Clinical trial NCT02848443: Study of S 95005 in Combination With Oxaliplatin in Metastatic Colorectal Cancer
Official title: Phase I Dose-escalation of S 95005 (TAS-102) in Combination With Oxaliplatin in Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Colorectal Cancer
Keywords: metastatic
colorectal
cancer
oxaliplatin
dose-escalation
Lonsurf
nivolumab
bevacizumab
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: ADIR, a Servier Group company
First posted: 2016-07-28
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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).

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of S95005 when given in combination with oxaliplatin
timeFrame: up to 4 weeks after the first treatment administration
measure: Dose Limiting Toxicity (DLT) of S95005 when given in combination with oxaliplatin
timeFrame: up to 4 weeks after the first treatment administration
measure: Number of participants with adverse events as a measure of safety and tolerability for S95005-oxaliplatin.
timeFrame: through study completion, an average of 9 months
measure: Changes in standard hematology as a measure of safety and tolerability for S95005-oxaliplatin
timeFrame: through study completion, an average of 9 months
measure: Changes in biochemistry as a measure of safety and tolerability for S95005-oxaliplatin
timeFrame: through study completion, an average of 9 months
measure: Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin
timeFrame: through study completion, an average of 9 months
measure: Changes in urinalysis as a measure of safety and tolerability for S95005-oxaliplatin
timeFrame: through study completion, an average of 9 months
measure: Changes in vital signs as a measure of safety for S95005-oxaliplatin
timeFrame: through study completion, an average of 9 months
measure: Changes in ECOG (Eastern Cooperative Oncology Group) performance status as a measure of safety and tolerability for S95005-oxaliplatin
timeFrame: through study completion, an average of 9 months
Secondary outcomes:
measure: Antitumor activity assessed by RECIST (Response Evaluation Criteria in Solid Tumors) and CEA (Carcinoembryonic Antigen)
timeFrame: through study completion, an average of 9 months
measure: Number of participants with adverse events as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab.
timeFrame: through study completion, an average of 9 months
measure: Changes in standard hematology as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab.
timeFrame: through study completion, an average of 9 months
measure: Changes in biochemistry as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab.
timeFrame: through study completion, an average of 9 months
measure: Changes in coagulation as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab.
timeFrame: through study completion, an average of 9 months
measure: Changes in urinalysis as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab.
timeFrame: through study completion, an average of 9 months
measure: Changes in vital signs as a measure of safety for S95005-oxaliplatin + bevacizumab or nivolumab.
timeFrame: through study completion, an average of 9 months
measure: Changes in ECOG (Eastern Cooperative Oncology Group) performance status as a measure of safety and tolerability for S95005-oxaliplatin + bevacizumab or nivolumab.
timeFrame: through study completion, an average of 9 months
measure: PDL-1 expression, tumour-infiltrating CD8 T cell density, for S95005-oxaliplatin + nivolumab
timeFrame: up to 8 weeks after the first treatment administration
Other outcomes:
measure: Circulating protein biomarkers analysis
timeFrame: through study completion, an average of 9 months
measure: Circulating tumour DNA analysis
timeFrame: day 1 of cycle 1 (each cycle is 28 days)
measure: Circulating protein biomarkers in relation to ICD (immune cell death)
timeFrame: through study completion, an average of 9 months
measure: Peripheral blood mononuclear cells
timeFrame: up to 10 weeks after the first treatment administration
Locations:
city: Wien
country: Austria
facility: Allgemeines Krankenhaus - Universitätskliniken Klinische Abteilung für Onkologie
city: Marseille
country: France
facility: CHU de la Timone Hépato-Gastro-Entérologie - Oncology Digestive
city: Paris
country: France
facility: Hôpital Saint-Antoine Service d'Oncologie Médicale
city: Paris
country: France
facility: La Pitié Salpêtrière Centre Investigation clinique Paris Est
city: Rennes
country: France
facility: Centre Eugène Marquis Service d'Oncologie Médicale
city: Villejuif
country: France
facility: Institut Gustave Roussy DITEP
city: Bochum
country: Germany
facility: St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum Abteilung für Hämatologie und Onkologie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf II. Medizin. Klinik und Poliklinik (Onkologie, Hämatologie)
city: Munchen
country: Germany
facility: Klinikum der Universität München Campus Großhadern, Medizinische Klinik und Poliklinik III
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Zentrum für Innere Medizin, Klinik für Innere Medizin I
city: Wolfsburg
country: Germany
facility: Klinikum Wolfsburg Medizinische Klinik II
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont Onkologiai Osztaly
city: Budapest
country: Hungary
facility: Semmelweis Egyetem I. sz. Belgyogyaszati Klinika - Klin. Farmakologiai Reszleg
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet "B" Belgyogyaszati-Onkologiai O. Es Klin. Farmakologiai O.
city: Catania
country: Italy
facility: ARNAS - Azienda Ospedaliera Garibaldi - Nesima Struttura Complessa di Oncologia Medica
city: Meldola
country: Italy
facility: Ist.Scientifico Romagnolo per lo Studio e la Cura dei Tumori Department of Clinical Oncology
city: Verona
country: Italy
facility: Policlinico G.B. Rossi A.O.U.I. di Verona U.O.C. di Oncologia
city: Badalona
country: Spain
facility: ICO Badalona. H. Germans Trials y Pujol - Servicio de Oncología médica
city: Barcelona
country: Spain
facility: H. Valle de Hebrón - Servicio de Oncología - (VHIR)
city: Madrid
country: Spain
facility: Hospital Unviersitario Gregorio Marañon - Servicio de Oncología Médica
city: Madrid
country: Spain
facility: H. Univ. Ramon y Cajal - Servicio de Oncología Medica
city: Madrid
country: Spain
facility: H. Uni. Madrid Sanchinarro - CIOCC Servicio de Oncología
city: Valencia
country: Spain
facility: H. Clinico de Valencia INCLIVA - Departamento de Hematologia y Oncologia Medica 8ª planta
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Foundation Trust GI & Endocrine
Study officials:
affiliation: Vall d'Hebron University Hospital, Institute of Oncology (VHIO)
name: Josef Tabernero, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bordonaro R, Calvo A, Auriemma A, Hollebecque A, Rubovszky G, Saunders MP, Papai Z, Prager G, Stein A, Andre T, Argiles G, Cubillo A, Dahan L, Edeline J, Leger C, Cattan V, Fougeray R, Amellal N, Tabernero J. Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study. ESMO Open. 2021 Oct;6(5):100270. doi: 10.1016/j.esmoop.2021.100270. Epub 2021 Sep 20.
citation: Argiles G, Andre T, Hollebecque A, Calvo A, Dahan L, Cervantes A, Leger C, Amellal N, Fougeray R, Tabernero J. Phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer. Eur J Cancer. 2019 May;112:12-19. doi: 10.1016/j.ejca.2019.01.101. Epub 2019 Mar 16.