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

Last updated: October 8, 2025
Sponsor: Novartis Pharmaceuticals
Overall Status: Terminated

Phase

1

Condition

Acute Myeloid Leukemia

Leukemia

Platelet Disorders

Treatment

siremadlin

azacitidine

venetoclax

Clinical Study ID

NCT05155709
CHDM201I12201
2021-001165-21
  • Ages 18-99
  • All Genders

Study 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 patients without unacceptable levels of treatment-emergent toxicities.

Eligibility Criteria

Inclusion

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 careintensive 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; Cardiachistory of congestive heart failure (CHF) requiring treatment or EjectionFraction ≤ 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 74years of age.

  • WBC < 25x109/L

  • AST and ALT ≤ 3 × ULN

  • Estimated Glomerular Filtration Rate (eGFR)≥ 60 mL/min/1.73 m2

Exclusion

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 toDown's syndrome.

  • Participants treated with FLT3 inhibitors for AML indication are not eligible.

  • Participants who require treatment with moderate or strong CYP3A4 inducers within 14days prior to starting study treatment, or are expected to receive moderate orstrong CYP3A4 inducers during the entire study

  • Participants who require treatment with substrates of CYP3A4/5 with a narrowtherapeutic index.

Other protocol-defined inclusion/exclusion criteria may apply at the end

Study Design

Total Participants: 14
Treatment Group(s): 3
Primary Treatment: siremadlin
Phase: 1
Study Start date:
May 17, 2022
Estimated Completion Date:
April 17, 2024

Study Description

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 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) is administered in cycles with a planned duration of 28 days and will continue until the participants experience 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 is 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) 27 sites were open for recruitment with 28 patients screened and 14 patients enrolled.

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) will not be open. The Novartis decision was not driven by any safety concerns.

Connect with a study center

  • Novartis Investigative Site

    Perth, Western Australia 6000
    Australia

    Site Not Available

  • Novartis Investigative Site

    Hong Kong,
    Hong Kong

    Site Not Available

  • Novartis Investigative Site

    Hong Kong 1819729,
    Hong Kong

    Site Not Available

  • Novartis Investigative Site

    Budapest, H-1083
    Hungary

    Site Not Available

  • Novartis Investigative Site

    Budapest 3054643, H-1083
    Hungary

    Site Not Available

  • Novartis Investigative Site

    Beer Sheva, 8457108
    Israel

    Site Not Available

  • Novartis Investigative Site

    Beer-Sheva, 8457108
    Israel

    Site Not Available

  • Novartis Investigative Site

    Beersheba 295530, 8457108
    Israel

    Site Not Available

  • Novartis Investigative Site

    Jerusalem, 91031
    Israel

    Site Not Available

  • Novartis Investigative Site

    Jerusalem 281184, 9112001
    Israel

    Site Not Available

  • Novartis Investigative Site

    Bologna, BO 40138
    Italy

    Site Not Available

  • Novartis Investigative Site

    Bologna 3181928, BO 40138
    Italy

    Site Not Available

  • Novartis Investigative Site

    Brescia, BR 25123
    Italy

    Site Not Available

  • Novartis Investigative Site

    Milano, MI 20162
    Italy

    Site Not Available

  • Novartis Investigative Site

    Alor Setar, Kedah 05460
    Malaysia

    Site Not Available

  • Novartis Investigative Site

    Alor Star 1736309, Kedah 1733048 05460
    Malaysia

    Site Not Available

  • Novartis Investigative Site

    Kuala Lumpur, 59100
    Malaysia

    Site Not Available

  • Novartis Investigative Site

    Kuala Selangor 1732891, 68000
    Malaysia

    Site Not Available

  • Novartis Investigative Site

    Selangor, 68000
    Malaysia

    Site Not Available

  • Novartis Investigative Site

    Hospitalet de LLobregat, Catalunya 08907
    Spain

    Site Not Available

  • Novartis Investigative Site

    Valencia, Comunidad Valenciana 46010
    Spain

    Site Not Available

  • Novartis Investigative Site

    Bern, 3010
    Switzerland

    Site Not Available

  • Novartis Investigative Site

    Lausanne, 1011
    Switzerland

    Site Not Available

  • Novartis Investigative Site

    Ankara, Yenimahalle 06200
    Turkey

    Site Not Available

  • Novartis Investigative Site

    Izmir, 35340
    Turkey

    Site Not Available

  • Novartis Investigative Site

    Izmir 311046, 35340
    Turkey (Türkiye)

    Site Not Available

  • UCLA Medical Center .

    Los Angeles, California 90095
    United States

    Active - Recruiting

  • University of California Los Angeles .

    Los Angeles, California 90095
    United States

    Site Not Available

  • Rocky Mountain Cancer Centers RMCC - Aurora

    Longmont, Colorado 80501
    United States

    Site Not Available

  • Dana Farber Cancer Institute Harvard Cancer Center

    Boston, Massachusetts 02215
    United States

    Site Not Available

  • Uni of Massachusetts Medical Center

    Worcester, Massachusetts 01655
    United States

    Site Not Available

  • Roswell Park Cancer Institute

    Buffalo, New York 14263
    United States

    Site Not Available

  • Cleveland Clinic Foundation

    Cleveland, Ohio 44195
    United States

    Site Not Available

  • Oregon Health Sciences University

    Portland, Oregon 97239
    United States

    Site Not Available

  • Oregon Health Sciences University .

    Portland, Oregon 97239
    United States

    Site Not Available

  • Oregon Health and Science Univ

    Portland, Oregon 97239
    United States

    Site Not Available

  • Oregon Health Sciences University

    Portland 5746545, Oregon 5744337 97239
    United States

    Site Not Available

  • UPMC Cancer Centers Division Hematology-Oncology

    Pittsburgh, Pennsylvania 15232
    United States

    Site Not Available

  • Texas Oncology Sammons Cancer Center

    Dallas, Texas 78246
    United States

    Site Not Available

  • Texas Oncology Sammons Cancer Center Sammons Cancer Center (SC)

    Dallas, Texas 78246
    United States

    Site Not Available

  • University of Texas MD Anderson Cancer Center

    Houston, Texas 77030-4099
    United States

    Site Not Available

  • Texas Oncology Sammons Cancer Center

    Dallas 4684888, Texas 4736286 78246
    United States

    Site Not Available

  • Virginia Cancer Specialists .

    Fairfax, Virginia 22031
    United States

    Site Not Available

  • Medical College of Wisconsin .

    Milwaukee, Wisconsin 53226
    United States

    Site Not Available

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