Clinical trial NCT03755154: Study of a New Intravenous Drug, Called S65487, in Patients With Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Multiple Myeloma or Chronic Lymphocytic Leukemia
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Relapsed or Refractory Acute Myeloid Leukemia
Relapsed or Refractory Non-Hodgkin Lymphoma
Relapsed or Refractory Multiple Myeloma
Relapsed or Refractory Chronic Lymphocytic Leukemia
Keywords: Leukemia
Lymphoma
Myeloma
Dose-escalation
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: ADIR, a Servier Group company
First posted: 2018-11-27
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility 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.

Primary outcomes:
measure: Incidence of Dose Limiting Toxicity (DLT)
timeFrame: until the end of the first cycle (each cycle is 21days)
measure: Incidence and severity of Adverse Events
timeFrame: through study completion an average of 6 months
measure: Incidence and severity of Serious Adverse Events
timeFrame: through study completion an average of 6 months
measure: Number of participants with dose reductions
timeFrame: through study completion an average of 6 months
measure: Number of participants with dose interruptions
timeFrame: through study completion an average of 6 months
measure: Dose intensity
timeFrame: through study completion an average of 6 months
Secondary outcomes:
measure: The pharmacokinetic (PK) profile of S65487: Area Under the Curve (AUC)
timeFrame: 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)
measure: PK profile of S65487: Volume of distribution at steady-state (Vss)
timeFrame: 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)
measure: PK profile of S65487: total CLearance (CL)
timeFrame: 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)
measure: PK profile of S65487: terminal half-life (t½z)
timeFrame: 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)
measure: Best Overall Response (BOR)
timeFrame: Through study completion, an average of 6 months
measure: Overall Response Rate (ORR)
timeFrame: Through study completion, an average of 6 months
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services
state: Victoria
city: Lille
country: France
facility: Centre Hospitalier Universitaire Régionale de Lille Hôpital Huriez
city: Nantes
country: France
facility: CHU Nantes Hôtel Dieu
city: Nice
country: France
facility: CHU de Nice - Hôpital l'Archet 1 Hématologie clinique
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra
city: Pamplona
country: Spain
facility: Clínica Universidad Navarra- Servicio de Hematología
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca- Servicio de Hematología (4a planta)
city: Valencia
country: Spain
facility: Hospital Universitario La Fe - Servicio de Hematología - Torre F - Planta 7
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS foundation Trust
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
Study officials:
References: