The purpose of this study is to assess the safety, tolerability and clinical activity of the combination S65487 with azacitidine in patients with acute myeloid leukaemia.

The study is designed in two parts: A dose escalation phase I part, and a dose expansion phase II part with an additional potential expansion cohort.

During dose escalation of S65487 in combination with azacitidine, only S65487 agent dose will escalate and a DDI (Drug-Drug interaction) assessment between S65487 and posaconazole (antifungal drug) will be performed. A ramp-up dose of S65487 will be administered on the first two days of cycle 1, then the full dose of S65487 will be administered for the remainder of cycle 1. Each treatment cycle is 28 days.

For the expansion phase, the dose will be the RP2D (Recommended Phase 2 Dose) determined during phase I part. An additional potential expansion cohort will be included if there is more than one promising dose/schedule candidate.

Inclusion Criteria:

• Male or female participant aged ≥ 18 years old

• Participants with cytologically confirmed and documented treatment naïve, de novo or secondary AML defined by WHO 2016 classification (Arber, 2016). Secondary AML includes:

  • Previous myelodysplastic syndrome transformed
  • 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

• Participants not eligible for standard induction chemotherapy

  • Aged ≥ 75 years old

  • Or Age ≥18 years with at least one of the following comorbidities:

    • 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

    • Other contraindication(s) to anthracycline therapy (must be documented)

    • Other comorbidity that the Investigator judges as incompatible with intensive remission induction chemotherapy, which must be documented

• ECOG (Eastern Cooperative Oncology Group) performance status should be (criterion should be rechecked at inclusion visit) ECOG ≤ 2.

• Written informed consent obtained prior any study-specific procedure as described in section 13.3 of the protocol.

• Adequate renal and hepatic function

• Circulating White Blood Cell Count (WBC count) < 25*109 G/L (with or without use of hydroxycarbamide/leukapheresis)

• Serum potassium, serum calcium, serum phosphates, serum magnesium within normal limits with or without supplementation.

Exclusion Criteria:

• Major surgery within 3 weeks prior to the first IMP administration, or participants who have not recovered from side effects of the surgery
• Any radiotherapy within 3 weeks before the first IMP administration,
• 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
• Acute promyelocytic leukemia (APL, French-American-British M3 classification)
• 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
• Treatment with hypomethylating agents (decitabine/azacitidine) or Venetoclax for AHD (antecedent hematologic disorders) in the 3 months prior to the first IMP intake

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.

After Marketing Authorisation in EEA or US if the study is used for the approval.

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.