Description:
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.
Title
- Brief Title: Dose-escalation Study of Oral Administration of S 55746 in Patients With Chronic Lymphocytic Leukaemia and B-Cell Non-Hodgkin Lymphoma
- 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 IDs
- ORG STUDY ID:
CL1-55746-001
- SECONDARY ID:
2013-003779-36
- SECONDARY ID:
ISRCTN04804337
- NCT ID:
NCT02920697
Conditions
- Chronic Lymphocytic Leukaemia (CLL)
- B-Cell Non-Hodgkin Lymphoma (NHL)
- Multiple Myeloma (MM)
Interventions
| Drug | Synonyms | Arms |
|---|
| S 55746 | | B-cell Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| B-cell Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) | Experimental | | |
| Chronic Lymphocytic Leukaemia (CLL) | Experimental | | |
Eligibility 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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Maximum Tolerated Dose (MTD) |
| Time Frame: | During cycle 1 (21 days) |
| Safety Issue: | |
| Description: | 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 |
Secondary Outcome Measures
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | Apoptotic activity from blood samples |
| Time Frame: | At Cycle 1(21 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Objective Response Rate (ORR) |
| Time Frame: | Up to study completion (maximum of 3 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Clinical Benefit Rate (CBR) |
| Time Frame: | Up to study completion (maximum of 3 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Duration of response |
| Time Frame: | Up to study completion (maximum of 3 years) |
| Safety Issue: | |
| Description: | |
| Measure: | 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) |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Institut de Recherches Internationales Servier |
Last Updated
November 25, 2019
