Clinical trial NCT02920697: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukaemia (CLL)
B-Cell Non-Hodgkin Lymphoma (NHL)
Multiple Myeloma (MM)
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: ADIR, a Servier Group company
First posted: 2016-09-30
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: During cycle 1 (21 days)
measure: Incidence of Adverse Events (AEs)
timeFrame: From first dose until 30 days after the last dose intake
Secondary outcomes:
measure: Plasma concentration of S 55746
timeFrame: 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
measure: The pharmacokinetic (PK) profile of S 55746: Area Under the Curve [AUC]
timeFrame: 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
measure: The PK profile of S 55746: Maximal Concentration [Cmax]
timeFrame: 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
measure: Apoptotic activity from blood samples
timeFrame: At Cycle 1(21 days)
measure: Objective Response Rate (ORR)
timeFrame: Up to study completion (maximum of 3 years)
measure: Clinical Benefit Rate (CBR)
timeFrame: Up to study completion (maximum of 3 years)
measure: Duration of response
timeFrame: Up to study completion (maximum of 3 years)
measure: Progression Free Survival (PFS)
timeFrame: 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)
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services
city: Lille
country: France
facility: Hopital Claude Huriez
city: Nantes
country: France
facility: CHU de Nantes
city: Pierre-Bénite
country: France
facility: Centre hospitalier Lyon Sud
city: Villejuif
country: France
facility: Gustave Roussy
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Munich
country: Germany
facility: Städtisches Klinikum Schwabing
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Budapest
country: Hungary
facility: National Oncology Institute
city: Miskolc
country: Hungary
facility: CRU Hungary Kft
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: St. Mary's Hospital
city: Warsaw
country: Poland
facility: Warsaw Institute of Oncology
city: Warsaw
country: Poland
facility: Warsaw Medical University
city: Singapore
country: Singapore
facility: National Cancer Center (NCC)
city: Singapore
country: Singapore
facility: National University Cancer Institute Singapore
city: London
country: United Kingdom
facility: University College London Hospitals
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
Study officials:
affiliation: Nantes University Hospital
name: Steven Le Gouill, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Le Gouill S, Wermke M, Morschhauser F, Lim ST, Salles G, Kloos I, de Burgat V, Becquart M, Paux G, Kraus-Berthier L, Pennaforte S, Stilgenbauer S, Walewski J, Ribrag V. A new BCL-2 Inhibitor (S55746/BCL201) as Monotherapy in Patients with Relapsed or Refractory Non-hodgkin Lymphoma: Preliminary Results of the First-in-human Study. Hematol Oncol. 2017 Jun 07;35(S5):14-17. doi: 10.1002/hon.2437_30