HDM201 Added to CT in R/R or Newly Diagnosed AML

Study Overview
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Brief Summary
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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.

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

Official Title
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A Phase I/II Multi-center Study of HDM201 Added to Chemotherapy in Adult Subjects With Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: HDM201
* Drug: cytarabine
* Drug: anthracycline
* Drug: midostaurin
* Drug: liposomal cytarabine/daunorubicin
* Drug: posaconazole
* Drug: midazolam


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 3 parts - two different populations Part 1 - escalation - parallel dose escalation in 1L AML subjects and in R/R subjects (up to 8 dose cohorts per arm. Part 2 - expansion - parallel expansion in 3 cohorts of 1L AML, and 1 cohort of R/R AML after recommended dose of expansion was determined. Part 3 - DDI - parallel enrollment or R/R AML subjects into 2 DDI Cohorts (one with CYP3A4 inhibitor, one with CYP3A4 substrate).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - first line (1L) AML<br>1L acute myeloid leukemia (AML) subjects receiving HDM201 in various doses/schedules in combination with cytarabine/anthracyclines | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;Drug: anthracycline<br>* 20mg or other strength as locally available given intravenously<br>* Other names: daunorubicin or idarubicin, Rubidomycin or Idamycin;|
| Experimental: Part 1 - relapsed/refractory (R/R) AML<br>R/R AML subjects receiving HDM201 in various doses/schedules in combination with cytarabine | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;|
| Experimental: Part 2 - Expansion Cohort 1<br>1L de novo AML subjects without documented FLT3 mutation receiving HDM201 at the recommended dose of expansion (RDE) in combination with cytarabine/anthracyclines | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;Drug: anthracycline<br>* 20mg or other strength as locally available given intravenously<br>* Other names: daunorubicin or idarubicin, Rubidomycin or Idamycin;|
| Experimental: Part 2 - Expansion Cohort 2<br>1L de novo AML subjects with documented FLT3 mutation status receiving HDM201 at RDE in combination with cytarabine/anthracyclines and midostaurin | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;Drug: anthracycline<br>* 20mg or other strength as locally available given intravenously<br>* Other names: daunorubicin or idarubicin, Rubidomycin or Idamycin;Drug: midostaurin<br>* 25mg capsules given orally<br>* Other names: PKC412, Rydapt;|
| Experimental: Part 2 - Expansion Cohort 3<br>1L secondary AML subjects receiving HDM201 at RDE in combination with liposomal cytarabine/daunorubicin | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;Drug: liposomal cytarabine/daunorubicin<br>* 100mg/44mg or other strength as locally available given intravenously<br>* Other names: Vyxeos;|
| Experimental: Part 2 - Expansion Cohort 4<br>R/R AML subjects receiving HDM201 at RDE in combination with cytarabine | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;|
| Experimental: Part 3 - DDI Cohort 1<br>R/R AML subjects receiving HDM201 at adjusted recommended Phase 3 dose (RP3D) determined in Part 2 in combination with cytarabine and posaconazole added in Cycle 1 | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;Drug: posaconazole<br>* 100mg delayed release tablet or other strength as locally available given orally<br>* Other names: Noxafil;|
| Experimental: Part 3 - DDI Cohort 2<br>R/R AML subjects receiving HDM201 at RP3D in combination with cytarabine and midazolam | Drug: HDM201<br>* 2.5 mg and 10mg capsules, given orally<br>* Other names: none available;Drug: cytarabine<br>* 20mg or 1000 mg or other strengths as locally available given intravenously<br>* Other names: Ara-C, Cytosar;Drug: midazolam<br>* 2mg/mL oral solution or in other strength as locally available<br>* Other names: midazolam HCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - Incidence of dose limiting toxicity (DLT) | number of DLTs by dose regimen of first line (1L) acute myeloid leukemia (AML) subjects during induction treatment; number of DLTs by dose regimen of relapsed/refractory (R/R) AML subjects during treatment | first day of study treatment to 3 months after start of study treatment | 
| Part 1 - Time to DLT | time from first dose to onset of DLT by dose regimen of 1L AML and R/R AML subjects | first day of study treatment to 3 months after start of study treatment | 
| Part 1 - Incidence and severity of Adverse Events (AEs) | number and grade of AEs by dose regimen of 1L AML and R/R AML subjects during DLT observation period | first day of study treatment to 3 months after start of study treatment | 
| Part 2 - Incidence and severity of AEs/serious adverse events (SAEs) | number and grade of AEs/SAEs by expansion cohort | first day of study treatment until 8.5 months after start of study treatment | 
| Part 2 - Percentage of participants with complete remission (CR)/CR with incomplete recovery (CRi) with adequate blood count recovery (ABCR) | Percentage of participants with CR/CRi with ABCR at the end of induction treatment for Expansion Cohort 1, and at the end of treatment for Expansion Cohort 4 | first day of study treatment until 4.5 months after start of study treatment | 
| Part 2 - Incidence and severity of abnormal laboratory values | number and grade of abnormal laboratory results by expansion cohort | first day of study treatment until 8.5 months after start of study treatment | 
| Part 2 - Incidence and severity of abnormal electrocardiogram (ECG) results | number and severity of abnormal ECG results by expansion cohort | first day of study treatment until 8.5 months after start of study treatment | 
| Part 2 - Incidence and severity of abnormal vital signs | number and severity of abnormal vital signs by expansion cohort | first day of study treatment until 8.5 months after start of study treatment | 
| Part 3 - DDI Cohort 1 HDM201 Pharmacokinetics (PK) area under the curve (AUC) | determine HDM201 AUC from time zero to the last measurable concentration sampling time (AUClast) in Cycle 1 | first day of HDM201 dose to 10 days after start of HDM201 | 
| Part 3 - DDI Cohort 1 HDM201 PK maximum observed plasma concentration (Cmax) | determine HDM201 Cmax in Cycle 1 | first day of HDM201 dose to 10 days after start of HDM201 | 
| Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration | determine HDM201 average plasma concentration in Cycle 1 | first day of HDM201 dose to 10 days after start of HDM201 | 
| Part 3 - DDI Cohort 1 HDM201 PK time of maximum observed plasma concentration (Tmax) | determine HDM201 Tmax in Cycle 1 | first day of HDM201 dose to 10 days after start of HDM201 | 
| Part 3 - DDI Cohort 2: midazolam PK AUC | determine midazolam AUC last and AUC from time zero to infinity (inf) | first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201) | 
| Part 3 - DDI Cohort 2: midazolam PK Cmax | determine midazolam Cmax | first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 +2: HDM201 PK AUC | determine HDM201 AUC by dose regimen in Part 1, and Expansion Cohort in Part 2 | first day of study treatment to 7.5 months after start of study treatment | 
| Part 1 +2: HDM201 PK Cmax | determine Cmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2 | first day of study treatment to 7.5 months after start of study treatment | 
| Part 1 +2: HDM201 PK Tmax | determine Tmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2 | first day of study treatment to 7.5 months after start of study treatment | 
| Part 1 - incidence of AEs/SAEs | number and grade of AEs/SAEs, by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days | first day of study treatment to 8.5 months after start of study treatment | 
| Part 2 - all Expansion Cohorts: time to platelet recovery | determine time to platelet recovery by Expansion Cohort for each cycle | first day of study treatment to 7.5 months after start of study treatment | 
| Part 2 - all Expansion Cohorts: time to neutrophil recovery | determine time to neutrophil recovery by Expansion Cohort for each cycle | first day of study treatment to 7.5 months after start of study treatment | 
| Part 2 - all Expansion Cohorts: overall survival | determine overall survival by Expansion Cohort | first day of study treatment to 3 years after last patient is enrolled to Part 2 | 
| Part 2 - all Expansion Cohorts: event-free survival | determine event-free survival by Expansion Cohort | first day of study treatment to 3 years after last patient is enrolled to Part 2 | 
| Part 2 - all Expansion Cohorts: Percentage of subjects receiving Hematopoietic stem cell transplant (HSCT) | percentage of subjects receiving HSCT after study treatment by Expansion Cohort. | first day of study treatment to 3 years after last patient was enrolled to Part 2 | 
| Part 2 - Expansion Cohorts 1 to 3: disease-free survival (DFS) | determine DFS by Expansion Cohort | first day of study treatment to 3 years after last patient enrolled to Part 2 | 
| Part 2 - Expansion Cohorts 1 to 3: cumulative incidence of relapse (CIR) | determine CIR by Expansion Cohort | first day of study treatment to 3 years after last patient enrolled to Part 2 | 
| Part 2 - Expansion Cohorts 2 and 3 - proportion of subjects with CR/CRi with ABCR | proportion of subjects achieving CR or CRi with ABCR by Expansion Cohort | first day of study treatment to 7.5 months after start of study treatment | 
| Part 2 - Expansion Cohorts 1 and 2: proportion of subjects with minimal/measurable residual disease (MRD) negativity | proportion of subjects achieving MRD negativity by Expansion Cohort | first day of study treatment to 7.5 months after start of study treatment | 
| Part 2 - expansion cohort 2: midostaurin PK AUC | determine midostaurin AUC | first day of study treatment to 7.5 month after start of study treatment | 
| Part 2 - expansion cohort 2: midostaurin PK Cmax | determine midostaurin Cmax during induction and consolidation treatment | first day of study treatment to 7.5 month after start of study treatment | 
| Part 2 - expansion cohort 2: midostaurin PK Tmax | determine midostaurin Tmax during induction and consolidation treatment | first day of study treatment to 7.5 month after start of study treatment | 
| Part 1 - incidence of abnormal laboratory values | number of abnormal laboratory results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days | first day of study treatment to 8.5 months after start of study treatment | 
| Part 1 - incidence of abnormal ECG results | number of abnormal ECG results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days | first day of study treatment to 8.5 months after start of study treatment | 
| Part 1 - incidence of abnormal vital signs | number of abnormal vital signs by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days | first day of study treatment to 8.5 months after start of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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