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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02848443
Recruitment Status : Active, not recruiting
First Posted : July 28, 2016
Last Update Posted : October 7, 2019
Sponsor:
Collaborator:
ADIR, a Servier Group company
Information provided by (Responsible Party):
Servier ( Institut de Recherches Internationales Servier )

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.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: Trifluridine/tipiracil hydrochloride (S 95005) Drug: Oxaliplatin Drug: Bevacizumab Drug: Nivolumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 94 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Dose-escalation of S 95005 (TAS-102) in Combination With Oxaliplatin in Metastatic Colorectal Cancer
Actual Study Start Date : May 2016
Actual Primary Completion Date : August 1, 2019
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Oxaliplatin

Arm Intervention/treatment
Experimental: S 95005 + oxaliplatin (+/- bevacizumab or nivolumab) 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.




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of S95005 when given in combination with oxaliplatin [ Time Frame: up to 4 weeks after the first treatment administration ]
  2. Dose Limiting Toxicity (DLT) of S95005 when given in combination with oxaliplatin [ Time Frame: up to 4 weeks after the first treatment administration ]
  3. 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

  4. Changes in standard hematology as a measure of safety and tolerability for S95005-oxaliplatin [ Time Frame: through study completion, an average of 9 months ]
  5. Changes in biochemistry as a measure of safety and tolerability for S95005-oxaliplatin [ Time Frame: through study completion, an average of 9 months ]
  6. Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin [ Time Frame: through study completion, an average of 9 months ]
  7. Changes in urinalysis as a measure of safety and tolerability for S95005-oxaliplatin [ Time Frame: through study completion, an average of 9 months ]
  8. 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.

  9. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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

  3. 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 ]
  4. 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 ]
  5. Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab. [ Time Frame: through study completion, an average of 9 months ]
  6. 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 ]
  7. 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.

  8. 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 ]
  9. 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


Other Outcome Measures:
  1. 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.

  2. 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

  3. 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.

  4. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02848443


Locations
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Austria
Allgemeines Krankenhaus - Universitätskliniken Klinische Abteilung für Onkologie
Wien, Austria, 1090
France
CHU de la Timone Hépato-Gastro-Entérologie - Oncology Digestive
Marseille, France, 13005
Hôpital Saint-Antoine Service d'Oncologie Médicale
Paris, France, 75012
La Pitié Salpêtrière Centre Investigation clinique Paris Est
Paris, France, 75013
Centre Eugène Marquis Service d'Oncologie Médicale
Rennes, France, 35042
HIA Bégin
Saint-Mandé, France, 94160
Institut Gustave Roussy DITEP
Villejuif, France, 94805
Germany
St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum Abteilung für Hämatologie und Onkologie
Bochum, Germany, 44791
Universitätsklinikum Hamburg-Eppendorf II. Medizin. Klinik und Poliklinik (Onkologie, Hämatologie)
Hamburg, Germany, 20246
Klinikum der Universität München Campus Großhadern, Medizinische Klinik und Poliklinik III
Munchen, Germany, 81377
Universitätsklinikum Ulm Zentrum für Innere Medizin, Klinik für Innere Medizin I
Ulm, Germany, 89081
Klinikum Wolfsburg Medizinische Klinik II
Wolfsburg, Germany, 38440
Hungary
Magyar Honvedseg Egeszsegugyi Kozpont Onkologiai Osztaly
Budapest, Hungary, 1062
Semmelweis Egyetem I. sz. Belgyogyaszati Klinika - Klin. Farmakologiai Reszleg
Budapest, Hungary, 1083
Orszagos Onkologiai Intezet "B" Belgyogyaszati-Onkologiai O. Es Klin. Farmakologiai O.
Budapest, Hungary, 1122
Italy
ARNAS - Azienda Ospedaliera Garibaldi - Nesima Struttura Complessa di Oncologia Medica
Catania, Italy, 95122
Ist.Scientifico Romagnolo per lo Studio e la Cura dei Tumori Department of Clinical Oncology
Meldola, Italy, 47014
Policlinico G.B. Rossi A.O.U.I. di Verona U.O.C. di Oncologia
Verona, Italy, 37134
Spain
ICO Badalona. H. Germans Trials y Pujol - Servicio de Oncología médica
Badalona, Spain, 08916
H. Valle de Hebrón - Servicio de Oncología - (VHIR)
Barcelona, Spain, 08035
Hospital Unviersitario Gregorio Marañon - Servicio de Oncología Médica
Madrid, Spain, 28007
H. Univ. Ramon y Cajal - Servicio de Oncología Medica
Madrid, Spain, 28034
H. Uni. Madrid Sanchinarro - CIOCC Servicio de Oncología
Madrid, Spain, 28050
H. Clinico de Valencia INCLIVA - Departamento de Hematologia y Oncologia Medica 8ª planta
Valencia, Spain, 46010
United Kingdom
Christie Hospital NHS Foundation Trust GI & Endocrine
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
Institut de Recherches Internationales Servier
ADIR, a Servier Group company
Investigators
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Principal Investigator: Josef Tabernero, Prof Vall d'Hebron University Hospital, Institute of Oncology (VHIO)

Additional Information:
Study Data/Documents: Individual Participant Data Set  This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Institut de Recherches Internationales Servier
ClinicalTrials.gov Identifier: NCT02848443     History of Changes
Other Study ID Numbers: CL1-95005-001
2015-004894-34 ( EudraCT Number )
First Posted: July 28, 2016    Key Record Dates
Last Update Posted: October 7, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Researchers can ask for a study protocol, patient-level and/or study-level clinical trial data including clinical study reports (CSRs).

They can ask all interventional clinical studies:

  • submitted for new medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
  • Where Servier or an affiliate are the Marketing Authorization Holders (MAH). The date of the first Marketing Authorization of the new medicine (or the new indication) in one of the EEA Member States will be considered within this scope.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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
Keywords provided by Servier ( Institut de Recherches Internationales Servier ):
metastatic
colorectal
cancer
oxaliplatin
dose-escalation
Lonsurf
nivolumab
bevacizumab
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Trifluridine
Bevacizumab
Nivolumab
Oxaliplatin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents