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

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

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.

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.

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).