Hepatic Arterial Infusion of Gemcitabine-oxaliplatin for Second-line Therapy in Non-metastatic Unresectable Intra-hepatic Cholangiocarcinoma

NCT ID: NCT03364530

Last Updated: 2026-01-05

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-11
• Study Completion Date: 2026-10-21

Brief Summary

We hypothesized that intra-arterial gemcitabine/oxaliplatin administered as second-line treatment could strongly improve objective response rate at 4 months after inclusion in patient with non-metastatic unresectable intra-hepatic cholangiocarcinoma.

Detailed Description

Cholangiocarcinomas are rare tumors with an extremely poor prognosis. The best therapeutic option (i.e. resection) can only be done in 20% of cases. Combinations of gemcitabine/platinum compounds were identified as the new standard first-line therapy

For patients with hepatic-only disease, therapy intensification using Intra-Arterial (IA) chemotherapy could be an attractive option since:

• Vascularisation of hepatic tumors is almost exclusively provided by the hepatic artery.
• Gemcitabine and oxaliplatin have a high rate of hepatic extraction during the first passage, thus allowing the drugs to reach high intra-tumoral concentrations with low systemic toxicity.
• The plasma concentration of gemcitabine after IA injection is 1/7th of that observed following Intra-Venous (IV) injection. No grade 3-4 toxicity has been observed in doses <1400mg/m².
• Phase I and I/II studies have shown dose-limiting toxicity between 150-175mg/m² for IA oxaliplatin every 3 weeks.
• We reported (Ghiringhelli, Chemotherapy 2013) in 12 patients with progressive intra-hepatic cholangiocarcinoma after IV gemcitabine/oxaliplatin, a partial response in 8 cases (stability in 3 cases) after IA gemcitabine/oxaliplatin. Among them, two were resected (R0) and three were treated by stereotactic radiation therapy).

Hepatic IA chemotherapy has rarely been used for the treatment of intra-hepatic cholangiocarcinoma (IHC), essentially in case-reports from Asia and in a few case-series that have mainly used IA monotherapy. The implantation of a hepatic arterial catheter has now been mastered by interventional radiologists and makes it possible to increase the intra-tumoral concentration of the drugs and probably to limit their systemic toxicity.

Very recently, we have reported that this combination in progressive IHC following systemic gemcitabine/oxaliplatin has led to partial responses and allowed certain patients to benefit from curative treatment.

This suggests that the intra-arterial approach increases the efficacy of these 2 drugs. For locally-advanced IHC, such a loco-regional approach is worth exploring in this poor-prognosis tumor, especially since so far 1) there is insufficient evidence to recommend a second-line chemotherapy schedule in this tumor and 2) targeted therapies have demonstrated no survival benefit over systemic chemotherapy alone.

It is a multicenter single-arm phase II trial aiming to determine the objective response rate 4 months after inclusion following IA gemcitabine / oxaliplatin administered as second-line treatment in patients with non-metastatic unresectable intra-hepatic cholangiocarcinoma.

It will be the first French phase II trial for 2nd line treatment in intrahepatic cholangiocarcinoma.

Conditions

Cholangiocarcinoma Non-resectable; Non-metastatic

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Gemcitabine-Oxaliplatin Regimen

Group Type: OTHER

Gemcitabine-Oxaliplatin Regimen

Intervention Type: DRUG

Vascularisation of hepatic tumors is almost exclusively provided by the hepatic artery.

Gemcitabine and oxaliplatin have a high rate of hepatic extraction during the first passage, thus allowing the drugs to reach high intra-tumoral concentrations with low systemic toxicity.

Hepatic intra arterial chemotherapy

Intervention Type: PROCEDURE

The implantation of a hepatic arterial catheter has now been mastered by interventional radiologists and makes it possible to increase the intra-tumoral concentration of the drugs and probably to limit their systemic toxicity.

Very recently, we have reported that this combination in progressive IHC following systemic gemcitabine/oxaliplatin has led to partial responses and allowed certain patients to benefit from curative treatment.

This suggests that the intra-arterial approach increases the efficacy of these 2 drugs. For locally-advanced IHC, such a loco-regional approach is worth exploring in this poor-prognosis tumor.

Interventions

Gemcitabine-Oxaliplatin Regimen

Vascularisation of hepatic tumors is almost exclusively provided by the hepatic artery.

Gemcitabine and oxaliplatin have a high rate of hepatic extraction during the first passage, thus allowing the drugs to reach high intra-tumoral concentrations with low systemic toxicity.

Intervention Type: DRUG

Hepatic intra arterial chemotherapy

The implantation of a hepatic arterial catheter has now been mastered by interventional radiologists and makes it possible to increase the intra-tumoral concentration of the drugs and probably to limit their systemic toxicity.

Very recently, we have reported that this combination in progressive IHC following systemic gemcitabine/oxaliplatin has led to partial responses and allowed certain patients to benefit from curative treatment.

This suggests that the intra-arterial approach increases the efficacy of these 2 drugs. For locally-advanced IHC, such a loco-regional approach is worth exploring in this poor-prognosis tumor.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Histologically-proven intrahepatic cholangiocarcinoma previously treated by first-line systemic therapy
• Absence of extra-hepatic metastasis or peritoneal carcinomatosis (as demonstrated by CT-scan)
• General health status : World Health Organization Performance Status = 0, 1
• Estimated life expectancy > 3 months
• Disease that is not suitable for resection with a curative intent, as validated by a multidisciplinary committee with at least one senior hepatic surgeon
• At least one measurable lesion according to RECIST 1.1 criteria
• Platelets ≥100,000/mm3, polynuclear neutrophils ≥ 2000/mm3 , hemoglobin 9g/dL (even transfused patients can be included)
• Creatininemia < 1.5 mol/L
• Creatinine clearance > 30 mL/min
• Bilirubinemia ≤2 N (after biliary drainage if necessary)
• Aspartate and Alanine Transaminase ≤ 5 mol/L
• Reference hepatic MRI (according to the foreseen protocol) done during the 30 days preceding the 1st cycle of treatment
• Written informed consent
• National health insurance cover

Exclusion Criteria

• Patients with cholangiocarcinoma of the gallbladder or common bile duct or those with hepatocholangiocarcinoma or a Klatskin tumor
• Patients who are eligible for surgical resection or liver transplantation
• Extra-hepatic metastases (Pulmonary micronodules <7mm without uptake on positron emission tomography are not a contra-indication)
• Presence of clinical ascites
• History of intra-arterial therapy or more than one line of systemic treatment
• Contra-indication or grade 3-4 allergy to any of the treatment drugs Gemcitabine, Oxaliplatin (notably myelosuppression developped before the beginning of the first cycle of therapy, peripheral sensory neuropathy before the first cycle of therapy, severe renal failure)
• Grade 2 peripheral neuropathy
• Ongoing participation or participation within the 21 days prior to inclusion in the study in another therapeutic trial with an experimental drug
• Concomitant systemic treatment with immunotherapy, chemotherapy or hormone therapy
• Serious non-stabilized disease, active uncontrolled infection or other serious underlying disorder likely to prevent the patient from receiving the treatment
• Pregnancy (beta-human chorionic gonadotropin positive), breast-feeding or the absence of effective contraception for women of child-bearing age
• Another cancer in the 5 years preceding or at the time of inclusion in the trial (except for in situ cervical cancer or basal cell carcinoma of the skin)
• Allergy or contra-indication to iodine contrast agents (thyrotoxicosis, allergy to the active substance or excipients)
• Treatment with anticoagulants (heparin or AVK) that cannot be interrupted for 12 hours
• Treatment with anti-platelets that cannot be interrupted for 5 days for aspirin or Plavix.
• Contra-indication for use of an intra-arterial approach (severe arteriopathy)
• Legal incapacity (persons in custody or under guardianship)
• Deprived of liberty Subject (by judicial or administrative decision)
• Impossibility to sign the informed consent document or to adhere to the medical follow-up of the trial for geographical, social or psychological reasons
• Contraindication for the MRI : Pacemaker or neurosensorial stimulator or implantable defibrillator, cochlear implant, ferromagnetic foreign body similar to the nervous structure.

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

Sponsors

Federation Francophone de Cancerologie Digestive

OTHER

Sponsor Role: collaborator

University Hospital, Montpellier

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Boris GUIU

Role: PRINCIPAL_INVESTIGATOR

Montpellier University Hospital

Locations

Amiens University Hospital

Amiens, , France

Site Status: RECRUITING

Angers University Hospital

Angers, , France

Site Status: RECRUITING

Bordeaux University Hospital

Bordeaux, , France

Site Status: RECRUITING

Centre Georges François Leclerc

Dijon, , France

Site Status: RECRUITING

Uhmontpellier

Montpellier, , France

Site Status: RECRUITING

Hôpital Européen Georges Pompidou

Paris, , France

Site Status: RECRUITING

Institut Gustave Roussy

Villejuif, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Chloé Guillot

Role: CONTACT

chloe-guillot@chu-montpellier.fr

+33467337327

Facility Contacts

Bruno CHAUFFERT

Role: primary

Antoine BOUVIER

Role: primary

Jean-Frédéric BLANC

Role: primary

François GHIRINGHELLI

Role: primary

BORIS GUIU, MD, phD

Role: primary

b-guiu@chu-montpellier.fr

467337152 ext. 33

Julien TAIEB

Role: primary

Valérie BOIGE

Role: primary

Other Identifiers

UF 9794

Identifier Type: OTHER

Identifier Source: secondary_id

RECHMPL17_0025

Identifier Type: -

Identifier Source: org_study_id