Trifluridine/Tipiracil in Combination With Irinotecan as a Second Line Therapy in Patients With Cholangiocarcinoma

Study Overview
=================
Brief Summary
-----------------
This is a prospective, single arm, open label, non-randomized, exploratory, multi-centre pilot study with median progression free survival as primary outcome. In total 28 patients (including 3 calculated drop outs and invalid cases) with advanced cholangiocellular carcinoma after failure of a gemcitabine based first-line therapy will be enrolled at 5 centres. To examine the efficacy of a combination therapy of Trifluridine/Tipiracil and Irinotecan in patients with advanced, non resectable or metastatic cholangio- and gallbladder carcinoma after failure to respond to a previous gemcitabine treatment. The study will be accompanied by a translational research program: Before treatment and after each radiological tumor assessment (Q6W) blood and stool will be collected and extensive panels of biomarkers will be accessed.

Detailed Description
-----------------
This is a prospective, single arm, open label, non-randomized, exploratory, multi-centre pilot study with median progression free survival as primary outcome. In total 28 patients (including 3 calculated drop outs and invalid cases) with advanced cholangiocellular carcinoma after failure of a gemcitabine based first-line therapy will be enrolled at 5 centres. To examine the efficacy of a combination therapy of Trifluridine/Tipiracil and Irinotecan in patients with advanced, non resectable or metastatic cholangio- and gallbladder carcinoma after failure to respond to a previous gemcitabine treatment. The study will be accompanied by a translational research program: Before treatment and after each radiological tumor assessment (Q6W) blood and stool will be collected and extensive panels of biomarkers will be accessed. Patients will be treated until radiological progression. In average this will be about 4 months. A follow up is planned every 3 months up to 6 months to asses life quality and progression data.

Official Title
-----------------
Efficacy and Safety of Trifluridine/Tipiracil in Combination With Irinotecan as a Second Line Therapy in Patients With Cholangiocarcinoma

Conditions
-----------------
Cholangiocarcinoma

Intervention / Treatment
-----------------
* Combination Product: Combination of Lonsurf® and Irinotecan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent incl. participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) prior to performing any protocol-related procedures, including screening evaluations Age ≥ 18 years at time of study entry Histologically or cytologically confirmed, non-resectable, locally advanced or metastatic cholangiocarcinoma or gall bladder carcinoma Measurable or assessable disease according to RECIST 1.1 Documented disease progression after prior gemcitabine or gemcitabine containing therapy. Examples of permitted therapies include, but are not limited to: a) Single agent gemcitabine); b) Any gemcitabine-based regimen, with or without maintenance gemcitabine Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Ability to take medications orally Adequate blood count, liver-enzymes, and renal function: Absolute neutrophil count (ANC) > 1,500 cells/μL without the use of hematopoietic growth factors; and Platelet count ≥ 100 x 109/L (>100,000 per mm3) and Hemoglobin > 9 g/dL (blood transfusions are permitted for patients with hemoglobin levels below 9 g/dL) Serum total bilirubin ≤ 1.5x upper normal limit (ULN) (biliary drainage is allowed for biliary obstruction; elevated bilirubin should be caused by obstruction not impaired liver function as assessed by albumin and international normalised ratio (INR) values): Albumin levels ≥ 3.0 g/dL Patients not receiving therapeutic anticoagulation must have an INR< 1.5 ULN and partial thromboplastin time (PTT) < 1.5 ULN within 7 days prior to inclusion. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion. aspartate aminotransferase (AST) (SGOT) and Alanine transaminase (ALT) (SGPT) ≤ 5 x institutional upper limit of normal Serum Creatinine ≤ 1.5 x ULN and a calculated glomerular filtration rate ≥ 30 mL per minute Adequate renal and bone marrow function In case of liver cirrhosis: Child-Pugh A Women of childbearing potential must have a negative pregnancy test and must agree to adequate birth control if conception is possible. Males must agree to adequate birth control Exclusion Criteria: Age < 18 years Central nerve system (CNS) metastases Active, uncontrolled infection Additional malignancy within the past 2 years (except adequately treated in-situ carcinoma of the cervix or non-melanoma skin cancer) Clinically significant gastrointestinal disorders including bleeding, inflammation, occlusion, or diarrhea > grade 1 Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results Known hypersensitivity to Trifluridine/Tipiracil or Camptothecin (CPT)-11 or their components Medication that is known to interfere with any of the agents applied in the trial Pregnancy or lactating female Prior partial or total gastrectomy Previous radio- or radiochemotherapy, previous transarterial chemoembolisation (TACE), radiofrequency ablation (RFA) or selective intraarterial radiotherapy (SIRT) within 3 months prior to inclusion (except radiation for bone metastases) Patients who might be dependent on the sponsor, site or the investigator Patients who have been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a German drug law (AMG)].

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
Interventional Model Description: Combination of Lonsurf® and Irinotecan in 28 patients with cholangiocarcinoma.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Combination of Lonsurf® and Irinotecan | Combination Product: Combination of Lonsurf® and Irinotecan<br>* Trifluridine/Tipiracil (Lonsurf®) and Irinotecan Trifluridine/Tipiracil will be administered at a dose of 25 mg/m2 / dose twice daily on days 1-5 followed by a 9-days recovery period from day 6 trough day 14 of each 14-days treatment cycle. Irinotecan will be administered at the same time as Trifluridine/Tipiracil (Lonsurf®) on day 1 of each cycle at a dose of 180 mg/m2 / dose.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median progression free survival (PFS) | Median progression free survival (PFS) | through study completion, an average of 1 year ( 4 months intervention + 6 months Follow Up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival rate | Progression-free survival rate @ 4 months defined as the proportion of patients with non-progressive disease 4 months after inclusion by intention to treat analysis | At 4 months | 
| Median overall survival | Median overall survival | through study completion, an average of 1 year ( 4 months intervention + 6 months Follow Up) | 
| Response according to RECIST 1.1 | Proportion of patients with an objective response according to RECIST 1.1 | through study completion, an average of 1 year ( 4 months intervention + 6 months Follow Up) | 
| Safety (type, grade and frequency of Adverse Events (AEs)/Serious Adverse Events (SAEs)) | Safety (type, grade and frequency of AEs/SAEs) | through study completion, an average of 1 year ( 4 months intervention + 6 months Follow Up) | 
| Quality of life - European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-30) | Analysis of quality of life (EORTC QLQ-30) | through study completion, an average of 1 year ( 4 months intervention + 6 months Follow Up) | 
| Quality of life - EuroQol-5Dimensions-3Levels (EQ-5D-5L) questionnaires | Analysis of quality of life (EQ-5D-5L questionnaires) | through study completion, an average of 1 year ( 4 months intervention + 6 months Follow Up) |