hdm201 added to ct in r/r or newly diagnosed aml

Conditions: Leukemia, Myeloid, Acute

Summary: 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.

Eligibility criteria:
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.

Keywords: hdm201 midostaurin cytarabine daunorubicin idarubicin liposomal cytarabine/daunorubicin acute myeloid leukemia (aml) 1l newly diagnosed aml relapsed/refractory aml flt3-mutation combination treatment dose escalation cr/cri minimal residual disease ddi with cyp3a4 inhibitors ddi with sensitive cyp3a4 substrate