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

NCT05155709 | Completed Phase 1 FDA Drug

• 2 other identifiers: CHDM201I122012021-001165-21
• Study Type: interventional
• Target: 14
• Locations: 7 countries
• Sites: 10

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Keywords

Acute myeloid leukemia; AML; Azacitidine; venetoclax; TP53; MDM2; siremadlin; HDM201; unfit AML; newly diagnosed unfit AML; presenting with high-risk clinical features

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• Percentage of participants achieving complete remission (CR) as per Investigator assessment (Arm 2 only)

  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)

  up to 3 years

• Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) (Arm 1 & 2)

  up to 3 years

• Percentage of participants achieving CR or complete remission with incomplete hematological recovery (CRi) (Arm 1 and Arm 2)

  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)

  up to 3 years

Study Arms (2)

Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care

EXPERIMENTAL

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: siremadlin; Drug: venetoclax; Drug: azacitidine

Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features

EXPERIMENTAL

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: siremadlin; Drug: venetoclax; Drug: azacitidine

Interventions

siremadlin DRUG

Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths

Also known as: HDM201

Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care; Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features

venetoclax DRUG

Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.

Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care; Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features

azacitidine DRUG

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.

Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care; Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• years of age; OR
• 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:
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (10)

Oregon Health Sciences University

Portland, Oregon, 97239, United States

Location

Texas Oncology Sammons Cancer Center

Dallas, Texas, 78246, United States

Location

Novartis Investigative Site

Hong Kong, 999077, Hong Kong

Location

Novartis Investigative Site

Budapest, H-1083, Hungary

Location

Novartis Investigative Site

Beersheba, 8457108, Israel

Location

Novartis Investigative Site

Jerusalem, 9112001, Israel

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Alor Star, Kedah, 05460, Malaysia

Location

Novartis Investigative Site

Kuala Selangor, 68000, Malaysia

Location

Novartis Investigative Site

Izmir, Balcova, 35340, Turkey (Türkiye)

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

siremadlin; venetoclax; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2021
• First Posted: December 14, 2021
• Study Start: May 17, 2022
• Primary Completion: April 17, 2024
• Study Completion: April 17, 2024
• Last Updated: May 7, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

TU (1); IL (2); HU (1); US (2); IT (1); MY (2); HK (1)