Acute Myeloid Leukaemia (AML) MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: S64315
Product Code: S64315
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: S64315
Other descriptive name: S64315/MIK665
Concentration unit: mg/ml milligr
Sponsors
Institut de Recherches Internationales Servier
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1-Patients aged = 18 years 2-Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML as defined by WHO 2016 classification (Arber, 2016) excluding acute promyelocytic leukaemia (APL, French-American-British M3 classification) with: relapsed or refractory disease and without established alternative therapy, or secondary to MDS and without established alternative therapy or, newly diagnosed AML, not previously treated for AML and who are not candidate for intensive chemotherapy due to age or comorbidities. 3-Eastern Cooperative Oncology Group (ECOG) performance status = 2. 4-Adequate haematological, renal and hepatic functions based on the last assessment performed within 7 days prior to the first IMP administration. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 87 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 93
Exclusion criteria
Exclusion criteria: 1-Previous myeloproliferative syndrome (MPS). 2-Patient previously treated with hypomethylating agents (HMAs) such as azacitidine or decitabine, during dose escalation phase I part. 3-Patients previously treated with any Mcl-1 inhibitor. 4-Patients who have not recovered from toxicity of previous anticancer therapy, including Grade = 2 toxicity (except alopecia of any grade) according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) version 5.0, prior to the first IMP administration. 5-Severe or uncontrolled active acute or chronic infection. 6-Uncontrolled hepatitis B or C infection. 7-Known carriers of HIV antibodies, history of significant liver disease, active acute or chronic pancreatitis, active central nervous system disease. 8-Troponin (I or T) > ULN. 9-Clinically significant cardiac dysfunction (including NYHA class =II heart failure, Left Ventricular Ejection Fraction (LVEF) 450 ms for males and > 470 ms for females, obtained from triplicate 12-lead ECG. 11-Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. 12-Uncontrolled arterial hypertension (systolic blood pressure (SBP) > 150 mmHg or diastolic blood pressure (DBP) > 95 mmHg).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I dose escalation To determine the safety profile and tolerability of S64315 in combination with azacitidine in patients with AML. Phase II dose expansion To evaluate the Objective Response rate (ORR) (including complete response (CR) and complete response with incomplete bone marrow recovery (CRi) rates) of S64315 in combination with azacitidine.;Secondary Objective: Phase I dose escalation To determine pharmacokinetic (PK) profile of S64315 and azacitidine administered in combination, and potential metabolites. To evaluate anti-leukemic activity of S64315 in combination with azacitidine. Phase II dose expansion To assess anti-leukemic activity of S64315 in combination with azacitidine in terms of overall survival (OS), duration of response (DOR), best overall response (BOR), progression-free survival (PFS), disease-free survival (DFS). To assess the safety and tolerability of S64315 in combination with azacitidine. To determine PK profile of S64315 and azacitidine administered in combination, and potential metabolites.;Primary end point(s): Phase I - dose escalation: Incidence of DLTs starting from the LID period to the end of the first cycle of treatment of S64315 in combination with azacitidine. Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0. Recording of any change or addition of a new concomitant treatment. Laboratory tests: haematology with differential, blood biochemistry, thyroid function, blood coagulation, urinary analysis, hepatitis markers, TLS monitoring, cardiac markers follow up Complete physical examination, ECOG performance status, vital signs measurements. ECG parameters, cardiac function assessment. Left ventricular ejection fraction (LVEF). Dose interruptions, reductions and dose intensity. Phase II - dose expansion: ORR (including CR+ CRi);Timepoint(s) of evaluation of this end point: Phase I - dose escalation: DLT: D-13 to C1D28 (i.e. from the start of S64315 Lead in dose period to the end of 1st cy | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I - dose escalation: PK parameters of S64315 and azacitidine administered in combination, and potential metabolites if applicable, in plasma (e.g. Cinf, tinf, AUClast, tlast, Clast, AUC, t1/2,z, CL and Vd) ORR (including CR/CRi), Best Overall Response (BOR), Duration of Response (DOR), Progression Free Survival (PFS), Overall survival (OS) Anti-leukemic activity assessment using blood, BMA and BMB if available according to ELN 2017 response criteria (Döhner, 2017) Phase II - dose expansion: BOR, DOR, PFS, OS Anti-leukemic activity assessment using blood/BMA and BMB if available according to ELN 2017 response criteria (Döhner, 2017) Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0 Laboratory tests: haematology with differential, blood biochemistry, thyroid function, blood coagulation and urinary analysis, hepatitis markers, TLS monitoring, cardiac markers follow up Complete physical examination, ECOG performance status, vital signs measurements ECG parameters, cardiac function assessment LVEF Dose interruptions, reductions and dose intensity PK parameters of S64315 and azacitidine administered in combination, and potential metabolites if applicable, in plasma;Timepoint(s) of evaluation of this end point: Phase I - dose escalation: PK parameters of S64315: D-13, C1D2, C1D3, C1D9, C1D10 PK parameters of azacitidine: C1D1, C1D2, C1D3, C1D5, C1D7 Haematology anti-leukemic activity assessment: Inclusion period, C1D1, C1D2, CxD1, WV BMA and BMB anti-leukemic activity assessment: Inclusion period, C2D1, C3D1, if suspected progression, WV ORR, BOR, DOR, PFS, OS: from inclusion period to FU | — |
Countries
Australia, France, Spain, United States
Contacts
Public ContactClinical Studies Department
Institut de Recherches Internationales Servier
Outcome results
None listed