Condition category
Cancer
Date applied
02/02/2016
Date assigned
02/03/2016
Last edited
12/04/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

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

Trial website

Contact information

Type

Scientific

Primary contact

Prof Josef Tabernero

ORCID ID

Contact details

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

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

http://www.servier.com/

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

Publication citations

Additional files

Editorial Notes

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.