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

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ClinicalTrials.gov Identifier: NCT02994251
Recruitment Status : Recruiting
First Posted : December 15, 2016
Last Update Posted : October 26, 2017
Sponsor:
Information provided by (Responsible Party):
Yale University

Brief Summary:
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 or disease Intervention/treatment Phase
Unresectable Intrahepatic Cholangiocarcinoma Drug: gemcitabine Drug: Cisplatin Drug: Conventional TACE (transarterial chemoembolization) with Doxorubicin/Mitomycin-C Phase 2

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  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (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)
Actual Study Start Date : December 2016
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020


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.




Primary Outcome Measures :
  1. progression-free survival [ Time Frame: 12 months ]
    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 :
  1. overall survival [ Time Frame: 18 months ]
    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.

  2. overall time to progression (TTP) [ Time Frame: up to 18 months ]
    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.

  3. time to untreatable progression (TTUP) [ Time Frame: up to 18 months ]
    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.

  4. 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 ]
    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.

  5. correlation between changes in dynamic contrast-enhanced MRI of liver lesions and progression free survival [ Time Frame: 18 months ]
    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

  6. correlation between changes in dynamic contrast-enhanced MRI of liver lesions and overall survival [ Time Frame: 18 months ]
    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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02994251


Contacts
Contact: Todd Schlachter, MD +1 (203) 785-4747 todd.schlachter@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: Todd Schlachter, MD    203-785-4747    todd.schlachter@yale.edu   
Sub-Investigator: Hyun Kim, MD         
Sub-Investigator: Stacey Stein, MD         
Sub-Investigator: Howard S Hochster, MD         
Sub-Investigator: Jill Lacy, MD         
Sub-Investigator: Jeffrey Pollak, MD         
Sponsors and Collaborators
Yale University
Investigators
Principal Investigator: Todd Schlachter Yale University

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02994251     History of Changes
Other Study ID Numbers: 1603017367
First Posted: December 15, 2016    Key Record Dates
Last Update Posted: October 26, 2017
Last Verified: October 2017

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

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