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

Multiple Myeloma (MM) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02920697
• Other study ID #: CL1-55746-001
• Secondary ID: 2013-003779-36IS
• Status: Completed
• Phase: Phase 1
• Start date: March 2014
• Est. completion date: October 22, 2018

Study information

• Verified date: November 2019
• Source: Servier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: October 22, 2018
• Est. primary completion date: October 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• B-Cell Non-Hodgkin Lymphoma (NHL)
• Chronic Lymphocytic Leukaemia (CLL)
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Multiple Myeloma
• Multiple Myeloma (MM)
• Neoplasms, Plasma Cell

Intervention

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.

Locations

Country	Name	City	State
Australia	The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services	Melbourne
France	Hopital Claude Huriez	Lille
France	CHU de Nantes	Nantes
France	Centre hospitalier Lyon Sud	Pierre-Bénite
France	Gustave Roussy	Villejuif
Germany	Universitätsklinikum Carl Gustav Carus	Dresden
Germany	Städtisches Klinikum Schwabing	Munich
Germany	Universitätsklinikum Ulm	Ulm
Hungary	National Oncology Institute	Budapest
Hungary	CRU Hungary Kft	Miskolc
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	St. Mary's Hospital	Seoul
Poland	Warsaw Institute of Oncology	Warsaw
Poland	Warsaw Medical University	Warsaw
Singapore	National Cancer Center (NCC)	Singapore
Singapore	National University Cancer Institute Singapore	Singapore
United Kingdom	University College London Hospitals	London
United Kingdom	Freeman Hospital	Newcastle

Sponsors (2)

Lead Sponsor	Collaborator
Institut de Recherches Internationales Servier	ADIR, a Servier Group company

Countries where clinical trial is conducted

Australia,  France,  Germany,  Hungary,  Korea, Republic of,  Poland,  Singapore,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	During cycle 1 (21 days)
Primary	Incidence of Adverse Events (AEs)	Characterized by severity and seriousness of AEs, laboratory abnormalities and other safety parameters such as electrocardiogram (ECG) changes	From first dose until 30 days after the last dose intake
Secondary	Plasma concentration of S 55746		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
Secondary	The pharmacokinetic (PK) profile of S 55746: Area Under the Curve [AUC]		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
Secondary	The PK profile of S 55746: Maximal Concentration [Cmax]		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
Secondary	Apoptotic activity from blood samples		At Cycle 1(21 days)
Secondary	Objective Response Rate (ORR)		Up to study completion (maximum of 3 years)
Secondary	Clinical Benefit Rate (CBR)		Up to study completion (maximum of 3 years)
Secondary	Duration of response		Up to study completion (maximum of 3 years)
Secondary	Progression Free Survival (PFS)		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)

External Links

•   Lay summary
•   Results summary