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Dose-escalation Study of Oral Administration of S 55746 in Patients With Chronic Lymphocytic Leukaemia and B-Cell Non-Hodgkin Lymphoma

Primary Purpose

Chronic Lymphocytic Leukaemia (CLL), B-Cell Non-Hodgkin Lymphoma (NHL), Multiple Myeloma (MM)

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
S 55746
Sponsored by
Institut de Recherches Internationales Servier
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukaemia (CLL)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Women or men aged >/=18 years
  • Patients with a measurable histologically confirmed Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Diffuse Large B-Cell Lymphoma (DLBCL), Small Lymphocytic Lymphoma (SLL) and Marginal Zone Lymphoma (MZL) (Arm A), or patients with an evaluable immunophenotypically confirmed CLL (Arm B), or patients with a measurable Multiple Myeloma t(11;14) (arm A expansion part) according to International Myeloma Working Group (IMWG) criteria
  • Relapsed after or refractory disease to standard treatments, and require treatment in the opinion of the investigator
  • Estimated life expectancy > 12 weeks
  • World Health Organization (WHO) performance status 0-2
  • Adequate bone marrow, renal and hepatic functions
  • No evidence or treatment for another malignancy within 2 years prior to study entry. Curatively treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia is allowed

Additional inclusion criteria for food interaction cohort:

  • B-cell NHL patients at low risk of tumour lysis syndrome (TLS)
  • Recent/concomitant treatment altering gastric pH

Exclusion Criteria:

  • Previous treatment with a BH3 mimetic
  • Previous therapy for the studied disease within 3 weeks before first intake
  • Radioimmunotherapy, radiotherapy within 8 weeks before first intake
  • Major surgery within 3 weeks before first day of study drug dosing
  • Corticosteroids >= 20 mg prednisone equivalent per day within 7 days before first intake
  • Anticoagulant oral drugs, aspirin > 325 mg/day within 7 days prior to first S 55746 intake
  • Positive direct antiglobulin test (Coombs test) and haptoglobin below normal value
  • Prior allogenic stem cell transplant
  • Autologous stem cell transplant within 3 months before first intake
  • NHL patients diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma/leukaemia
  • Human immunodeficiency virus (HIV)
  • Known acute or chronic hepatitis B or hepatitis C
  • Impaired cardiac function
  • Medications known to prolong corrected QT (QTc) interval
  • History or/ clinically suspicious for cancer- related Central Nervous System disease
  • Solitary extramedullary plasmacytoma
  • Laboratory Signs of TLS
  • Strong or moderate CYP3A4 inhibitors/inducers (treatment, food or drink products)
  • Treatment highly metabolized by the CYP3A4 or CYP2D6 and/or substrates with a narrow therapeutic index, multienzyme and/or OATP and/or P-gp substrates or herbal products.
  • Known hypersensitivity to rasburicase
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency and other cellular metabolic disorders known to cause haemolytic anaemia
  • Patients receiving proton pump inhibitor

Sites / Locations

  • The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services
  • Hopital Claude Huriez
  • CHU de Nantes
  • Centre hospitalier Lyon Sud
  • Gustave Roussy
  • Universitätsklinikum Carl Gustav Carus
  • Städtisches Klinikum Schwabing
  • Universitätsklinikum Ulm
  • National Oncology Institute
  • CRU Hungary Kft
  • Severance Hospital
  • St. Mary's Hospital
  • Warsaw Institute of Oncology
  • Warsaw Medical University
  • National Cancer Center (NCC)
  • National University Cancer Institute Singapore
  • University College London Hospitals
  • Freeman Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

B-cell Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM)

Chronic Lymphocytic Leukaemia (CLL)

Arm Description

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD)
The MTD is the highest drug dosage that is unlikely (<25% posterior probability) to cause DLT in more than 33% of the treated patients in the first cycle of S 55746 treatment
Incidence of Adverse Events (AEs)
Characterized by severity and seriousness of AEs, laboratory abnormalities and other safety parameters such as electrocardiogram (ECG) changes

Secondary Outcome Measures

Plasma concentration of S 55746
The pharmacokinetic (PK) profile of S 55746: Area Under the Curve [AUC]
The PK profile of S 55746: Maximal Concentration [Cmax]
Apoptotic activity from blood samples
Objective Response Rate (ORR)
Clinical Benefit Rate (CBR)
Duration of response
Progression Free Survival (PFS)

Full Information

First Posted
August 23, 2016
Last Updated
November 22, 2019
Sponsor
Institut de Recherches Internationales Servier
Collaborators
ADIR, a Servier Group company
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1. Study Identification

Unique Protocol Identification Number
NCT02920697
Brief Title
Dose-escalation Study of Oral Administration of S 55746 in Patients With Chronic Lymphocytic Leukaemia and B-Cell Non-Hodgkin Lymphoma
Official Title
Phase I Dose-escalation Study of Oral Administration of the Selective Bcl2 Inhibitor S 55746 in Patients With Refractory or Relapsed Chronic Lymphocytic Leukaemia and B-Cell Non-Hodgkin Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
March 2014 (undefined)
Primary Completion Date
October 22, 2018 (Actual)
Study Completion Date
October 22, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut de Recherches Internationales Servier
Collaborators
ADIR, a Servier Group company

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to determine the safety profile and tolerability of S 55746 in patients with CLL, B-Cell NHL and MM, in terms of Dose-Limiting Toxicities (DLTs), Maximum Tolerated Dose (MTD) and determine the Recommended Phase 2 Dose (RP2D) through safety profile (DLT, MTD), PK profile, PD profile and preliminary efficacy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukaemia (CLL), B-Cell Non-Hodgkin Lymphoma (NHL), Multiple Myeloma (MM)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
65 (Actual)

8. Arms, Groups, and Interventions

Arm Title
B-cell Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM)
Arm Type
Experimental
Arm Title
Chronic Lymphocytic Leukaemia (CLL)
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
S 55746
Intervention Description
S 55746, per os administration, from 50 to 1500 mg, once a day during a 21-day cycle. Participants will receive 21-day cycles of treatment until a discontinuation criterion is met.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD)
Description
The MTD is the highest drug dosage that is unlikely (<25% posterior probability) to cause DLT in more than 33% of the treated patients in the first cycle of S 55746 treatment
Time Frame
During cycle 1 (21 days)
Title
Incidence of Adverse Events (AEs)
Description
Characterized by severity and seriousness of AEs, laboratory abnormalities and other safety parameters such as electrocardiogram (ECG) changes
Time Frame
From first dose until 30 days after the last dose intake
Secondary Outcome Measure Information:
Title
Plasma concentration of S 55746
Time Frame
Pre-dose on Cycle 1 Day 1 (C1D1), C1D2, C1D3, C1D4, C1D5, C1D8, C1D9, C2D1 ; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10-12 hours post-dose on C1D1, C1D8
Title
The pharmacokinetic (PK) profile of S 55746: Area Under the Curve [AUC]
Time Frame
Pre-dose on Cycle 1 Day 1 (C1D1), C1D2, C1D3, C1D4, C1D5, C1D8, C1D9, C2D1 ; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10-12 hours post-dose on C1D1, C1D8
Title
The PK profile of S 55746: Maximal Concentration [Cmax]
Time Frame
Pre-dose on Cycle 1 Day 1 (C1D1), C1D2, C1D3, C1D4, C1D5, C1D8, C1D9, C2D1 ; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10-12 hours post-dose on C1D1, C1D8
Title
Apoptotic activity from blood samples
Time Frame
At Cycle 1(21 days)
Title
Objective Response Rate (ORR)
Time Frame
Up to study completion (maximum of 3 years)
Title
Clinical Benefit Rate (CBR)
Time Frame
Up to study completion (maximum of 3 years)
Title
Duration of response
Time Frame
Up to study completion (maximum of 3 years)
Title
Progression Free Survival (PFS)
Time Frame
From date of inclusion until the date of progression or date of death, whichever occurs first, assessed up to study completion (maximum of 3 years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Women or men aged >/=18 years Patients with a measurable histologically confirmed Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Diffuse Large B-Cell Lymphoma (DLBCL), Small Lymphocytic Lymphoma (SLL) and Marginal Zone Lymphoma (MZL) (Arm A), or patients with an evaluable immunophenotypically confirmed CLL (Arm B), or patients with a measurable Multiple Myeloma t(11;14) (arm A expansion part) according to International Myeloma Working Group (IMWG) criteria Relapsed after or refractory disease to standard treatments, and require treatment in the opinion of the investigator Estimated life expectancy > 12 weeks World Health Organization (WHO) performance status 0-2 Adequate bone marrow, renal and hepatic functions No evidence or treatment for another malignancy within 2 years prior to study entry. Curatively treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia is allowed Additional inclusion criteria for food interaction cohort: B-cell NHL patients at low risk of tumour lysis syndrome (TLS) Recent/concomitant treatment altering gastric pH Exclusion Criteria: Previous treatment with a BH3 mimetic Previous therapy for the studied disease within 3 weeks before first intake Radioimmunotherapy, radiotherapy within 8 weeks before first intake Major surgery within 3 weeks before first day of study drug dosing Corticosteroids >= 20 mg prednisone equivalent per day within 7 days before first intake Anticoagulant oral drugs, aspirin > 325 mg/day within 7 days prior to first S 55746 intake Positive direct antiglobulin test (Coombs test) and haptoglobin below normal value Prior allogenic stem cell transplant Autologous stem cell transplant within 3 months before first intake NHL patients diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma/leukaemia Human immunodeficiency virus (HIV) Known acute or chronic hepatitis B or hepatitis C Impaired cardiac function Medications known to prolong corrected QT (QTc) interval History or/ clinically suspicious for cancer- related Central Nervous System disease Solitary extramedullary plasmacytoma Laboratory Signs of TLS Strong or moderate CYP3A4 inhibitors/inducers (treatment, food or drink products) Treatment highly metabolized by the CYP3A4 or CYP2D6 and/or substrates with a narrow therapeutic index, multienzyme and/or OATP and/or P-gp substrates or herbal products. Known hypersensitivity to rasburicase Glucose-6-phosphate dehydrogenase (G6PD) deficiency and other cellular metabolic disorders known to cause haemolytic anaemia Patients receiving proton pump inhibitor
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Le Gouill, M.D., Ph.D.
Organizational Affiliation
Nantes University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services
City
Melbourne
ZIP/Postal Code
3004
Country
Australia
Facility Name
Hopital Claude Huriez
City
Lille
Country
France
Facility Name
CHU de Nantes
City
Nantes
Country
France
Facility Name
Centre hospitalier Lyon Sud
City
Pierre-Bénite
Country
France
Facility Name
Gustave Roussy
City
Villejuif
Country
France
Facility Name
Universitätsklinikum Carl Gustav Carus
City
Dresden
Country
Germany
Facility Name
Städtisches Klinikum Schwabing
City
Munich
Country
Germany
Facility Name
Universitätsklinikum Ulm
City
Ulm
Country
Germany
Facility Name
National Oncology Institute
City
Budapest
Country
Hungary
Facility Name
CRU Hungary Kft
City
Miskolc
Country
Hungary
Facility Name
Severance Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
St. Mary's Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Warsaw Institute of Oncology
City
Warsaw
Country
Poland
Facility Name
Warsaw Medical University
City
Warsaw
Country
Poland
Facility Name
National Cancer Center (NCC)
City
Singapore
Country
Singapore
Facility Name
National University Cancer Institute Singapore
City
Singapore
Country
Singapore
Facility Name
University College London Hospitals
City
London
Country
United Kingdom
Facility Name
Freeman Hospital
City
Newcastle
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing Time Frame
After Marketing Authorisation in EEA or US if the study is used for the approval.
IPD Sharing 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.
IPD Sharing URL
http://clinicaltrials.servier.com
Links:
URL
https://clinicaltrials.servier.com/wp-content/uploads/CL1-55746-001-laysummary-2019.09.16.pdf
Description
Lay summary
URL
https://clinicaltrials.servier.com/wp-content/uploads/CL1-55746-001-anonymisedsynopsis-2019.09.16-1.pdf
Description
Results summary
Available IPD and Supporting Information:
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Study Protocol
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Statistical Analysis Plan
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Informed Consent Form
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
study-level clinical trial data
Available IPD/Information URL
https://clinicaltrials.servier.com/
Available IPD/Information Type
Clinical Study Report
Available IPD/Information URL
https://clinicaltrials.servier.com/

Learn more about this trial

Dose-escalation Study of Oral Administration of S 55746 in Patients With Chronic Lymphocytic Leukaemia and B-Cell Non-Hodgkin Lymphoma

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