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

• ClinicalTrials.gov Identifier: NCT02848443
• Recruitment Status: Completed
• First Posted: July 28, 2016
• Last Update Posted: June 30, 2021
• Sponsor: Institut de Recherches Internationales Servier
• Collaborator: ADIR, a Servier Group company
• Information provided by (Responsible Party): Servier ( Institut de Recherches Internationales Servier )

Tracking Information

• First Submitted Date: February 24, 2016
• First Posted Date: July 28, 2016
• Last Update Posted Date: June 30, 2021
• Actual Study Start Date: May 2016
• Actual Primary Completion Date: August 1, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 5, 2017)

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

Original Primary Outcome Measures (submitted: July 25, 2016)

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

Current Secondary Outcome Measures (submitted: April 5, 2017)

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

• Original Secondary Outcome Measures (submitted: July 25, 2016): Antitumor activity assessed by RECIST (Response Evaluation Criteria in Solid Tumors) [ Time Frame: through study completion, an average of 9 months ]

Current Other Pre-specified Outcome Measures (submitted: April 5, 2017)

• Circulating protein biomarkers analysis [ Time Frame: through study completion, an average of 9 months ]
  Samples collected at C1D1 (day 1 of cycle 1) and at withdrawal will be subjected to proteomic analysis for identification of potential predictive and resistance biomarkers for S 95005 and/or oxaliplatin response or biological activity.
• Circulating tumour DNA analysis [ Time Frame: day 1 of cycle 1 (each cycle is 28 days) ]
  Samples collected at C1D1 will be subjected to genomic analysis to study mutations currently observed in colorectal cancer
• Circulating protein biomarkers in relation to ICD (immune cell death) [ Time Frame: through study completion, an average of 9 months ]
  Samples collected at C1D1, C2D1, C3D1 and C5D1 pre-dose then every 4 cycles will be subjected to proteomic analysis to measure immune cell death (ICD) biomarkers potentially induced by the treatment S95005-oxaliplatin + nivolumab.
• Peripheral blood mononuclear cells [ Time Frame: up to 10 weeks after the first treatment administration ]
  Samples collected at C1D1 and C5D1 will be subject to analysis for identification of lymphocytes cells phenotypes, for S95005-oxaliplatin + nivolumab

Original Other Pre-specified Outcome Measures (submitted: July 25, 2016)

• Circulating protein biomarkers analysis [ Time Frame: through study completion, an average of 9 months ]
  Samples collected at C1D1 (day 1 of cycle 1) and at withdrawal will be subjected to proteomic analysis for identification of potential predictive and resistance biomarkers for S 95005 and/or oxaliplatin response or biological activity. Biomarkers in relation to the metabolic pathway of S 95005 will be assessed.
• Circulating tumour DNA analysis [ Time Frame: day 1 of cycle 1 (each cycle is 28 days) ]
  Samples collected at C1D1 will be subjected to genomic analysis to study mutations currently observed in colorectal cancer

Descriptive Information

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

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Colorectal Cancer

Intervention

• Drug: Trifluridine/tipiracil hydrochloride (S 95005)
  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.
• Drug: Oxaliplatin
  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.
• Drug: Bevacizumab
  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.
• Drug: Nivolumab
  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.

Study Arms

Experimental: S 95005 + oxaliplatin (+/- bevacizumab or nivolumab)

Interventions:

• Drug: Trifluridine/tipiracil hydrochloride (S 95005)
• Drug: Oxaliplatin
• Drug: Bevacizumab
• Drug: Nivolumab

• Publications *: Argiles G, Andre T, Hollebecque A, Calvo A, Dahan L, Cervantes A, Leger C, Amellal N, Fougeray R, Tabernero J. Phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer. Eur J Cancer. 2019 May;112:12-19. doi: 10.1016/j.ejca.2019.01.101. Epub 2019 Mar 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 31, 2020): 78
• Original Estimated Enrollment (submitted: July 25, 2016): 54
• Actual Study Completion Date: April 9, 2020
• Actual Primary Completion Date: August 1, 2019 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, France, Germany, Hungary, Italy, Spain, United Kingdom

Administrative Information

• NCT Number: NCT02848443
• Other Study ID Numbers: CL1-95005-001; 2015-004894-34 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• URL: http://clinicaltrials.servier.com

• Current Responsible Party: Servier ( Institut de Recherches Internationales Servier )
• Original Responsible Party: Same as current
• Current Study Sponsor: Institut de Recherches Internationales Servier
• Original Study Sponsor: Same as current
• Collaborators: ADIR, a Servier Group company

Investigators

• Principal Investigator: Josef Tabernero, Prof; Vall d'Hebron University Hospital, Institute of Oncology (VHIO)

• PRS Account: Servier
• Verification Date: June 2021