A Trial of Systemic Chemotherapy in Combination With Conventional Tran

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

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Purpose
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.

Condition Intervention Phase
Unresectable Intrahepatic Cholangiocarcinoma
Drug: gemcitabine
Drug: Cisplatin
Drug: Conventional TACE (transarterial chemoembolization) with Doxorubicin/Mitomycin-C
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:

Genetics Home Reference related topics: cholangiocarcinoma
Drug Information available for: Gemcitabine
Genetic and Rare Diseases Information Center resources: Intrahepatic Cholangiocarcinoma
U.S. FDA Resources

Further study details as provided by Yale University:

Primary Outcome Measures:
progression-free survival [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
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.

Secondary Outcome Measures:
overall survival [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
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.

overall time to progression (TTP) [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]
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.

time to untreatable progression (TTUP) [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]
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.

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. [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
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.

correlation between changes in dynamic contrast-enhanced MRI of liver lesions and progression free survival [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
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

correlation between changes in dynamic contrast-enhanced MRI of liver lesions and overall survival [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
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

Estimated Enrollment: 25
Study Start Date: December 2016
Estimated Study Completion Date: June 2020
Estimated Primary Completion Date: June 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

Eligibility

Ages Eligible for Study: 18 Years and older (Adult, Senior)
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
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.
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02994251

Contacts
Contact: Jean-Francois (Jeff) Geschwind, MD +1 (203) 785-5865 jeff.geschwind@yale.edu
Contact: Eliot Funai (203) 785-4246 eliot.funai@yale.edu

Locations
United States, Connecticut
Smilow Cancer Center Recruiting
New Haven, Connecticut, United States, 06510
Contact: Jeff Geschwind, MD 203-785-5865 jeff.geschwind@yale.edu
Sub-Investigator: Hyun Kim, MD
Sub-Investigator: Stacey Stein, MD
Sub-Investigator: Howard S Hochster, MD
Sub-Investigator: Todd Schlachter, MD
Sub-Investigator: Jill Lacy, MD
Sub-Investigator: Jeffrey Pollak, MD
Sponsors and Collaborators
Yale University
Investigators
Principal Investigator: Jean-Francois (Jeff) Geschwind Yale University
More Information

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02994251 History of Changes
Other Study ID Numbers: 1603017367
Study First Received: December 6, 2016
Last Updated: December 14, 2016
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

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

ClinicalTrials.gov processed this record on December 16, 2016