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Trifluridine/Tipiracil and Irinotecan for the Treatment of Advanced Refractory Biliary Tract Cancer

Primary Purpose

Advanced Bile Duct Carcinoma, Advanced Gallbladder Carcinoma, Refractory Bile Duct Carcinoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Irinotecan
Irinotecan Hydrochloride
Trifluridine and Tipiracil Hydrochloride
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Bile Duct Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histological confirmation of advanced biliary tract cancers including cancers originating in the gallbladder who have received at least one line of systemic anticancer therapy

    • Note: Patients who have either progressed on or are intolerant to the prior therapy can be included in this study

  • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria

    • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease. Disease that is measurable by physical examination only is not eligible
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (=< 21 days prior to registration)
  • Platelet count >= 100,000/mm^3 (=< 21 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (=< 21 days prior to registration)
  • Aspartate transaminase (AST) or alanine transaminase (ALT) =< 3 x ULN (=< 21 days prior to registration)
  • Creatinine =< 1.5 x ULN (=< 21 days prior to registration)
  • Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only
  • Provide written informed consent
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Willingness to provide mandatory blood and tissue specimens for correlative research

Exclusion Criteria:

  • Any of the following because this study involves an agent that has potential genotoxic, mutagenic and teratogenic effects:

    • Pregnant persons
    • Nursing persons
    • Persons of childbearing potential who are unwilling to employ adequate contraception for at least 3 months after the last dose of the study drug
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy

    • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 21 days prior to registration
  • Receiving any anticancer therapy for biliary tract cancer =< 21 days prior to registration

  • Other active malignancy requiring treatment in =< 6 months prior to registration

    • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
    • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
  • History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Previous treatment with irinotecan or irinotecan-based chemotherapy for biliary tract cancers

Sites / Locations

  • Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (trifluridine and tipiracil, irinotecan)

Arm Description

Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and irinotecan hydrochloride IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Progression-free Survival (PFS)
Will be defined as the proportion of evaluable patients who are progression-free (stable disease, partial response, complete response) at 16 weeks and assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson.

Secondary Outcome Measures

Overall Response Rate (ORR)
Will be defined as the proportion of patients who experience either a partial response or complete response as their best response. ORR will be reported descriptively and a 95% confidence interval will be reported.
Disease Control Rate (DCR)
Will be defined as the proportion of patients who experience a partial response, complete response, or have stable disease as their best response. DCR will be reported descriptively and a 95% confidence interval will be reported.
PFS
Will be determined based on RECIST v 1.1. PFS will be estimated using the Kaplan-Meier method. The median PFS and 95% confidence interval will be reported. Patients will be censored at the last disease assessment date.
Overall Survival (OS)
Will be estimated using the Kaplan-Meier method. The median OS and 95% confidence interval will be reported. Patients will be censored at the date patient was last known to be alive.
Number of Participants With Adverse Events
The maximum grade for each type of adverse event by patient will be summarized by frequencies and percentages using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Full Information

First Posted
August 27, 2019
Last Updated
August 8, 2023
Sponsor
Mayo Clinic
Collaborators
National Comprehensive Cancer Network
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1. Study Identification

Unique Protocol Identification Number
NCT04072445
Brief Title
Trifluridine/Tipiracil and Irinotecan for the Treatment of Advanced Refractory Biliary Tract Cancer
Official Title
Phase II Trial of Trifluridine/Tipiracil in Combination With Irinotecan in Biliary Tract Cancers
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
October 18, 2019 (Actual)
Primary Completion Date
August 13, 2021 (Actual)
Study Completion Date
August 13, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mayo Clinic
Collaborators
National Comprehensive Cancer Network

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well trifluridine/tipiracil and irinotecan work in treating patients with biliary tract cancer that has spread to other places in the body (advanced) and has not responded to treatment (refractory). Trifluridine/tipiracil and irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVE: I. Determine the efficacy of trifluridine and tipiracil hydrochloride (trifluridine/tipiracil) in combination with irinotecan hydrochloride (irinotecan) in patients with refractory biliary tract cancers using progression-free survival (PFS) at 16 weeks. SECONDARY OBJECTIVES: I. Assess the safety and tolerability of trifluridine/tipiracil in combination with irinotecan in patients with refractory biliary tract cancers through adverse event monitoring. II. Further explore the efficacy of trifluridine/tipiracil in combination with irinotecan in patients with refractory biliary tract cancers by overall response rates (ORR), disease control rates (DCR), and overall survival (OS). CORRELATIVE RESEARCH: I. To determine if the number of circulating tumor cells (CTCs) or the level of cell-free deoxyribonucleic acid (DNA) (cfDNA) at baseline is prognostic or predictive to the response to therapy. II. To determine if changes in CTCs or cfDNA correlate with efficacy endpoints. III. To determine if drug response from a parallel ex vivo trial using patient-derived tumor organoid correlates with clinical response to trifluridine/tipiracil plus irinotecan. IV. To evaluate the role of thymidine kinase 1 (TK1) in predicting the clinical benefit of trifluridine/tipiracil plus irinotecan and discover potential mechanisms of resistance using patient-derived tumor organoid and pre-treatment biopsy specimen. EXPLORATORY RESEARCH: I. To evaluate patients who received prior treatment with fluorouracil (5-FU) independently from the entire population in the following areas: PFS, safety and tolerability, ORR, DCR, and OS. OUTLINE: Patients receive trifluridine and tipiracil hydrochloride orally (PO) twice daily (BID) on days 1-5 and irinotecan hydrochloride (IV) over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 2 years after study registration.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Bile Duct Carcinoma, Advanced Gallbladder Carcinoma, Refractory Bile Duct Carcinoma, Refractory Gallbladder Carcinoma, Stage III Distal Bile Duct Cancer AJCC v8, Stage III Gallbladder Cancer AJCC v8, Stage III Intrahepatic Bile Duct Cancer AJCC v8, Stage IIIA Distal Bile Duct Cancer AJCC v8, Stage IIIA Gallbladder Cancer AJCC v8, Stage IIIA Intrahepatic Bile Duct Cancer AJCC v8, Stage IIIB Distal Bile Duct Cancer AJCC v8, Stage IIIB Gallbladder Cancer AJCC v8, Stage IIIB Intrahepatic Bile Duct Cancer AJCC v8, Stage IV Distal Bile Duct Cancer AJCC v8, Stage IV Gallbladder Cancer AJCC v8, Stage IV Intrahepatic Bile Duct Cancer AJCC v8, Stage IVA Gallbladder Cancer AJCC v8, Stage IVB Gallbladder Cancer AJCC v8

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (trifluridine and tipiracil, irinotecan)
Arm Type
Experimental
Arm Description
Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and irinotecan hydrochloride IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Irinotecan
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Irinotecan Hydrochloride
Other Intervention Name(s)
Campto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, Irinotecan Hydrochloride Trihydrate, Irinotecan Monohydrochloride Trihydrate, U-101440E
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Trifluridine and Tipiracil Hydrochloride
Other Intervention Name(s)
Lonsurf, TAS 102, TAS-102, Tipiracil Hydrochloride Mixture with Trifluridine, Trifluridine/Tipiracil, Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Progression-free Survival (PFS)
Description
Will be defined as the proportion of evaluable patients who are progression-free (stable disease, partial response, complete response) at 16 weeks and assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson.
Time Frame
Up to 16 weeks
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
Will be defined as the proportion of patients who experience either a partial response or complete response as their best response. ORR will be reported descriptively and a 95% confidence interval will be reported.
Time Frame
Up to 20 months
Title
Disease Control Rate (DCR)
Description
Will be defined as the proportion of patients who experience a partial response, complete response, or have stable disease as their best response. DCR will be reported descriptively and a 95% confidence interval will be reported.
Time Frame
Up to 20 months
Title
PFS
Description
Will be determined based on RECIST v 1.1. PFS will be estimated using the Kaplan-Meier method. The median PFS and 95% confidence interval will be reported. Patients will be censored at the last disease assessment date.
Time Frame
From study entry to the first of either disease progression or death from any cause, assessed up to 20 months
Title
Overall Survival (OS)
Description
Will be estimated using the Kaplan-Meier method. The median OS and 95% confidence interval will be reported. Patients will be censored at the date patient was last known to be alive.
Time Frame
From study entry to death from any cause, assessed up to 20 months
Title
Number of Participants With Adverse Events
Description
The maximum grade for each type of adverse event by patient will be summarized by frequencies and percentages using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time Frame
Up to 28 days
Other Pre-specified Outcome Measures:
Title
Circulating Tumor Cells (CTCs) or Cell-free Deoxyribonucleic Acid (cfDNA) at Baseline
Description
Will determine if CTCs or cfDNA at baseline will correlate with prognosis or response to therapy.
Time Frame
Baseline
Title
Change in CTCs or cfDNA
Description
Will determine if change in CTCs or cfDNA will correlate with efficacy endpoints.
Time Frame
Baseline up to 20 months
Title
Correlation of Response
Description
Will determine if drug response from a parallel ex vivo trial using patient-derived tumor organoid correlates with clinical response to trifluridine and tipiracil hydrochloride (trifluridine/tipiracil) plus irinotecan hydrochloride (irinotecan).
Time Frame
Up to 20 months
Title
Prediction of Clinical Benefit by Thymidine Kinase 1 (TK1)
Description
Will evaluate the role of TK1 in predicting the clinical benefit of trifluridine/tipiracil plus irinotecan and discover potential mechanisms of resistance using patient-derived tumor organoid and pre-treatment biopsy specimen.
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histological confirmation of advanced biliary tract cancers including cancers originating in the gallbladder who have received at least one line of systemic anticancer therapy Note: Patients who have either progressed on or are intolerant to the prior therapy can be included in this study Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease. Disease that is measurable by physical examination only is not eligible Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Absolute neutrophil count (ANC) >= 1500/mm^3 (=< 21 days prior to registration) Platelet count >= 100,000/mm^3 (=< 21 days prior to registration) Total bilirubin =< 1.5 x upper limit of normal (ULN) (=< 21 days prior to registration) Aspartate transaminase (AST) or alanine transaminase (ALT) =< 3 x ULN (=< 21 days prior to registration) Creatinine =< 1.5 x ULN (=< 21 days prior to registration) Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only Provide written informed consent Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) Willingness to provide mandatory blood and tissue specimens for correlative research Exclusion Criteria: Any of the following because this study involves an agent that has potential genotoxic, mutagenic and teratogenic effects: Pregnant persons Nursing persons Persons of childbearing potential who are unwilling to employ adequate contraception for at least 3 months after the last dose of the study drug Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 21 days prior to registration Receiving any anticancer therapy for biliary tract cancer =< 21 days prior to registration Other active malignancy requiring treatment in =< 6 months prior to registration EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias Previous treatment with irinotecan or irinotecan-based chemotherapy for biliary tract cancers
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amit Mahipal
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Links:
URL
https://www.mayo.edu/research/clinical-trials
Description
Mayo Clinic Clinical Trials

Learn more about this trial

Trifluridine/Tipiracil and Irinotecan for the Treatment of Advanced Refractory Biliary Tract Cancer

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