Previously untreated Acute Myeloid Leukemia (AML) MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Institut de Recherches Internationales Servier
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female participant aged = 18 years 2. Participants with cytologically confirmed and documented treatment naïve, de novo or secondary AML defined by WHO 2016 classification (Arber, 2016). Secondary AML includes: a. Previous myelodysplastic syndrome transformed b. AML due to exposure to potentially leukemogenic therapies or agents (e.g. radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 3 years 3. Participants not eligible for standard induction chemotherapy a. Aged = 75 years old b. Or Age =18 years with at least one of the following comorbidities: i. Clinically significant heart or lung comorbidities, as reflected by at least one of: - Lung diffusing capacity for carbon monoxide (DLCO) =65% of expected - Forced expiratory volume in 1 second (FEV1) =65% of expected ii. Other contraindication(s) to anthracycline therapy (must be documented) iii. Other comorbidity that the Investigator judges as incompatible with intensive remission induction chemotherapy, which must be documented 4. ECOG (Eastern Cooperative Oncology Group) performance status should be (criterion should be rechecked at inclusion visit) ECOG = 2. 5. Written informed consent obtained prior any study-specific procedure as described in section 13.3 of the protocol. 6. Adequate renal and hepatic function 7. Circulating White Blood Cell Count (WBC count) =65 years) yes F.1.3.1 Number of subjects for this age range 98
Exclusion criteria
Exclusion criteria: 8. Major surgery within 3 weeks prior to the first IMP administration, or participants who have not recovered from side effects of the surgery 9. Any radiotherapy within 3 weeks before the first IMP administration, (except for palliative radiotherapy at localised lesions not considered as target lesions) 10. Allogenic stem cell transplant within 3 months before the first IMP administration and/or participants with active Graft-versus-host disease within 3 months before the first IMP administration and/or participants who still receive immunosuppressive treatment within 3 months before the first IMP administration and/or participant who receive donor lymphocyte infusion (DLI) within 3 months before the first IMP administration 11. Acute promyelocytic leukemia (APL, French-American-British M3 classification) 12. Favorable risk cytogenetics such as t(8;21), inv(16) or t(16;16) or t(15;17) as per the National Comprehensive Cancer Network (NCCN) Guidelines Version 3, 2019 for Acute Myeloid Leukemia 13. Treatment with hypomethylating agents (decitabine/azacitidine) or Bcl-2 inhibitor,particularly venetoclax for AHD (antecedent hematologic disorders)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: To determine the safety profile and tolerability of S65487 combined with azacitidine (including Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)) To determine the Recommended Phase II Dose (RP2D) of S65487 combined with azacitidine Phase II: To assess the efficacy of S65487 combined with azacitidine ;Secondary Objective: Phase I: To determine the PK parameters of S65487 and azacitidine administered in combination and of potential metabolites (if applicable) To assess the anti-leukemic activity of S65487 combined with azacitidine Phase II: To assess anti-leukemic activity of S65487 combined with azacitidine To evaluate the depth and the duration of response Safety profile and tolerability of S65487 in combination with azacitidine To determine the PK parameters of S65487 and azacitidine administered in combination and of potential metabolites (if applicable);Primary end point(s): Phase I: DLT assessment at the end of cycle 1 AE recording throughout the study evaluated according to CTCAE v5.0, dose interruptions, reductions, and intensity Vitals signs, Laboratory tests, ECG Phase II: CR rate: Complete Remission (CR) rate. Antileukemic activity assessment using blood, bone marrow aspirate and bone marrow biopsies, if available, according to ELN 2022 response criteria and FDA;Timepoint(s) of evaluation of this end point: All along the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): For phase I: PK parameters of S65487, azacitidine and potential metabolite(s) if applicable will be determined in plasma (e.g. Cinf, tinf, AUClast, tlast, Clast, AUC, t½, z, CL and Vss) CR rate: Complete Response (CR) rate, CR rate by initiation of cycle 2 (CR2) CR plus CRi rate: Complete Response rate with incomplete hematologic recovery, CR plus CRh rate: Complete Response with partial hamatologic recovery Duration of Response (DOR), Event Free Survival (EFS) Progression Free Survival (PFS), Overall Survival (OS), time to first response Antileukemic activity assessment using blood, bone marrow aspirate and medullary biopsies if available according to ELN 2017 response criteria and FDA Phase II: CR plus CRi and CR plus CRh rate, CR by initiation of cycle 2, DOR, EFS, PFS, OS, time to first response Minimal Residual Disease analysed centrally on pre- and on-treatment Bone marrow samples of participants at the same time as clinical response assessment. Incidence and severity of adverse events.;Timepoint(s) of evaluation of this end point: All along the study | — |
Countries
Belgium, France, Hungary, Korea, Republic of, Poland, Spain, United Kingdom
Contacts
Public ContactClinical Studies Department
Institut de Recherches Internationales Servier
Outcome results
None listed