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

Study Overview
=================
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.

Official Title
-----------------
Phase II Trial of Trifluridine/Tipiracil in Combination With Irinotecan in Biliary Tract Cancers

Conditions
-----------------
Refractory Bile Duct Carcinoma, Advanced Bile Duct Carcinoma, Advanced Gallbladder 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

Intervention / Treatment
-----------------
* Drug: Irinotecan
* Drug: Irinotecan Hydrochloride
* Drug: Trifluridine and Tipiracil Hydrochloride


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (trifluridine and tipiracil, irinotecan)<br>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. | Drug: Irinotecan<br>* Given IV<br>Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: Trifluridine and Tipiracil Hydrochloride<br>* Given PO<br>* Other names: Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 20 months | 
| 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. | Up to 20 months | 
| 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. | From study entry to the first of either disease progression or death from any cause, assessed up to 20 months | 
| 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. | From study entry to death from any cause, assessed up to 20 months | 
| 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. | Up to 28 days |