Additional identifiers
EudraCT number
2015-004894-34
ClinicalTrials.gov number
NCT02848443
Protocol/serial number
CL1-95005-001
Study information
Scientific title
Phase I dose-escalation of S 95005 (TAS-102) in combination with oxaliplatin in metastatic colorectal cancer
Acronym
Study hypothesis
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.
Ethics approval
Comité Ético de Investigación Clínica del Hospital Universitari Vall d’Hebron, 04/03/2016
Study design
Multicentre open-label non-randomised non-comparative study
Primary study design
Interventional
Secondary study design
Non randomised study
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet
Condition
Metastatic colorectal cancer
Intervention
This is a one-arm study, which will be conducted in 2 parts:
1. A dose-escalation part to determine the maximum tolerated dose (MTD) of S 95005 in combination with oxaliplatin: a minimum of 3 patients will be enrolled at the initial dose level of 25 mg/m² of S95005 in combination with 85 mg/m² of oxalipatin. Patients will be included by groups of 3.
2. 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.
The treatments will be given until unacceptable toxicity according to the investigator, disease progression or patient withdrawal. The follow-up will last up to 6 months after the end of the participation in the study.
S95005 : 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
Oxaliplatin: concentrate for solution for infusion containing 5mg/ml of oxaliplatin, administered intravenously at the dose of 65 to 85 mg/m2
Bevacizumab: concentrate for solution for infusion containing 25mg/ml of bevacizumab, administered intravenously at the dose of 5 mg/kg
Added 05/04/2017:
Nivolumab: concentrate for solution for infusion containing 10 mg/ml of nivolumab, administered intravenously at the dose of 3 mg/kg.
Intervention type
Drug
Phase
Phase I
Drug names
1. S95005 (trifluridine/tipiracil hydrochloride)
2. Oxaliplatin
3. Bevacizumab
4. Nivolumab
Primary outcome measures
1. Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of S95005 when given in combination with oxaliplatin, during the first two cycles in the dose-escalation part
2. Safety tolerance profile of S 95005 given in combination with oxaliplatin, at each visit, from the informed consent signature to the withdrawal visit, assessed by: adverse events, physical examinations and ECOG performance status, laboratory examinations (haematology, biochemistry and urinalysis), vital signs, ECG and body weight
Secondary outcome measures
Secondary outcome measures as of 05/04/2017:
1. Main pharmacokinetic parameters of S 95005 and its main metabolites, and oxaliplatin, from day 1 of cycle 1 to day 5 of cycle 2
2. Antitumor activity (objective response rate, duration of response, Progression-free survival and Overall survival) assessed by RECIST (Response Evaluation Criteria in Solid Tumors) and CEA (Carcinoembryonic Antigen), from the informed consent signature to the withdrawal visit
3. Safety tolerance profile of S 95005 in combination with oxaliplatin and either bevacizumab or nivolumab assessed by: adverse events, physical examinations and performance status, laboratory examinations (haematology, biochemistry and urinalysis), vital signs and body weight, from the informed consent signature to the withdrawal visit
4. PDL-1 expression, tumour-infiltrating CD8 T cell density: tumor biopsy at baseline and at the end of cycle 4
5. Exploratory endpoints: Proteomic and genomic biomarkers using blood samples, after consent signature from day 1 of cycle 1 to the withdrawal visit (all patients), and tumour biopsies (for patients receiving nivolumab, at baseline and at the end of cycle 4)
Original secondary outcome measures:
1. Main pharmacokinetic parameters of S 95005 and its main metabolites, and oxaliplatin, from day 1 of cycle 1 to day 5 of cycle 2
2. Antitumor activity (objective response rate, duration of response, Progression-free survival and Overall survival) assessed by RECIST (Response Evaluation Criteria in Solid Tumors), from the informed consent signature to the withdrawal visit
3. Exploratory endpoints: Proteomic and genomic biomarkers using blood samples, after consent signature from day 1 of cycle 1 to the withdrawal visit
Overall trial start date
14/12/2015
Overall trial end date
10/07/2019
Reason abandoned
Eligibility
Participant inclusion criteria
Inclusion criteria as of 24/11/2016:
1. Age 18 years or older
2. Histologically confirmed metastatic colorectal cancer pretreated by at least one line of standard chemotherapy
3. Restaging scan within 28 days before the first study drug intake
4. 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
5. Life expectancy of more than 3 months
6. Performance status Eastern Cooperative Oncology Group (ECOG): 0-1
7. Adequate bone marrow, liver, and kidney function
8. For patient who will receive bevacizumab: coagulation parameters in normal limit or in therapeutic limit for patients treated with anticoagulant
9. 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.
10. Capacity to take oral tablet(s) without difficulty
11. Has provided written informed consent
12. Is willing and able to comply with scheduled visits and study procedures
Added 06/04/2017: For patients who will receive nivolumab: patients eligible for tumour biopsy and who agree to have two sequential biopsies during the study
Original inclusion criteria:
1. Age 18 years or older
2. Histologically confirmed metastatic colorectal cancer pretreated by at least one line of standard chemotherapy and naïve to oxaliplatin in the metastatic setting
3. Restaging scan within 28 days before the first study drug intake
4. 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
5. Life expectancy of more than 3 months
6. Performance status Eastern Cooperative Oncology Group (ECOG): 0-1
7. Adequate bone marrow, liver, and kidney function
8. For patient who will receive bevacizumab: coagulation parameters in normal limit and adequate proteinuria
9. Women of childbearing potential must have a negative pregnancy test
Both males and females must agree to use effective birth control method
10. Capacity to take oral tablet(s) without difficulty
11. Has provided written informed consent
12. Is willing and able to comply with scheduled visits and study procedures
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
94
Participant exclusion criteria
Exclusion criteria as of 05/04/2017:
1. Grade 2 or higher peripheral neuropathy
2. During expansion part, patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy with oxaliplatin
3. Patients with brain metastases or leptomeningeal metastasis
4. Other active malignancy within the last 3 years (except for basal cell carcinoma or a non-invasive/in situ cervical cancer)
5. 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
6. For patient 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.
7. Grade 3 or higher hypersensitivity reaction to oxaliplatin, or grade 1-2 hypersensitivity reaction to oxaliplatin not controlled with premedication
8. Patient previously treated by S 95005 or history of allergic reactions attributed to compounds of similar or biologic composition to S 95005 or any of its excipient, or has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
9. Certain serious illnesses or serious medical conditions
10. 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
11. Pregnancy or breast feeding
12. For patients planned to receive nivolumab:
12.1. Patients with active autoimmune disease or history of clinically severe autoimmune disease.
12.2. 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 drugs intake.
12.3. 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.
12.4. 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.
12.5. Allergic reactions/hypersensitivity to nivolumab or any components used in its formulation or previous severe hypersensitivity reaction to treatment with another monoclonal antibody.
12.6. Has a known history of active tuberculosis (Bacillus Tuberculosis).
Exclusion criteria as of 24/11/2016:
1. Grade 2 or higher peripheral neuropathy
2. During expansion part, patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy with oxaliplatin
3. Patients with brain metastases or leptomeningeal metastasis
4. Other active malignancy within the last 3 years (except for basal cell carcinoma or a non-invasive/in situ cervical cancer)
5. Has had certain other recent treatment e.g. major surgery, field radiation, received investigational agent, within the specified time frames prior to study drug administration
6. History of allergic reactions/hypersensitivity to bevacizumab (for patient who will receive bevacizumab) or any components used in the formulation
7. Grade 3 or higher hypersensitivity reaction to oxaliplatin, or grade 1-2 hypersensitivity reaction to oxaliplatin not controlled with premedication
8. Patient previously treated by S 95005 or history of allergic reactions attributed to compounds of similar or biologic composition to S 95005 or any of its excipient, or has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
9. Certain serious illnesses or serious medical conditions
10. 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
11. Pregnancy or breast feeding
Original exclusion criteria:
1. Grade 2 or higher peripheral neuropathy
2. Patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy with oxaliplatin
3. Patients with brain metastases or leptomeningeal metastasis
4. Other active malignancy within the last 3 years (except for basal cell carcinoma or a non-invasive/in situ cervical cancer)
5. Has had certain other recent treatment e.g. major surgery, field radiation, received investigational agent, within the specified time frames prior to study drug administration
6. History of allergic reactions/hypersensitivity to bevacizumab (for patient who will receive bevacizumab) or any components used in the formulation
7. Grade 3 or higher hypersensitivity reaction to oxaliplatin, or grade 1-2 hypersensitivity reaction to oxaliplatin not controlled with premedication
8. Patient previously treated by S 95005 or history of allergic reactions attributed to compounds of similar or biologic composition to S 95005
9. Certain serious illnesses or serious medical conditions
10. 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
11. Pregnancy or breast feeding
Recruitment start date
09/05/2016
Recruitment end date
10/07/2018
Locations
Countries of recruitment
France, Spain
Trial participating centre
Vall d'Hebron University Hospital (Hospital Vall D'Hebron) [VHIO]
Passeig de la Vall d'Hebron, 119-129
Barcelona
08035
Spain
Trial participating centre
University Hospital of Valencia (Hospital Clínic Universitari de València)
nº, Av. de Blasco Ibáñez, 17
Valencia
46010
Spain
Trial participating centre
Gustave Roussy Institute of Oncology (Institut Gustave Roussy)
14 Rue Edouard Vaillant
Villejuif
94805
France
Trial participating centre
Hôpital Saint Antoine
184 Rue du Faubourg Saint-Antoine
Paris
75571
France
Trial participating centre
CHU Timone
264 Rue Saint-Pierre
Marseille
13005
France
Trial participating centre
Centre Eugène Marquis
Avenue de la Bataille Flandres-Dunkerque
Rennes
35042
France
Trial participating centre
Oncología Médica
Calle de Velázquez, 7
Madrid
28007
Spain
Trial participating centre
Hospital Universitario Madrid Sanchinarro
Centro Integral Oncológico Clara Campal
Calle Oña, 10
Madrid
28050
Spain
Trial participating centre
Hospital Universitario Ramón y Cajal de Madrid Unidad de Oncología Digestiva
Servicio de Oncología Médica (consulta 5)
Ctra. De Colmenar Viejo km 9.100
Madrid
28034
Spain
Trial participating centre
Hôpital Pitié
Salpêtrière Pavillon Antonin Gosset
Centre d’investigation clinique Paris Est
47/89 Boulevard de l’Hôpital
Paris
75013
France
Trial participating centre
Policlinico G.B. Rossi
A.O.U.I. di Verona
Piazzale L. Scuro, 10
Verona
37134
Italy
Trial participating centre
Azienda Ospedaliera Garibaldi
Nesima
S.C. di Oncologia Medica ARNAS
Via Palermo, 636
Catania
95122
Italy
Trial participating centre
Azienda Ospedaliera Universitaria Policlinico di Modena
Dipartimento ad attività integrata di oncologia ed ematologia
Viale del Pozzo, 71
Modena
41124
Italy
Trial participating centre
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
Oncologia Medica e Patologia Gastroenterica IRCCS -
Via Piero Maroncelli, 40
Meldola
47014
Italy
Trial participating centre
Klinikum der Universität München
Campus Großhadern
Medizinische Klinik und Poliklinik III
Marchioninistr. 15
Munich
81377
Germany
Trial participating centre
St. Josef-Hospital
Klinikum der Ruhr-Universität Bochum
Abt. für Hämatologie, Onkologie und Palliativmedizin
Gudrunstr. 56
Bochum
44791
Germany
Trial participating centre
Universitätsklinikum Hamburg
Eppendorf II. Medizinische Klinik und Poliklinik
(Onkologie, Hämatologie, KMT mit Sektion Pneumologie)
Hubertus Wald Tumorzentrum - UCCH
Martinistr. 52, Gebäude Ost 24
Hamburg
20246
Germany
Trial participating centre
Medizinische Universität Wien
Klinische Abteilung für Onkologie
Allgemeines Krankenhaus – Universitätskliniken
Währinger Gürtel 18-20
Wien
1090
Germany
Sponsor information
Organisation
Institut de Recherche Internationales Servier
Sponsor details
50
rue Carnot
Suresnes
92284
France
Sponsor type
Industry
Website
Funders
Funder type
Industry
Funder name
ADIR
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
The current publication plan for the current study are unknown and will be made available at a later date.
IPD sharing plan:
The datasets generated during and/or analysed during the current study will be available upon request from www.servier.com after the Marketing Authorisation has been granted.
Intention to publish date
Participant level data
To be made available at a later date
Results - basic reporting
Publication summary