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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: S 55746


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: B-cell Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM)<br> | Drug: S 55746<br>* 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.<br>|
| Experimental: Chronic Lymphocytic Leukaemia (CLL)<br> | Drug: S 55746<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |