Study of a New Intravenous Drug, Called S65487, in Patients With Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Multiple Myeloma or Chronic Lymphocytic Leukemia

• ClinicalTrials.gov Identifier: NCT03755154
• Recruitment Status: Active, not recruiting
• First Posted: November 27, 2018
• Last Update Posted: February 28, 2023
• Sponsor: Institut de Recherches Internationales Servier
• Collaborator: ADIR, a Servier Group company
• Information provided by (Responsible Party): Servier ( Institut de Recherches Internationales Servier )

Study Description

Brief Summary:

The purpose of this first in human study is to assess safety, tolerability, Pharmacokinetic (PK) and preliminary clinical activity and to estimate the Maximum Tolerated Doses (MTD(s))/ Recommended Phase 2 Doses (RP2D(s)) of S65487 as single agent administered intravenously (i.v.) in adult patients with refractory or relapsed Acute Myeloid Leukemia (AML), Non-Hodgkin Lymphoma (NHL), Multiple Myeloma (MM) or Chronic Lymphocytic Leukemia (CLL).

Condition or disease	Intervention/treatment	Phase
Relapsed or Refractory Acute Myeloid Leukemia; Relapsed or Refractory Non-Hodgkin Lymphoma; Relapsed or Refractory Multiple Myeloma; Relapsed or Refractory Chronic Lymphocytic Leukemia	Drug: S65487- initial scheme; Drug: S65487 - alternative scheme	Phase 1

Detailed Description:

This study is designed in two parts: one part for dose escalation, one part for dose expansion.The dose escalation part will be followed by expansion part at the MTD(s)/RP2D(s)

This study will utilize an adaptative Bayesian Logistic Regression model to guide dose escalation and estimate the MTD(s) based on the Dose Limiting Toxicity (DLT) relationship(s) for S65487 in the indications.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I, Open Label, Non-randomised, Non-comparative, Multi-center Study, Evaluating S65487, a Bcl-2 Inhibitor Intravenously Administered, in Patients With Relapsed or Refractory Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Multiple Myeloma or Chronic Lymphocytic Leukemia
• Actual Study Start Date: July 17, 2019
• Estimated Primary Completion Date: July 10, 2023
• Estimated Study Completion Date: July 10, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: S65487 - initial scheme	Drug: S65487- initial scheme; S65487 is administered as single agent via i.v. infusion once a week on a 3-week cycle.
Experimental: S65487 - alternative scheme	Drug: S65487 - alternative scheme; S65487 is administered in 3 to 5 i.v. infusions the first week of each cycle then once a week on the rest of the 3-week cycle.

Outcome Measures

Primary Outcome Measures :

1. Incidence of Dose Limiting Toxicity (DLT) [ Time Frame: until the end of the first cycle (each cycle is 21days) ]
   Safety criterion
2. Incidence and severity of Adverse Events [ Time Frame: through study completion an average of 6 months ]
   Safety and tolerability criteria
3. Incidence and severity of Serious Adverse Events [ Time Frame: through study completion an average of 6 months ]
   Safety and tolerability criteria
4. Number of participants with dose reductions [ Time Frame: through study completion an average of 6 months ]
5. Number of participants with dose interruptions [ Time Frame: through study completion an average of 6 months ]
6. Dose intensity [ Time Frame: through study completion an average of 6 months ]

Secondary Outcome Measures :

1. The pharmacokinetic (PK) profile of S65487: Area Under the Curve (AUC) [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3 (alternative schedule only), Cyle 1 Day 5 (alternative schedule only), Cycle 1 Day 8, Cycle 1 Day 9, Day 1 of next cycles (one cycle is 21 days) ]
2. PK profile of S65487: Volume of distribution at steady-state (Vss) [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3 (alternative schedule only), Cyle 1 Day 5 (alternative schedule only), Cycle 1 Day 8, Cycle 1 Day 9, Day 1 of next cycles (one cycle is 21 days) ]
3. PK profile of S65487: total CLearance (CL) [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3 (alternative schedule only), Cyle 1 Day 5 (alternative schedule only), Cycle 1 Day 8, Cycle 1 Day 9, Day 1 of next cycles (one cycle is 21 days) ]
4. PK profile of S65487: terminal half-life (t½z) [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3 (alternative schedule only), Cyle 1 Day 5 (alternative schedule only), Cycle 1 Day 8, Cycle 1 Day 9, Day 1 of next cycles (one cycle is 21 days) ]
5. Best Overall Response (BOR) [ Time Frame: Through study completion, an average of 6 months ]
   Best Response observed during the treatment period
6. Overall Response Rate (ORR) [ Time Frame: Through study completion, an average of 6 months ]
   Proportion of patients in whom a complete response (CR) or a partial response (PR)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML, excluding acute promyelocytic leukaemia with relapsed or refractory disease without established alternative therapy. Or patients with measurable confirmed Multiple Myeloma (IMWG) with relapsed or refractory disease who have previously received at least three lines of treatment and without established alternative therapy. Or patients with histologically and measurable confirmed Non Hodgkin Lymphoma defined as Diffuse Large B cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), High-Grade B cell Lymphoma with relapsed or refractory disease who have received at least two lines of therapy (including rituximab) and without established alternative therapy. Or patients with Chronic Lymphocytic Leukemia (CLL) who have relapsed or are refractory (except treatment failure), as defined per iwCLL, from venetoclax treatment and without established alternative therapy.
• ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2.
• For NHL, MM patients and CLL patients: haematological function (independent of any growth factor support) based on the last assessment performed before inclusion, defined as: absolute neutrophil count (ANC) ≥ 1 x 109/L, haemoglobin ≥ 8 g/dL, platelet count ≥ 50 x 109/L for NHL and MM patients, platelet count ≥ 30 x 109/L for CLL patients.
• For AML patients: circulating Blood White Cell count (WBC count) < 25 x 109/L (with or without use of hydroxycarbamide/leukapheresis) based on the last assessment performed before inclusion.
• Adequate renal function based on the last assessment performed before inclusion, assessed as Glomerular Filtration Rate (GFR) using Modification of Diet in Renal Disease (MDRD) Formula.
• Adequate hepatic function based on the last assessment performed before inclusion.

Exclusion Criteria:

• Pregnancy, breastfeeding or possibility of becoming pregnant during the study.
• Participation in another interventional study at the same time or another interventional study requiring investigational treatment intake within 3 weeks or at least 5 half-lives (whichever is longer) prior to the first S65487 administration.
• Participant already enrolled in the study (informed consent signed) and has received at least one dose of S65487.
• Patients who have not recovered from toxicity of previous anticancer therapy, including grade ≥ 2 non-hematologic toxicity, prior to the first IMP administration (including peripheral neurotoxicity). Certain toxicities will not be considered in this category (e.g. alopecia).
• Patients refractory to a previous treatment with a Bcl-2 inhibitor.
• For AML patients : Allogenic stem cell transplant within 3 months before the first IMP administration and/or patients who still receive immunosuppressive treatment within 3 months before the first IMP administration and/or patients with active Graft-versus-host disease within 3 months before the first IMP administration and/or patient who receive donor lymphocyte infusion (DLI) within 3 months before the first IMP administration.
• For NHL, MM and CLL patients : Prior allogenic stem cell transplant before the first IMP administration and/or Autologous stem cell transplant within 3 months before the first IMP administration.

Contacts and Locations

Locations

Australia, Victoria

The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services

Melbourne, Victoria, Australia, 3004

France

Centre Hospitalier Universitaire Régionale de Lille Hôpital Huriez

Lille, France, 59037

CHU Nantes Hôtel Dieu

Nantes, France, 44093

CHU de Nice - Hôpital l'Archet 1 Hématologie clinique

Nice, France, 06200

Spain

Clinica Universidad de Navarra

Madrid, Spain, 28027

Clínica Universidad Navarra- Servicio de Hematología

Pamplona, Spain, 31008

Hospital Clínico Universitario de Salamanca- Servicio de Hematología (4a planta)

Salamanca, Spain, 37007

Hospital Universitario La Fe - Servicio de Hematología - Torre F - Planta 7

Valencia, Spain, 46026

United Kingdom

King's College Hospital NHS Foundation Trust

London, United Kingdom, SE5 9RS

The Christie NHS foundation Trust

Manchester, United Kingdom, M20 4BX

Freeman Hospital

Newcastle, United Kingdom, NE7 7DN

Sponsors and Collaborators

Institut de Recherches Internationales Servier

ADIR, a Servier Group company

More Information

Additional Information:

Find Results on Servier Clinical Trial Data website 

Study Data/Documents: Individual Participant Data Set 

Study Protocol 

Statistical Analysis Plan 

Informed Consent Form 

Clinical Study Report 

Study-level clinical trial data 

• Responsible Party: Institut de Recherches Internationales Servier
• ClinicalTrials.gov Identifier: NCT03755154
• Other Study ID Numbers: CL1-65487-002; 2018-004170-97 ( EudraCT Number )
• First Posted: November 27, 2018
• Last Update Posted: February 28, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• URL: https://clinicaltrials.servier.com/

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Servier ( Institut de Recherches Internationales Servier ):

Leukemia; Lymphoma; Myeloma; Dose-escalation

Additional relevant MeSH terms:

Lymphoma; Leukemia; Leukemia, Myeloid; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Leukemia, B-Cell