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

NCT02920697

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Multiple Myeloma
  • Small Lymphocytic Lymphoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

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

DrugSynonymsArms
S 55746B-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

NameTypeDescriptionInterventions
B-cell Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM)Experimental
  • S 55746
Chronic Lymphocytic Leukaemia (CLL)Experimental
  • S 55746

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

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