Phase I study of S 95005 in combination with oxaliplatin in metastatic colorectal cancer

ISRCTN	ISRCTN15566373
DOI	https://doi.org/10.1186/ISRCTN15566373
EudraCT/CTIS number	2015-004894-34
ClinicalTrials.gov number	NCT02848443
Secondary identifying numbers	CL1-95005-001

Submission date: 02/02/2016
Registration date: 02/03/2016
Last edited: 23/06/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration and not expected to be available in the future

Contact information

Prof Josef Tabernero
Scientific

Vall d'Hebron University Hospital
Institute of Oncology (VHIO)
P. Vall d'Hebron 119-129
Barcelona
08035
Spain

Dr Institut de Recherches Internationales Servier
Public

50, rue Carnot
Suresnes
92284
France

Phone	+33 1 55 72 43 66
Email	clinical.trial.management@servier.com

Study information

Study design	Multicentre open-label non-randomised non-comparative study
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet
Scientific title	Phase I dose-escalation of S 95005 (TAS-102) in combination with oxaliplatin in metastatic colorectal cancer
Study objectives	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(s)	Comité Ético de Investigación Clínica del Hospital Universitari Vall d’Hebron, 04/03/2016
Health condition(s) or problem(s) studied	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
Pharmaceutical study type(s)
Phase	Phase I
Drug / device / biological / vaccine name(s)	1. S95005 (trifluridine/tipiracil hydrochloride) 2. Oxaliplatin 3. Bevacizumab 4. Nivolumab
Primary outcome measure	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 study start date	14/12/2015
Completion date	09/04/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	94
Total final enrolment	78
Key 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
Key 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
Date of first enrolment	09/05/2016
Date of final enrolment	24/01/2019

Locations

Countries of recruitment

Austria
England
France
Germany
Hungary
Italy
Spain
United Kingdom

Study participating centres

Vall d'Hebron University Hospital (Hospital Vall D'Hebron) [VHIO]

Passeig de la Vall d'Hebron, 119-129
Barcelona
08035
Spain

University Hospital of Valencia (Hospital Clínic Universitari de València)

nº, Av. de Blasco Ibáñez, 17
Valencia
46010
Spain

Institut Gustave Roussy

114 Rue Edouard Vaillant
Villejuif
94805
France

Hôpital Saint Antoine

184 Rue du Faubourg Saint-Antoine
Paris
75012
France

CHU Timone

264 Rue Saint-Pierre
Marseille
13005
France

Centre Eugène Marquis

Avenue de la Bataille Flandres-Dunkerque
Rennes
35042
France

HOSPITAL UNIV. GREGORIO MARAÑON

Planta -1 Unidad de investigación Oncológica
Edificio de Oncología
C/Maiquez nº 7
Madrid
28007
Spain

Hospital Universitario Madrid Sanchinarro

Centro Integral Oncológico Clara Campal
Calle Oña, 10
Madrid
28050
Spain

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

Hôpital Pitié

Groupe Hospitalier La Pitié Salpêtrière
47-83 Bd de l’Hôpital
Paris
75013
France

Policlinico G.B. Rossi

A.O.U.I. di Verona Piazzale L. Scuro, 10
U.O.C. di Oncologia - Centro Ricerche Cliniche di Verona s.r.l.
Verona
37134
Italy

Azienda Ospedaliera Garibaldi

Nesima
S.C. di Oncologia Medica ARNAS
Via Palermo, 636
Catania
95122
Italy

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

Klinikum der Universität München

Campus Großhadern
Medizinische Klinik und Poliklinik III
Marchioninistr. 15
Munich
81377
Germany

St. Josef-Hospital

Klinikum der Ruhr-Universität Bochum
Abt. für Hämatologie, Onkologie und Palliativmedizin
Gudrunstr. 56
Bochum
44791
Germany

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

Medizinische Universität Wien

Klinische Abteilung für Onkologie
Allgemeines Krankenhaus – Universitätskliniken
Währinger Gürtel 18-20
Wien
1090
Austria

Orszagos Onkologiai Intezet

"B" Belgyogyaszati-Onkologiai O.
Es Klin. Farmakologiai O.
Rath Gyorgy u. 7-9.
Budapest
1122
Hungary

Magyar Honvedseg Egeszsegugyi

Kozpont
Onkologiai Osztaly
Podmaniczky u. 111.
Budapest
1062
Hungary

Semmelweis Egyetem

I. sz. Belgyogyaszati Klinika - Klin.
Farmakologiai Reszleg
Koranyi S. u. 2/a.
Budapest
1083
Hungary

Christie Hospital NHS Foundation Trust

GI & Endocrine
550 Wilmslow Road
Manchester
M20 4BX
United Kingdom

Universitätsklinikum Ulm

Zentrum für Innere Medizin
Klinik für Innere Medizin I
Albert-Einstein-Allee 23
Ulm
89081
Germany

Klinikum Wolfsburg

Medizinische Klinik II
Sauerbruchstrasse 7
38440 Wolfsburg
Wolfsburg
38440
Germany

ICO Badalona. H. Germans Trials y Pujol

Servicio de Oncología médica
Carretera de Canyet s/n
Badalona
08916
Spain

HIA Bégin

69, avenue de Paris
Saint Mandé
Saint Mandé
94160
France

Sponsor information

Servier (France)
Industry

50, rue Carnot
Suresnes
92284
France

Website	https://clinicaltrials.servier.com/
"ROR"	https://ror.org/034e7c066

Funders

Funder type

Industry

ADIR

No information available

Results and Publications

Intention to publish date	09/04/2021
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Summary results and a lay summary will be published on https://clinicaltrials.servier.com/ within 12 months after the end of the study.
IPD sharing plan	The datasets generated during and/or analysed during the current study will be available upon request from https://clinicaltrials.servier.com/ after the Marketing Authorisation has been granted.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results			17/05/2021	No	No
Plain English results			23/06/2021	No	Yes

Editorial Notes

23/06/2021: Results (plain English) added.
17/05/2021: Basic results summary link and total final enrolment added.
04/06/2020: The following changes have been made to the trial record:
1. The overall trial end date was changed from 30/06/2020 to 09/04/2020.
2. The intention to publish date was changed from 31/01/2021 to 09/04/2021.
17/02/2020: The following changes have been made to the trial record:
1. The overall trial end date has been changed from 24/01/2020 to 30/06/2020.
2. The public and scientific contact details have been updated.
3. The trial participating centre addresses have been updated.
22/02/2019: The following changes have been made to the trial record:
1. The overall trial end date has been changed from 31/12/2019 to 24/01/2020.
2. The recruitment end date has been changed from 31/12/2018 to 24/01/2019.
3. Hungary, Austria, Italy, Germany and United Kingdom have been added to the recruiting countries.
4. The trial participating centre addresses have been updated.
5. The sponsor website has been updated.
6. The participant level data summary has been changed from 'Available on request' to 'To be made available at a later date'.
7. The intention to publish date has been changed from 10/07/2020 to 31/01/2021.
8. Public contact details have been added.
14/09/2018: The following changes have been made to the trial record:
1. The overall trial end date has been changed from 10/07/2019 to 31/12/2019
2. The recruitment end date has been changed from 10/07/2018 to 31/12/2018
3. Orszagos Onkologiai Intezet, Magyar Honvedseg Egeszsegugyi, Semmelweis Egyetem, Christie Hospital NHS Foundation Trust, Universitätsklinikum Ulm, Klinikum Wolfsburg, ICO Badalona. H. Germans Trials y Pujol and HIA Bégin were added as trial participating centres.
4. Azienda Ospedaliera Universitaria Policlinico di Modena was removed as a trial participating centre
10/04/2018: Publication and dissemination plan and IPD sharing statement updated.
10/04/2017: The IPD sharing plan has been added.
05/04/2017: The following changes have been made to the record:
1. The overall trial end date has been updated from 27/02/2018 to 10/07/2019 and the recruitment dates have been updated from 30/04/2016 - 30/04/2017 to 09/05/2016 - 10/07/2018
2. The target number of participants has been changed from 54 to 94
3. The interventions have been updated to include a further study drug (nivolumab)
4. The secondary outcome measures and exclusion criteria have been updated
5. 11 additional trial participating centres have been added.
24/11/2016: The inclusion and exclusion criteria have been updated, and four additional trial participating centres have been added.
30/03/2016: Ethics approval information added.