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NCT Number: NCT02920697

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

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.

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Key information

Conditions

Chronic Lymphocytic Leukaemia (CLL) B-Cell Non-Hodgkin Lymphoma (NHL) Blood Protein Disorders Cardiovascular Diseases Hematologic Diseases Hemic and Lymphatic Diseases Hemorrhagic Disorders Hemostatic Disorders Immune System Diseases Immunoproliferative Disorders Leukemia Leukemia, B-Cell Leukemia, Lymphoid Lymphatic Diseases Lymphoma Lymphoma, B-Cell Lymphoma, Non-Hodgkin Lymphoproliferative Disorders Multiple Myeloma Multiple Myeloma (MM) Neoplasms Neoplasms by Histologic Type Neoplasms, Plasma Cell Paraproteinemias Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services, Melbourne, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

S 55746

Drug

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.

Primary outcomes

  1. Maximum Tolerated Dose (MTD)

    Time frame: 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

  2. Incidence of Adverse Events (AEs)

    Time frame: 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 outcomes

  1. 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

  2. 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

  3. 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

  4. Apoptotic activity from blood samples

    Time frame: At Cycle 1(21 days)

  5. Objective Response Rate (ORR)

    Time frame: Up to study completion (maximum of 3 years)

  6. Clinical Benefit Rate (CBR)

    Time frame: Up to study completion (maximum of 3 years)

  7. Duration of response

    Time frame: Up to study completion (maximum of 3 years)

  8. 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)

Sponsors and collaborators

Lead sponsor

Institut de Recherches Internationales Servier

Other

Collaborators

  • ADIR, a Servier Group company

Registry information

Official study 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

Important dates

Study start
2014
Primary completion
2018
Study completion
2018
First posted
Sep 30, 2016
Registry last updated
Jul 25, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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