Study of S 95005 in Combination With Oxaliplatin in Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to assess the safety and tolerability and to determine the recommended phase 2 dose of S 95005 given in combination with oxaliplatin in patients with metastatic colorectal cancer.

Detailed Description
-----------------
This is a one-arm study, which will be conducted in 2 parts: A dose-escalation part to determine the Maximum Tolerated Dose (MTD) of S 95005 in combination with oxaliplatin. An expansion part in patients treated at the recommended dose defined in the dose escalation part of this study to evaluate the safety, PK, and preliminary efficacy of S 95005 in combination with oxaliplatin and either bevacizumab or nivolumab.

Official Title
-----------------
Phase I Dose-escalation of S 95005 (TAS-102) in Combination With Oxaliplatin in Metastatic Colorectal Cancer

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: Trifluridine/tipiracil hydrochloride (S 95005)
* Drug: Oxaliplatin
* Drug: Bevacizumab
* Drug: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 years or older. Histologically confirmed metastatic colorectal cancer pretreated by at least one line of standard chemotherapy. Restaging scan within 28 days before the first study drug intake. During the dose-escalation part, patient must have at least one evaluable or measurable metastatic lesion; and during the expansion part, patient must have at least one measurable metastatic lesion. Life expectancy of more than 3 months. Performance status Eastern Cooperative Oncology Group (ECOG): 0-1. Adequate bone marrow, liver, and kidney function. For patients who will receive bevacizumab: coagulation parameters in normal limit or in therapeutic limit for patients treated with anticoagulant. For patients who will receive nivolumab: patients eligible for tumour biopsy and who agree to have two sequential biopsies during the study. Women of childbearing potential must have a negative pregnancy test. Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use highly effective birth control method. Women and female partners using hormonal contraceptive must also use a barrier method. Capacity to take oral tablet(s) without difficulty. Has provided written informed consent. Is willing and able to comply with scheduled visits and study procedures. Exclusion Criteria: Grade 2 or higher peripheral neuropathy. During expansion part, patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy with oxaliplatin. Patients with brain metastases or leptomeningeal metastasis. Other malignancy within the last 3 years (except for basal cell carcinoma or a non-invasive/in situ cervical cancer) Has had certain other recent treatment e.g. major surgery, field radiation, participation in another interventional study, within the specified time frames prior to study drug administration. Certain serious illnesses or serious medical conditions For patients who will receive bevacizumab: history of allergic reactions/hypersensitivity to bevacizumab, to any components used in the formulation, to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies. Grade 3 or higher hypersensitivity reaction to oxaliplatin or garde 1-2 hypersensitivity reaction to oxaliplatin not controlled with premedication. Patient previously treated by S 95005 or history of allergic reactions attributed to compounds of similar composition to S 95005 or any of its excipient. Patient with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Any condition that, in the judgment of the Investigator, may affect the patient's ability to understand and sign the informed consent and fully comply with all study procedure. Pregnancy or breast feeding. For patients planned to receive nivolumab: Patients with active autoimmune disease or history of clinically severe autoimmune disease. Patients with a condition requiring systemic treatment with either corticosteroids (> 20 mg daily prednisone equivalent) or other immunosuppressive medications within the specified time frames prior to first study drug intake. Prior treatment with anti-PD-1, anti-PD-L1, anti-programmed cell death ligand-2, anti-CD137, anti-OX-40, anti-CD40, anti-cytotoxic T lymphocyte-associated antigen-4 antibodies (CTLA-4), or any other immune checkpoint inhibitors. Prior events of immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis and renal dysfunction, immune-mediated rash, immune-mediated encephalitis. Allergic reactions/hypersensitivity to nivolumab or any components used in its formulation or previous severe hypersensitivity reaction to treatment with another monoclonal antibody. Has a known history of active tuberculosis (Bacillus Tuberculosis).

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: S 95005 + oxaliplatin (+/- bevacizumab or nivolumab)<br> | Drug: Trifluridine/tipiracil hydrochloride (S 95005)<br>* Film-coated tablets containing 15mg of trifluridine and 7.065mg of tipiracil hydrochloride, or 20mg of trifluridine and 9.42mg of tipiracil hydrochloride, given orally at the dose of 25 or 30 or 35 mg/m2/dose, until unacceptable toxicity according to the investigator, disease progression or patient withdrawal.<br>Drug: Oxaliplatin<br>* Concentrate for solution for infusion containing 5mg/ml of oxaliplatin, administered intravenously at the dose of 65 to 85 mg/m2, until unacceptable toxicity according to the investigator, disease progression or patient withdrawal.<br>Drug: Bevacizumab<br>* Concentrate for solution for infusion containing 25mg/ml of bevacizumab, administered intravenously at the dose of 5 mg/kg, until unacceptable toxicity according to the investigator, disease progression or patient withdrawal.<br>Drug: Nivolumab<br>* Concentrate for solution for infusion containing 10mg/ml of nivolumab, administered intravenously at the dose of 3 mg/kg, until unacceptable toxicity according to the investigator, disease progression or patient withdrawal.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of S95005 when given in combination with oxaliplatin |  | up to 4 weeks after the first treatment administration | 
| Dose Limiting Toxicity (DLT) of S95005 when given in combination with oxaliplatin |  | up to 4 weeks after the first treatment administration | 
| Number of participants with adverse events as a measure of safety and tolerability for S95005-oxaliplatin. | Adverse event reporting will be graded following the National Cancer Institute of Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 | through study completion, an average of 9 months | 
| Changes in standard hematology as a measure of safety and tolerability for S95005-oxaliplatin |  | through study completion, an average of 9 months | 
| Changes in biochemistry as a measure of safety and tolerability for S95005-oxaliplatin |  | through study completion, an average of 9 months | 
| Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin |  | through study completion, an average of 9 months | 
| Changes in urinalysis as a measure of safety and tolerability for S95005-oxaliplatin |  | through study completion, an average of 9 months | 
| Changes in vital signs as a measure of safety for S95005-oxaliplatin | Vital sign measurements will include temperature, systolic and diastolic blood pressure, heart rate, and respiratory rate. | through study completion, an average of 9 months | 
| Changes in ECOG (Eastern Cooperative Oncology Group) performance status as a measure of safety and tolerability for S95005-oxaliplatin |  | through study completion, an average of 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor activity assessed by RECIST (Response Evaluation Criteria in Solid Tumors) and CEA (Carcinoembryonic Antigen) |  | through study completion, an average of 9 months | 
| Number of participants with adverse events as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab. | Adverse event reporting will be graded following the National Cancer Institute of Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 | through study completion, an average of 9 months | 
| Changes in standard hematology as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab. |  | through study completion, an average of 9 months | 
| Changes in biochemistry as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab. |  | through study completion, an average of 9 months | 
| Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab. |  | through study completion, an average of 9 months | 
| Changes in urinalysis as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab. |  | through study completion, an average of 9 months | 
| Changes in vital signs as a measure of safety for S95005-oxaliplatin + bevacizumab or nivolumab. | Vital sign measurements will include temperature, systolic and diastolic blood pressure, heart rate, and respiratory rate. | through study completion, an average of 9 months | 
| Changes in ECOG (Eastern Cooperative Oncology Group) performance status as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab. |  | through study completion, an average of 9 months | 
| PDL-1 expression, tumour-infiltrating CD8 T cell density, for S95005-oxaliplatin + nivolumab | Tumour biopsy at baseline and at the end of Cycle 4 | up to 8 weeks after the first treatment administration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic, colorectal, cancer, oxaliplatin, dose-escalation, Lonsurf, nivolumab, bevacizumab