A Trial of Systemic Chemotherapy in Combination With Conventional Transarterial Chemoembolization in Patients With Advanced Intra-Hepatic Cholangiocarcinoma

A Phase II Trial of Systemic Chemotherapy (Gemcitabine and Cisplatin) in Combination With Conventional Transarterial Chemoembolization (cTACE) in Patients With Advanced Intra-Hepatic Cholangiocarcinoma (ICC)

The study will be a single-center, single-arm, Phase II study of gemcitabine and cisplatin in combination with conventional trans-arterial chemoembolization therapy in adult patients with advanced ICC. 25 patients will be enrolled over the course of 2 years, with an additional 1.5 years for patient follow-up.

Study Overview

• Status: Terminated
• Conditions: Unresectable Intrahepatic Cholangiocarcinoma
• Intervention / Treatment: Drug: gemcitabine; Drug: Cisplatin; Drug: Conventional TACE (transarterial chemoembolization) with Doxorubicin/Mitomycin-C

Detailed Description

Eligible patients enrolled on study will receive a chemotherapy regimen of gemcitabine and cisplatin administered intravenously on Days 1 and 8 of a 21-day cycle. After every 2 cycles of systemic chemotherapy, patients will receive contrast-enhanced MRI to assess liver disease; conventional trans-arterial chemoembolization (TACE) will be performed as indicated based on this assessment. Patients will receive a maximum of 8 cycles of the gemcitabine/cisplatin combination. Up to 3 TACE treatments may be delivered in this same time frame, with the first TACE taking place after 2 cycles of systemic chemotherapy. Following the treatment period, patients will continue clinical follow-up at 3 month intervals until study exit at 18 months post the start of treatment.

It is hypothesized that the addition of conventional transarterial chemoembolization to standard chemotherapy will result in an improvement in PFS in patients with advanced, unresectable ICC, including patients with extra-hepatic disease.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Smilow Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient is at least 18 years of age.
• Patient has advanced, unresectable intrahepatic cholangiocarcinoma (ICC). Advanced, unresectable ICC is defined as biopsy-confirmed adenocarcinoma in the liver, with an immunohistochemical profile consistent with a pancreatico-biliary primary, not involving the common bile duct or bifurcation, and not amenable to surgical resection.
• Eligible for conventional TACE as defined by local treatment guidelines.
• Child-Pugh class of A to B7.

• Adequate end-organ and bone marrow function as manifested as:

  • Hemoglobin ≥ 9 g/dL
  • Absolute neutrophil count ≥ 1500/mm3
  • Creatinine ≤ 2.0 g/dL
  • AST and ALT ≤ 5 x ULN
  • Albumin ≥ 2.4 mg/dL
  • Total bilirubin ≤ 2.5 mg/dL
  • Platelets ≥ 100,000/mm3
  • For TACE procedures, subjects are allowed to have platelets ≥ 75,000/mm3.
• Disease is liver-dominant with >70% of measurable disease burden within the hepatic parenchyma.
• No prior surgery or chemotherapy for ICC.
• ECOG performance status of 0-1.
• No other active malignancy within 2 years.
• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of the study.
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior or concurrent chemotherapy treatment for advanced ICC.
• History of allergic reactions attributed to compounds of similar chemical or biological composition to gemcitabine, cisplatin, doxorubicin, or mitomycin-C.
• Active treatment with CYP3A4 strong inhibitors or inducers.
• Recent surgical procedure within 21 days of study enrollment.
• Severe and/or uncontrolled co-morbid medical conditions including, but not limited to, active infection, viral hepatitis, congestive heart failure, cardiac arrhythmia, unstable angina pectoris, and psychiatric illness or social circumstance that would limit compliance with study requirements.
• Pregnancy during study duration.
• Active immunosuppressive medications.
• Presence of grade 2 or higher hepatic encephalopathy.
• Complete occlusion of the entire portal venous system. Partial or branch portal vein occlusion allowed if without reversal of flow.
• Radiotherapy within 21 days from treatment with study interventions or medications.
• Current, recent (within 4 weeks of first infusion of this study), or planned participation in additional experimental drug.
• Unstable angina.
• New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix C).
• History of myocardial infarction or CVA within 6 months prior to study enrollment.
• Clinically significant peripheral vascular disease.
• Inability to comply with study and/or follow-up procedures.
• Life expectancy of less than 12 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: All subjects; Patients must have advanced, unresectable intrahepatic cholangiocarcinoma (ICC) defined as biopsy-confirmed adenocarcinoma in the liver, with an immunohistochemical profile consistent with a pancreatico-biliary primary, not involving the common bile duct or bifurcation, and not amenable to surgical resection.

Drug: gemcitabine; 1000 mg/m^2 of gemcitabine on Day 1 and 8, Dosages may be modified or delayed due to toxicities; Drug: Cisplatin; 25 mg/m^2 on Day 1 and 8, Dosages may be modified or delayed due to toxicities; Drug: Conventional TACE (transarterial chemoembolization) with Doxorubicin/Mitomycin-C; If conventional transarterial chemoembolization (TACE) is warranted based on MRI assessment and the patient meets all the eligibility criteria for TACE therapy, then cTACE will be scheduled to take place during Week 3 of that cycle. Patients will always receive the first cTACE for study; follow-up cTACE will occur on demand.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	The primary objective of this study is to evaluate the 12-month progression-free survival (PFS) rate in adult patients with intrahepatic cholangiocarcinoma (ICC) after treatment with gemcitabine and cisplatin in combination with conventional TACE. This is the percentage of patients alive and free of progression at 12-months from enrollment on study. Radiographic assessment of disease burden will be evaluated by mRECIST and qEASL using an MRI scan obtained at the IR clinic visit.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Evaluation of overall survival (OS) of adult patients with advanced ICC treated with gemcitabine and cisplatin in combination with conventional TACE. Overall survival is the time from enrollment on study until death of the patient from any cause.	18 months
Overall Time to Progression (TTP)	Overall TTP is the time from enrollment on study until radiographic evidence of overall disease progression. Radiographic assessment will be evaluated by mRECIST using MRI every 2 cycles after intra-arterial therapy.	up to 18 months
Time to Untreatable Progression (TTUP)	TTUP in liver lesions is measured from the time of initiation on cTACE therapy until radiographic evidence of disease progression in targeted lesions. Radiographic assessment will be evaluated by mRECIST using MRI every 2 cycles after intra-arterial therapy.	up to 18 months
Toxicities of the Gemcitabine and Cisplatin Regimen in Combination With cTACE Therapy Using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.	To evaluate the toxicities of the gemcitabine and cisplatin regimen in combination with cTACE therapy in adult patients with advanced ICC. Safety will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	18 months
Correlation Between Changes in Dynamic Contrast-enhanced MRI of Liver Lesions and Progression Free Survival	early changes in dynamic contrast-enhanced MRI (DCE-MRI) will correlate with long term PFS or OS, specifically as they relate to lesions targeted with cTACE therapy	18 months
Correlation Between Changes in Dynamic Contrast-enhanced MRI of Liver Lesions and Overall Survival	early changes in dynamic contrast-enhanced MRI (DCE-MRI) will correlate with long term OS, specifically as they relate to lesions targeted with cTACE therapy	18 months

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Todd Schlachter, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2017
• Primary Completion (Actual): November 6, 2018
• Study Completion (Actual): November 6, 2018

Study Registration Dates

• First Submitted: December 6, 2016
• First Submitted That Met QC Criteria: December 14, 2016
• First Posted (Estimate): December 15, 2016

Study Record Updates

• Last Update Posted (Actual): December 30, 2019
• Last Update Submitted That Met QC Criteria: December 6, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Gemcitabine; Cisplatin; Doxorubicin; Mitomycins; Mitomycin
• Other Study ID Numbers: 1603017367

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes