It was determined that the study design may not be optimal given the changing AML treatment landscape.

This is a multi-center open-label Phase I/II study investigating orally administered HDM201 in combination with chemotherapy in two populations: subjects with first line AML or subjects with relapsed/refractory AML. This study is conducted in three parts: dose escalation, dose expansion and DDI study.

This is a Phase 1 / 2 study. No patients were screened / enrolled. There are no data collected. There will be no CSR.

Inclusion Criteria:

All Subjects

• Signed informed consent must be obtained prior to participation in the study
• Age ≥18
• Diagnosis of AML based on WHO 2016 classification. Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) that is 0 - 2.
• Adequate organ functions
• Left ventricular ejection fraction > 45%

For 1L AML population:

• For Part 1 or Part 2 Expansion Cohorts 1 or 2: subjects with de novo AML suitable for induction treatment with cytarabine and anthracyclines as per investigator judgement
• For Part 2 Expansion Cohort 2: documented presence of FLT3 mutation (ITD or TKD ) and suitable for midostaurin treatment as per investigator judgement.
• For Part 2 Expansion Cohort 3: Subjects with secondary AML (e.g. AML-MRC , secondary to myelodysplasia/MDS or therapy-related AML). Prior use of hypomethylating agents or other therapies with curative intent for treatment previous hematological malignancies or therapy-related AML is allowed. Subjects suitable for induction treatment with liposomal cytarabine/daunorubicin as per investigator judgement.

For R/R AML population:

• All Parts: Diagnosis of relapsed or refractory AML and suitable for treatment with IDAC as per investigator judgement.
• For Part 3 only: willingness and suitability to participate in DDI Cohort 1 or 2.

Exclusion Criteria:

• Prior exposure to MDM2 and MDM4 inhibitor (e.g. idasanutlin)
• Known symptomatic CNS leukemia not controlled by adequate therapy.
• Isolated extramedullary leukemia
• Subjects with prior malignancy (some exceptions apply)
• QTcF > 470 ms at screening
• Subjects who require treatment with moderate or strong CYP3A4 inducers within 14 days prior to starting study treatment or during the study
• Subjects who require use of herbal preparations/medications and dietary supplements within 7 days prior to first dose and during the study
• Subjects who require treatment with substrates of CYP3A4/5 with narrow therapeutic index (within 24 hours prior to during and 48 hours after HDM201 administration)
• Subjects who require treatment with moderate or strong CYP3A4 inhibitors within 48 hours prior to, during and 48 hours post HDM201 administration. (except for Part 3 DDI Cohort 1 and 2)
• Subject is pregnant or breastfeeding
• WOCBP unless using highly effective methods of contraception during study treatment and for an appropriate time period after last study treatment
• Sexually active males unless they use a condom during intercourse while taking study drug and for an appropriate time period after last study treatment

For Part 1 only:

- Subjects with a known favorable risk AML subtype at screening or subjects with FLT3 mutation

For Part 3 only:

• DDI Cohort 1: use of posaconazole (other than the planned dosing required by the protocol) within 7 days prior to start of the DDI investigation and for the duration of the DDI period
• DDI Cohort 2: use of midazolam (other than the planned dosing required by the protocol) within 2 days prior to start of the DDI investigation and for the duration of the DDI period
• DDI Cohort 1 and 2: subjects who have received, or are expected to receive moderate or strong inhibitors of CYP3A4 within 7 days prior to start of the DDI investigation, for the duration of the investigation, and 24 hours after last blood sample collection for PK assessment

Other protocol-defined inclusion/exclusion may apply.

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.