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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

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ClinicalTrials.gov Identifier: NCT02920697
Recruitment Status : Completed
First Posted : September 30, 2016
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
Servier ( Institut de Recherches Internationales Servier )

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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukaemia (CLL) B-Cell Non-Hodgkin Lymphoma (NHL) Multiple Myeloma (MM) Drug: S 55746 Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : March 2014
Actual Primary Completion Date : October 22, 2018
Actual Study Completion Date : October 22, 2018


Arm Intervention/treatment
Experimental: B-cell Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) Drug: S 55746
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.

Experimental: Chronic Lymphocytic Leukaemia (CLL) Drug: S 55746
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 Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: During cycle 1 (21 days) ]
    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

  2. Incidence of Adverse Events (AEs) [ Time Frame: From first dose until 30 days after the last dose intake ]
    Characterized by severity and seriousness of AEs, laboratory abnormalities and other safety parameters such as electrocardiogram (ECG) changes


Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. Apoptotic activity from blood samples [ Time Frame: At Cycle 1(21 days) ]
  5. Objective Response Rate (ORR) [ Time Frame: Up to study completion (maximum of 3 years) ]
  6. Clinical Benefit Rate (CBR) [ Time Frame: Up to study completion (maximum of 3 years) ]
  7. Duration of response [ Time Frame: Up to study completion (maximum of 3 years) ]
  8. 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) ]


Information from the National Library of Medicine

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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:

  • 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

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): NCT02920697


Locations
Australia
The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services
Melbourne, Australia, 3004
France
Hopital Claude Huriez
Lille, France
CHU de Nantes
Nantes, France
Centre hospitalier Lyon Sud
Pierre-Bénite, France
Gustave Roussy
Villejuif, France
Germany
Universitätsklinikum Carl Gustav Carus
Dresden, Germany
Städtisches Klinikum Schwabing
Munich, Germany
Universitätsklinikum Ulm
Ulm, Germany
Hungary
National Oncology Institute
Budapest, Hungary
CRU Hungary Kft
Miskolc, Hungary
Korea, Republic of
Severance Hospital
Seoul, Korea, Republic of
St. Mary's Hospital
Seoul, Korea, Republic of
Poland
Warsaw Institute of Oncology
Warsaw, Poland
Warsaw Medical University
Warsaw, Poland
Singapore
National Cancer Center (NCC)
Singapore, Singapore
National University Cancer Institute Singapore
Singapore, Singapore
United Kingdom
University College London Hospitals
London, United Kingdom
Freeman Hospital
Newcastle, United Kingdom
Sponsors and Collaborators
Institut de Recherches Internationales Servier
Investigators
Principal Investigator: Steven Le Gouill, M.D., Ph.D. CHU de Nantes

Responsible Party: Institut de Recherches Internationales Servier
ClinicalTrials.gov Identifier: NCT02920697     History of Changes
Other Study ID Numbers: CL1-55746-001
2013-003779-36 ( EudraCT Number )
ISRCTN04804337 ( Registry Identifier: ISRCTN )
First Posted: September 30, 2016    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018
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

Additional relevant MeSH terms:
Lymphoma
Leukemia
Multiple Myeloma
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Leukemia, B-Cell