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

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

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

The primary purpose of this study was to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML participants without unacceptable levels of treatment-emergent toxicities.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: venetoclax; Drug: siremadlin; Drug: azacitidine

Detailed Description

The recommended dose of siremadlin in combination with venetoclax plus azacitidine was to be determined to be explored further in the expansion phase and the preliminary efficacy in achieving Complete Remission (CR) evaluated in participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment.

The study was planned to be conducted in two parts. The primary purpose of Part 1 (Safety Run- in) was to rule out excessive toxicity of siremadlin when administered in combination with venetoclax plus azacitidine while the primary purpose of Part 2 (Expansion) was 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) was administered in cycles with a planned duration of 28 days for each cycle and would continue until the participants experienced disease progression/relapse or unacceptable toxicity.

The initial enrollment plan and safety review was as follow:

• In the Safety run-in part, 9-15 participants were planned to be enrolled in each arm. Approximately 3-6 participants were planned to be enrolled at the starting dose level of siremadlin in combination with venetoclax plus azacitidine in both arms independently. Provided the starting dose level was determined to be safe, approximately 6-9 additional participants were planned to be enrolled at dose level +1. Safety review meetings were planned to 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 were planned to be treated at the recommended dose in the expansion part.

In the safety run-(Part 1) 10 sites in 7 countries enrolled 14 patients.

After enrolling 14 patients (6 patients in Arm 1 and 8 patients in Arm 2), Novartis took the decision to put the enrollment in permanent halt and terminate the siremadlin program. For that reason, the enrollment in Part 2 (expansion phase) did not open. The Novartis decision was not driven by any safety concerns.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong, 999077
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H-1083
    • Novartis Investigative Site
• Israel
  • Beersheba, Israel, 8457108
    • Novartis Investigative Site
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
• Italy
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
• Malaysia
  • Kuala Selangor, Malaysia, 68000
    • Novartis Investigative Site
  • Kedah
    • Alor Star, Kedah, Malaysia, 05460
      • Novartis Investigative Site
• Turkey (Türkiye)
  • Balcova
    • Izmir, Balcova, Turkey (Türkiye), 35340
      • Novartis Investigative Site
• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Texas
    • Dallas, Texas, United States, 78246
      • Texas Oncology Sammons Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (in both arms) 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 for AML indication are not eligible.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care; Unfit adult participants with unfit AML who responded sub-optimally to at least 2 and not more than 4 cycles of first-line venetoclax plus azacitidine therapy. Siremadlin was adminstered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.	Drug: venetoclax; Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.; Drug: siremadlin; Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths; Other Names: HDM201; Drug: azacitidine; Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously comes in 100 mg but was administered according to standard local clinical practice.
Experimental: Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features; Adult participants with unfit AML who were newly diagnosed and presenting with high-risk clinical features (which related to factors conferring to a low likelihood of response to venetoclax plus azacitidine) and with adverse genetic risk stratification (according to ELN 2022) (Except TP53 mutation positive participants). Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.	Drug: venetoclax; Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.; Drug: siremadlin; Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths; Other Names: HDM201; Drug: azacitidine; Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously comes in 100 mg but was administered according to standard local clinical practice.

What is the study measuring?

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)	A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal laboratory value considered by the Investigator to be at least possibly related to siremadlin as a single contributor or in combination with other component(s) of study treatment that occurs beginning the first day of siremadlin dosing in the study until end of cycle 1.	From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days)
Percentage of participants achieving a complete remission (CR) rate at recommended dose for expansion (RDE) as per investigator assessment (Arm 1 only)	Assessed by CR rate. CR rate is defined as the percentage of participants with best overall response of complete remission (CR) as per investigator assessment.	At least 7 cycles (196 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Pharmacokinetic (PK) parameters: AUCs of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)	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)	To characterize the PK of siremadlin, venetoclax and azacitidine administered in combination in each arm. 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
Percentage of participants achieving complete remission (CR) as per Investigator assessment (Arm 2 only)	Assessed by CR rate. CR rate is defined as the percentage of participants with best overall response of complete remission (CR) as per investigator assessment.	up to 3 years
Time from 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 separately)	Duration of CR is defined as time from the date of the first documented CR to the date of first documented relapse or death due to any cause, whichever occurs first. Assessment of duration of CR in participants who achieved a CR. This endpoint was not analyzed since the recommended dose was not determined due to early termination.	up to 3 years
Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) (Arm 1 & 2)	Assessed by CR/CRh rate. CR/CRh rate is defined as the percentage of participants with best overall response of either CR or CRh as per investigator assessment.	up to 3 years
Percentage of participants achieving CR or complete remission with incomplete hematological recovery (CRi) (Arm 1 and Arm 2)	Assessed by CR/CRi rate. CR/CRi rate is defined as the percentage of participants with best overall response of either CR or CRi as per investigator assessment.	up to 3 years
Time from the date of the first documented CR/CRh to the date of first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2 separately)	Assessed by duration of CR/CRh. Duration of CR/CRh is defined as time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first. This endpoint will not be analyzed since the recommended dose was not determined due to early termination.	up to 3 years
Time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2 separately)	Assessed by duration of CR/CRi. Duration of CR/CRi is defined as time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first. This endpoint will not be analyzed since the recommended dose was not determined due to early termination	up to 3 years
Overall Survival (OS) (Arm 1 and Arm 2 separately)	OS is the time from start of treatment to death due to any cause. This endpoint was not analyzed since the recommended dose was not determined due to early termination.	up to 3 years
Early mortality (Arm 1 and Arm 2)	Early mortality is the percentage of participants who died due to any cause from start of treatment until 30- and 60-day.	30 days & 60 days from start of study treatment
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)	Assessed by MRD-negativity rate. MRD negativity rate is defined as the percentage of participants with a CR/CRh/CRi-MRD negative sample.	up to 3 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Novartis Results Database (NovCTRD)
• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2022
• Primary Completion (Actual): April 17, 2024
• Study Completion (Actual): April 17, 2024

Study Registration Dates

• First Submitted: October 20, 2021
• First Submitted That Met QC Criteria: November 29, 2021
• First Posted (Actual): December 14, 2021

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: AML; Azacitidine; HDM201; TP53; venetoclax; Acute myeloid leukemia; MDM2; siremadlin; newly diagnosed unfit AML; presenting with high-risk clinical features; unfit AML
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax; siremadlin
• Other Study ID Numbers: CHDM201I12201; 2021-001165-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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 review 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 availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No