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

Metastatic Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02848443
• Other study ID #: CL1-95005-001
• Secondary ID: 2015-004894-34
• Status: Completed
• Phase: Phase 1
• Start date: May 2016
• Est. completion date: April 9, 2020

Study information

• Verified date: June 2021
• Source: Servier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: April 9, 2020
• Est. primary completion date: August 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Colorectal Neoplasms
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Austria	Allgemeines Krankenhaus - Universitätskliniken Klinische Abteilung für Onkologie	Wien
France	CHU de la Timone Hépato-Gastro-Entérologie - Oncology Digestive	Marseille
France	Hôpital Saint-Antoine Service d'Oncologie Médicale	Paris
France	La Pitié Salpêtrière Centre Investigation clinique Paris Est	Paris
France	Centre Eugène Marquis Service d'Oncologie Médicale	Rennes
France	Institut Gustave Roussy DITEP	Villejuif
Germany	St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum Abteilung für Hämatologie und Onkologie	Bochum
Germany	Universitätsklinikum Hamburg-Eppendorf II. Medizin. Klinik und Poliklinik (Onkologie, Hämatologie)	Hamburg
Germany	Klinikum der Universität München Campus Großhadern, Medizinische Klinik und Poliklinik III	Munchen
Germany	Universitätsklinikum Ulm Zentrum für Innere Medizin, Klinik für Innere Medizin I	Ulm
Germany	Klinikum Wolfsburg Medizinische Klinik II	Wolfsburg
Hungary	Magyar Honvedseg Egeszsegugyi Kozpont Onkologiai Osztaly	Budapest
Hungary	Orszagos Onkologiai Intezet "B" Belgyogyaszati-Onkologiai O. Es Klin. Farmakologiai O.	Budapest
Hungary	Semmelweis Egyetem I. sz. Belgyogyaszati Klinika - Klin. Farmakologiai Reszleg	Budapest
Italy	ARNAS - Azienda Ospedaliera Garibaldi - Nesima Struttura Complessa di Oncologia Medica	Catania
Italy	Ist.Scientifico Romagnolo per lo Studio e la Cura dei Tumori Department of Clinical Oncology	Meldola
Italy	Policlinico G.B. Rossi A.O.U.I. di Verona U.O.C. di Oncologia	Verona
Spain	ICO Badalona. H. Germans Trials y Pujol - Servicio de Oncología médica	Badalona
Spain	H. Valle de Hebrón - Servicio de Oncología - (VHIR)	Barcelona
Spain	H. Uni. Madrid Sanchinarro - CIOCC Servicio de Oncología	Madrid
Spain	H. Univ. Ramon y Cajal - Servicio de Oncología Medica	Madrid
Spain	Hospital Unviersitario Gregorio Marañon - Servicio de Oncología Médica	Madrid
Spain	H. Clinico de Valencia INCLIVA - Departamento de Hematologia y Oncologia Medica 8ª planta	Valencia
United Kingdom	Christie Hospital NHS Foundation Trust GI & Endocrine	Manchester

Sponsors (2)

Lead Sponsor	Collaborator
Institut de Recherches Internationales Servier	ADIR, a Servier Group company

Countries where clinical trial is conducted

Austria,  France,  Germany,  Hungary,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Circulating protein biomarkers analysis	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.	through study completion, an average of 9 months
Other	Circulating tumour DNA analysis	Samples collected at C1D1 will be subjected to genomic analysis to study mutations currently observed in colorectal cancer	day 1 of cycle 1 (each cycle is 28 days)
Other	Circulating protein biomarkers in relation to ICD (immune cell death)	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.	through study completion, an average of 9 months
Other	Peripheral blood mononuclear cells	Samples collected at C1D1 and C5D1 will be subject to analysis for identification of lymphocytes cells phenotypes, for S95005-oxaliplatin + nivolumab	up to 10 weeks after the first treatment administration
Primary	Maximum Tolerated Dose (MTD) of S95005 when given in combination with oxaliplatin		up to 4 weeks after the first treatment administration
Primary	Dose Limiting Toxicity (DLT) of S95005 when given in combination with oxaliplatin		up to 4 weeks after the first treatment administration
Primary	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
Primary	Changes in standard hematology as a measure of safety and tolerability for S95005-oxaliplatin		through study completion, an average of 9 months
Primary	Changes in biochemistry as a measure of safety and tolerability for S95005-oxaliplatin		through study completion, an average of 9 months
Primary	Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin		through study completion, an average of 9 months
Primary	Changes in urinalysis as a measure of safety and tolerability for S95005-oxaliplatin		through study completion, an average of 9 months
Primary	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
Primary	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	Antitumor activity assessed by RECIST (Response Evaluation Criteria in Solid Tumors) and CEA (Carcinoembryonic Antigen)		through study completion, an average of 9 months
Secondary	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
Secondary	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
Secondary	Changes in biochemistry as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab.		through study completion, an average of 9 months
Secondary	Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab.		through study completion, an average of 9 months
Secondary	Changes in urinalysis as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab.		through study completion, an average of 9 months
Secondary	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
Secondary	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
Secondary	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

External Links

•   Lay Summary
•   Results Summary