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

Sponsor

Institut de Recherches Internationales Servier (Other)

Overall Status

Completed

CT.gov ID

NCT02920697

Collaborator

ADIR, a Servier Group company (Industry)

Enrollment

Locations

Arms

55.7

Duration (Months)

3.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

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 Design

Study Type:

Interventional

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 :

Mar 1, 2014

Actual Primary Completion Date :

Oct 22, 2018

Actual Study Completion Date :

Oct 22, 2018

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose (MTD) [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
Incidence of Adverse Events (AEs) [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

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]
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]
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]
Apoptotic activity from blood samples [At Cycle 1(21 days)]
Objective Response Rate (ORR) [Up to study completion (maximum of 3 years)]
Clinical Benefit Rate (CBR) [Up to study completion (maximum of 3 years)]
Duration of response [Up to study completion (maximum of 3 years)]
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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services	Melbourne	Australia	3004
2	Hopital Claude Huriez	Lille	France
3	CHU de Nantes	Nantes	France
4	Centre hospitalier Lyon Sud	Pierre-Bénite	France
5	Gustave Roussy	Villejuif	France
6	Universitätsklinikum Carl Gustav Carus	Dresden	Germany
7	Städtisches Klinikum Schwabing	Munich	Germany
8	Universitätsklinikum Ulm	Ulm	Germany
9	National Oncology Institute	Budapest	Hungary
10	CRU Hungary Kft	Miskolc	Hungary
11	Severance Hospital	Seoul	Korea, Republic of
12	St. Mary's Hospital	Seoul	Korea, Republic of
13	Warsaw Institute of Oncology	Warsaw	Poland
14	Warsaw Medical University	Warsaw	Poland
15	National Cancer Center (NCC)	Singapore	Singapore
16	National University Cancer Institute Singapore	Singapore	Singapore
17	University College London Hospitals	London	United Kingdom
18	Freeman Hospital	Newcastle	United Kingdom