B-Cell Non-Hodgkin Lymphoma (NHL), Chronic Lymphocytic Leukaemia (CLL), Multiple Myeloma (MM)
Conditions
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.
Interventions
DRUGS 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.
Sponsors
ADIR, a Servier Group company
Institut de Recherches Internationales Servier
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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) |
| 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 |
| 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) |
| Clinical Benefit Rate (CBR) | Up to study completion (maximum of 3 years) |
| 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 |
Countries
Australia, France, Germany, Hungary, Poland, Singapore, South Korea, United Kingdom
Outcome results
None listed