3 years, and 83·3% (95% CI; 27·3-97·5) at 5 years. Three patients developed post-transplant recurrence at a median of 7·6 months with 50% (95% CI; 11·1-80·4) RFS at 1-, 3-, and 5-years. Since publication, an additional 5 patients have been transplanted, and all patients have been followed for an additional 24 months. More recent data indicates a 5-year OS of 79.5% with RFS of 42.4%. In regards to recurrence, 4 of 5 occurred within 12 months of transplant. Retrospective evaluation of the pre-transplant imaging demonstrated evidence of pre-transplant extrahepatic disease. More stringent patient selection, such as the addition of a PET-CT scan, would likely avoid early recurrence in the majority of patients. Adverse events have been reported, including grade 3 postoperative ileus in one patient and grade 4 acute kidney injury requiring temporary dialysis in another patient. Both adverse events were among those commonly occurring with liver transplantation for any indication. No post-operative complications could be directly related to this protocol. Therefore, the investigators anticipate that selected patients with locally advanced non-metastatic iCCA who show pre-transplant disease stability on neoadjuvant therapy might benefit from liver transplantation.
Research Design and Methods:
This is a single-center phase II study. Patients with locally advanced unresectable iCCA with no evidence of vascular invasion or extrahepatic disease who have at least 6 months of disease stability or regression on neoadjuvant systemic therapy will be enrolled. Eligible patients who also meet center-specific medical criteria for transplant listing will be listed in the United Network of Organ Sharing (UNOS) national registry. When a decision is made to list the patient, the patient will be assigned a subject identification number. All organ offers will be received as per UNOS regulations. When a matching donor liver becomes available, the inclusion and exclusion criteria will be re-verified.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 5 Years
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Intrahepatic cholangiocarcinoma listed for liver transplant | – | Procedure: Liver TransplantListed patients enrolled with diagnosis of intrahepatic cholangiocarcinoma will be enrolled on an intent to treat basis with comparison between patients receiving transplant versus those who expire or are removed from the waitlist. |
Who may qualify
- Ages
- 18 to 89 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic chemotherapy with a radiographic disease stability or regression.
Key inclusion criteria (14 listed)
- Age ≥18 years of age on the day of consenting to the study.
- Patients must have histologically confirmed diagnosis of locally advanced intrahepatic cholangiocarcinoma
- Confirmed diagnosis of locally advanced unresectable iCCA with no vascular invasion, lymph node, or extrahepatic disease.
- Unresectable disease based on tumor location or underlying liver disease
- Patients must have ≥ 6 months of disease stability or tumor regression on neoadjuvant therapy. In cases in which patients had received second-line therapy, disease must also have been controlled for ≥ 6 months on that regimen.
Key exclusion criteria (11 listed)
- Age <18 years of age on the day of consenting to the study.
- Patients who have extrahepatic metastases, lymph node involvement, invasion or encasement of major hepatic vascular structures, perforation of the visceral peritoneum, invasion of extrahepatic structures, invasion of perihilar fat, periductular invasion, concurrent hepatoma or mixed hepatocellular cholangiocarcinoma.
- Concurrent severe and/or uncontrolled concurrent illness including, but not limited to, ongoing or active infection, acute fulminant liver failure, symptomatic congestive heart failure, unstable angina pectoris, severe uncorrected coronary artery disease, severe cerebrovascular disease, severe pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements and that would exclude the patient from eligibility for liver transplantation per institutional protocol.
- Prior solid organ or bone marrow transplant
- Dependent on ≥2 IV inotropic support to maintain hemodynamics
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Liver TransplantAlso: Orthotopic liver transplantationWhole liver allotransplantation will be performed for patients on the liver transplant waiting list | Procedure or surgery | Intrahepatic cholangiocarcinoma listed for liver transplant |
Primary outcome
5-year Overall Survival Rate (ORS)
Time frame: 5 years from the time of transplant or until death of patient, whichever came first
5-year ORS is the length of time that patients diagnosed with locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic therapy followed by liver transplant (LT) are still alive post-LT.
3 secondary outcomes
Recurrence-free survival (RFS)
Time frame: From date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years
Intent-to-treat Overall Survival Rate (ITT ORS)
Time frame: 5 years from time of waitlist or until death of patient, whichever came first
Post-liver transplant functional assessments to identify postoperative complications, short-term morbidities, and long-term morbidities
Time frame: From date of emergence of a post-transplant adverse event until the date the adverse event is designated as resolved by investigator or its effect on patient's condition stabilizes, whichever came first, assessed up to 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2026.
- Background: PubMed 27095655Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, Lind GE, Folseraas T, Forbes SJ, Fouassier L, Geier A, Calvisi DF, Mertens JC, Trauner M, Benedetti A, Maroni L, Vaquero J, Macias RI, Raggi C, Perugorria MJ, Gaudio E, Boberg KM, Marin JJ, Alvaro D. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016 May;13(5):261-80. doi: 10.1038/nrgastro.2016.51. Epub 2016 Apr 20.
- Background: PubMed 25831462Spolverato G, Kim Y, Ejaz A, Alexandrescu S, Marques H, Aldrighetti L, Gamblin TC, Pulitano C, Bauer TW, Shen F, Sandroussi C, Poultsides G, Maithel SK, Pawlik TM. Conditional Probability of Long-term Survival After Liver Resection for Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis of 535 Patients. JAMA Surg. 2015 Jun;150(6):538-45. doi: 10.1001/jamasurg.2015.0219.
- Background: PubMed 19406039Benson AB 3rd, Abrams TA, Ben-Josef E, Bloomston PM, Botha JF, Clary BM, Covey A, Curley SA, D'Angelica MI, Davila R, Ensminger WD, Gibbs JF, Laheru D, Malafa MP, Marrero J, Meranze SG, Mulvihill SJ, Park JO, Posey JA, Sachdev J, Salem R, Sigurdson ER, Sofocleous C, Vauthey JN, Venook AP, Goff LW, Yen Y, Zhu AX. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw. 2009 Apr;7(4):350-91. doi: 10.6004/jnccn.2009.0027. No abstract available.
- Background: PubMed 18580211Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D'Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O'Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008 Jul;248(1):84-96. doi: 10.1097/SLA.0b013e318176c4d3.
- Background: PubMed 23499016Hyder O, Hatzaras I, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L, Ferrone CR, Zhu AX, Bauer TW, Walters DM, Groeschl R, Gamblin TC, Marsh JW, Nguyen KT, Turley R, Popescu I, Hubert C, Meyer S, Choti MA, Gigot JF, Mentha G, Pawlik TM. Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery. 2013 Jun;153(6):811-8. doi: 10.1016/j.surg.2012.12.005. Epub 2013 Mar 15.
- Background: PubMed 25395176Tabrizian P, Jibara G, Hechtman JF, Franssen B, Labow DM, Schwartz ME, Thung SN, Sarpel U. Outcomes following resection of intrahepatic cholangiocarcinoma. HPB (Oxford). 2015 Apr;17(4):344-51. doi: 10.1111/hpb.12359. Epub 2014 Nov 14.
- Background: PubMed 23358969Wang Y, Li J, Xia Y, Gong R, Wang K, Yan Z, Wan X, Liu G, Wu D, Shi L, Lau W, Wu M, Shen F. Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J Clin Oncol. 2013 Mar 20;31(9):1188-95. doi: 10.1200/JCO.2012.41.5984. Epub 2013 Jan 28.
- Background: PubMed 27296525Doussot A, Gonen M, Wiggers JK, Groot-Koerkamp B, DeMatteo RP, Fuks D, Allen PJ, Farges O, Kingham TP, Regimbeau JM, D'Angelica MI, Azoulay D, Jarnagin WR. Recurrence Patterns and Disease-Free Survival after Resection of Intrahepatic Cholangiocarcinoma: Preoperative and Postoperative Prognostic Models. J Am Coll Surg. 2016 Sep;223(3):493-505.e2. doi: 10.1016/j.jamcollsurg.2016.05.019. Epub 2016 Jun 11.
- Background: PubMed 27997682Gupta R, Gupta J. Strategies to improve survival of patients with intrahepatic cholangiocarcinoma undergoing liver transplantation. Hepatology. 2017 May;65(5):1777-1778. doi: 10.1002/hep.28994. Epub 2017 Feb 3. No abstract available.
- Background: PubMed 22333563Rana A, Hong JC. Orthotopic liver transplantation in combination with neoadjuvant therapy: a new paradigm in the treatment of unresectable intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. 2012 May;28(3):258-65. doi: 10.1097/MOG.0b013e32835168db.
- Background: PubMed 27481548Sapisochin G, Facciuto M, Rubbia-Brandt L, Marti J, Mehta N, Yao FY, Vibert E, Cherqui D, Grant DR, Hernandez-Alejandro R, Dale CH, Cucchetti A, Pinna A, Hwang S, Lee SG, Agopian VG, Busuttil RW, Rizvi S, Heimbach JK, Montenovo M, Reyes J, Cesaretti M, Soubrane O, Reichman T, Seal J, Kim PT, Klintmalm G, Sposito C, Mazzaferro V, Dutkowski P, Clavien PA, Toso C, Majno P, Kneteman N, Saunders C, Bruix J; iCCA International Consortium. Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment. Hepatology. 2016 Oct;64(4):1178-88. doi: 10.1002/hep.28744. Epub 2016 Aug 24.
- Background: PubMed 8273866Goldstein RM, Stone M, Tillery GW, Senzer N, Levy M, Husberg BS, Gonwa T, Klintmalm G. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg. 1993 Dec;166(6):768-71; discussion 771-2. doi: 10.1016/s0002-9610(05)80696-8.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results reported in this study after deidentification (text, tables, figures and appendices)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Angenie Preval, PA contact
Keri E Lunsford, MD, PhD principal investigator
Rutgers University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Intrahepatic Cholangiocarcinoma and Cholangiocarcinoma, Intrahepatic, run by Rutgers, The State University of New Jersey at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Melissa Lugardo (973-972-8412, lugardme@uhnj.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
5-year Overall Survival Rate (ORS) (time frame: 5 years from the time of transplant or until death of patient, whichever came first). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06140134, which also lists 30 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2026.