A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.

Study Overview
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Brief Summary
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A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy.

Detailed Description
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The primary purpose of this study is to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML patients without unacceptable levels of treatment-emergent toxicities. The recommended dose of siremadlin in combination with venetoclax plus azacitidine will be determined to be explored further in the expansion phase and the preliminary efficacy in achieving Complete Remission (CR) will be evaluated in participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment. The study will be conducted in two parts. The primary purpose of Part 1 (Safety Run-in) is to rule out excessive toxicity of siremadlin when administered in combination with venetoclax plus azacitidine while the primary purpose of Part 2 (Expansion) is to evaluate the preliminary efficacy of siremadlin when combined with venetoclax plus azacitidine in the respective patient population. The study treatment (siremadlin in combination with venetoclax plus azacitidine) will be administered in cycles with a planned duration of 28 days and will continue until the participants experience disease progression/relapse or unacceptable toxicity. In the Safety run-in part, 9-15 participants will be enrolled in each arms. Approximately 3-6 participants will be enrolled at the starting dose level of siremadlin in combination with venetoclax plus azacitidine in both arms independently. Provided the starting dose level is determined to be safe, approximately 6-9 additional participants will be enrolled at dose level +1. Safety review meetings will take place involving participating investigators and the Sponsor Team to make decisions regarding siremadlin dose and determine the recommended dose for expansion. Approximately 26 patients will be treated at the recommended dose in the expansion part.

Official Title
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A Phase Ib/II Open Label Dose Confirmation, Proof of Concept Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Unfit Adult AML Participants Who Responded Sub-optimally to First-line Venetoclax Plus Azacitidine Treatment and in Participants With Newly Diagnosed Unfit AML Presenting With High-risk Clinical Features

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: siremadlin
* Drug: venetoclax
* Drug: azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Age at the date of signing the informed consent form (ICF): Arm 1 and Arm 2: ≥ 18 years - Participants diagnosed with AML based on WHO 2016 classification (Arber et al 2016) who are ineligible for standard induction chemotherapy and: Arm 1 : have received at least 2 cycles and not more than 4 cycles of first-line venetoclax plus azacitidine treatment and have not achieved a CR, CRi, CRh or MLFS. Arm 2 : newly diagnosed AML with adverse genetic risk stratification (according to ELN 2022) (except TP53 mutation positive participants). Participant must be considered ineligible for standard of care intensive induction chemotherapy defined by the following: 75 years of age; OR 18 to 74 years of age with at least one of the following co-morbidities: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; Cardiac history of congestive heart failure (CHF) requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina; DLCO ≤ 65% or FEV1 ≤ 65%. Participants must have an ECOG performance status: 0 to 2 for participants ≥ 75 years of age. OR 0 to 3 for participants ≥ 18 to 74 years of age. WBC < 25x109/L AST and ALT ≤ 3 × ULN Estimated Glomerular Filtration Rate (eGFR)≥ 60 mL/min/1.73 m2 Exclusion Criteria: Prior exposure to MDM2-inhibitor therapy at any time. Participants with TP53 mutation positive. Participants with del17p. Participants with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA (Promyelocytic leukemia/retinoic acid receptor alpha) or with AML secondary to Down's syndrome. Participants treated with FLT3 inhibitors Participants who require treatment with moderate or strong CYP3A4 inducers within 14 days prior to starting study treatment, or are expected to receive moderate or strong CYP3A4 inducers during the entire study Participants who require treatment with substrates of CYP3A4/5 with a narrow therapeutic index. Other protocol-defined inclusion/exclusion criteria may apply at the end

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Unfit adult participants with AML who responded sub-optimally to standard of care<br>Unfit adult participants with AML who responded sub-optimally to at least 2 and not more than 4 cycles ( 1 cycle=28 days) of first-line venetoclax plus azacitidine therapy | Drug: siremadlin<br>* Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths<br>* Other names: HDM201;Drug: venetoclax<br>* Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.<br>Drug: azacitidine<br>* Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously according to standard local clinical practice<br>|
| Experimental: Arm 2: Newly diagnosed unfit adult participants with high-risk AML<br>Unfit adult participants with newly diagnosed AML and with adverse genetic risk stratification (according to ELN 2022)(Except TP53 mutation positive participants). | Drug: siremadlin<br>* Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths<br>* Other names: HDM201;Drug: venetoclax<br>* Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.<br>Drug: azacitidine<br>* Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously according to standard local clinical practice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2) | Assessment of Dose Limiting Toxicity (DLT); Safety/Tolerability during the first cycle of study treatment | From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days) | 
| Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only) | Assessment of Complete remission (CR) in order to evaluate preliminary efficacy of siremadlin (in combination of venetoclax plus azacitidine) at the determined recommended dose for expansion | At least 7 cycles (196 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants treated at the recommended dose for expansion, achieving CR as per investigator assessment (Arm 2 only; for Arm 1 assessment of CR is a primary outcome measure)) | Assessment of CR in order to evaluate preliminary efficacy of siremadlin (in combination of venetoclax plus azacitidine) at the determined recommended dose for expansion in participants with newly diagnosed AML having high-risk disease features. | up to 3 years | 
| Time of the date of the first documented CR to the date of the first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2) | Assessment of duration of CR in participants who achieved a CR. | up to 3 years | 
| Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) and percentage of participants achieving CR or complete remission with incomplete hematological recovery (CRi) (Arm 1 and Arm 2) | CRh is defined as CR with partial hematological recovery (i.e. neutrophil >0.5 X109/L and platelet > 50X109/L) and CRi is defined as CR with incomplete hematological recovery (i.e. neutrophil <1.0X109/L and/or platelet <100X109/L) | up to 3 years | 
| Time from the date of the first documented CR/CRh and CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2) | Assessment of duration of CR/CRh and duration of CR/CRi | up to 3 years | 
| The time from start of treatment to death due to any cause (Arm 1 and Arm 2) | Assessment of Overall Survival (OS) | up to 3 years | 
| Percentage of participants died due to any cause from start of treatment until 30- and 60-day (Arm 1 and Arm 2) | To assess rate of early mortality at 30 day and 60 days from start of study treatment | 30 days & 60 days from start of study treatment | 
| Pharmacokinetic (PK) parameters: AUCs of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2) | PK parameters AUC and concentration vs time profiles of siremadlin, venetoclax and azacitidine. AUC0-t: The area under the concentration vs. time Curve (AUC) from time zero to specified time point. AUClast is the AUC from time zero to the last quantifiable concentration point (last) (mass x time x volume -1). AUCtau is the AUC to the end of the dosing interval as when possible PK samples will be collected up to 24 h postdose for siremadlin and venetoclax. Steady-state will be assumed on Day 5 (AUCtau, ss) in case of continuous dosing. | up to 3 years | 
| PK parameter: Cmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2) | PK parameter Cmax and concentration vs time profiles of siremadlin, venetoclax and azacitidine. Cmax is the maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume -1) | up to 3 years | 
| PK parameter: Tmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2) | PK parameter Tmax and concentration vs time profiles of siremadlin, venetoclax and azacitidine. Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after drug administration (time). | up to 3 years | 
| Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Arm 1 and Arm 2) | To assess the effect of siremadlin in combination with venetoclax plus azacitidine in MRD | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, AML, Azacitidine, venetoclax, p53, MDM2, siremadlin, HDM201, unfit adult AML participants, newly diagnosed unfit AML, presenting with high-risk clinical features