A Phase I Study of TAS-102 in Patients With Advanced Gastrointestinal Tumors.

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate the safety and determine the maximum tolerated dose of TAS-102 administered in combination with CPT-11 in patients with advanced gastrointestinal tumors.

Detailed Description
-----------------
This is an open-label, non-randomized, dose-escalation, Phase 1 study of TAS-102 administered in combination with CPT-11. The study will be conducted in 2 parts: a Dose Escalation Phase (Part 1) to determine the maximum tolerated dose and an Expansion Phase (Part 2) to further evaluate the safety, pharmacokinetics, and preliminary efficacy of the maximum tolerated dose. Patients will be assigned to sequential dose-level cohorts with each cohort corresponding to a pre-specified dose of TAS-102 and CPT-11 combination. Escalation to the subsequent dose level will occur only after the previous dose level is determined to be safe.

Official Title
-----------------
A Phase 1, Open-label, Non-randomized, Dose-escalating Safety, Tolerability, and Pharmacokinetic Study of TAS-102 in Combination With CPT-11 and Bevacizumab in Patients With Advanced Gastrointestinal Tumors

Conditions
-----------------
Advanced Gastrointestinal Tumors

Intervention / Treatment
-----------------
* Drug: TAS-102
* Drug: CPT-11
* Drug: Bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has provided written informed consent Has advanced gastrointestinal tumors refractory to at least 1 chemotherapy ECOG performance status of 0 or 1 Is able to take medications orally Has adequate organ function (bone marrow, kidney and liver) 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: Has had certain other recent treatment e.g. major surgery, extended field radiation, anticancer therapy, received investigational agent, within the specified time frames prior to study drug administration Presence of serious illnesses or medical condition(s) e.g. brain metastases, systemic infection, heart failure Has unresolved toxicity of greater than or equal to CTCAE Grade 1 attributed to any prior therapies Known sensitivity to TAS-102, CPT-11, Bevacizumab, or their components Is a pregnant or lactating female Has had either partial or total gastrectomy

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: TAS-102 and CPT-11 with or without Bevacizumab<br> | Drug: TAS-102<br>* Escalating doses (20-35 mg/m2/dose, based on tolerability), orally, twice daily on days 1-5 of each 14-day cycle. Number of cycles: until at least one of the discontinuation criteria is met.<br>Drug: CPT-11<br>* Escalating doses (30-minute infusion of 120-180 mg/m2/dose, based on tolerability), IV (in the vein) on Day 1 of each 14-day treatment cycle. Number of cycles: until at least one of the discontinuation criteria is met.<br>* Other names: camptothecin-11, irinotecan;Drug: Bevacizumab<br>* Dose (infusion of 5 mg/kg administered per site standard practice), IV (in the vein) on Day 1 of each 14-day treatment cycle. Number of cycles: until at least one of the discontinuation criteria is met.<br>* Other names: Avastin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine maximum tolerated dose | The maximum tolerated dose is defined as the highest dose level at which less than 33% of the evaluable patients treated experience a dose-limiting toxicity during Cycle 1 or Cycle 2 (ie, during the first 4 weeks) of study drug administration. | Through Cycle 1 and Cycle 2 (ie, 4 weeks) | 
| Safety monitoring including adverse events, vital signs, and laboratory assessments | Standard safety monitoring and grading using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) will be used. | Safety is assessed through 30 days following last administration of study medication or until initiation of new anticancer treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigate the safety of TAS-102 and CPT-11 at the MTD administered in combination with Bevacizumab (5 mg/kg IV). | Standard safety monitoring and grading using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) will be used. | Through 30 days following last administration of study medication or until initiation of new anticancer treatment | 
| Investigate the clinical pharmacokinetics (PK) of TAS-102, CPT-11, and their metabolites. | PK analysis for FTD, FTY, TPI, CPT-11, and SN-38 in plasma and will include Cmax, Tmax, AUC0-last, AUC0-inf, and T1/2. FTD and TPI: CL/F, Vd/F will be calculated. | Blood samples will be collected in Cycle 1 at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24 and 48 hours post AM dose of TAS-102 in combination with CPT-11. | 
| Document any preliminary antitumor activity of TAS-102 administered in combination with CPT-11 and in combination with CPT-11 and Bevacizumab. | Tumor assessments using Response Evlauation Criteria in Solid Tumors (RECIST) | After every 4 cycles (i.e., every 8 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Angiogenesis Inhibitor, Monoclonal Antibody, Vascular Endothelial Growth Factor A (VEGF-A)