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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05155709
Recruitment Status : Recruiting
First Posted : December 14, 2021
Last Update Posted : January 23, 2023
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: siremadlin Drug: venetoclax Drug: azacitidine Phase 1 Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 17, 2022
Estimated Primary Completion Date : December 30, 2025
Estimated Study Completion Date : January 27, 2026


Arm Intervention/treatment
Experimental: Arm 1: Unfit adult participants with AML who responded sub-optimally to standard of care
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
Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths
Other Name: HDM201

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

Drug: azacitidine
Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously according to standard local clinical practice

Experimental: Arm 2: Newly diagnosed unfit adult participants with high-risk AML
Unfit adult participants with newly diagnosed AML and with adverse genetic risk stratification (according to ELN 2022)(Except TP53 mutation positive participants).
Drug: siremadlin
Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths
Other Name: HDM201

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

Drug: azacitidine
Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously according to standard local clinical practice




Primary Outcome Measures :
  1. Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2) [ Time Frame: From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days) ]
    Assessment of Dose Limiting Toxicity (DLT); Safety/Tolerability during the first cycle of study treatment

  2. Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only) [ Time Frame: At least 7 cycles (196 days) ]
    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


Secondary Outcome Measures :
  1. 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)) [ Time Frame: up to 3 years ]
    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.

  2. 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) [ Time Frame: up to 3 years ]
    Assessment of duration of CR in participants who achieved a CR.

  3. 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) [ Time Frame: up to 3 years ]
    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)

  4. 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) [ Time Frame: up to 3 years ]
    Assessment of duration of CR/CRh and duration of CR/CRi

  5. The time from start of treatment to death due to any cause (Arm 1 and Arm 2) [ Time Frame: up to 3 years ]
    Assessment of Overall Survival (OS)

  6. Percentage of participants died due to any cause from start of treatment until 30- and 60-day (Arm 1 and Arm 2) [ Time Frame: 30 days & 60 days from start of study treatment ]
    To assess rate of early mortality at 30 day and 60 days from start of study treatment

  7. Pharmacokinetic (PK) parameters: AUCs of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2) [ Time Frame: up to 3 years ]

    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.


  8. PK parameter: Cmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2) [ Time Frame: up to 3 years ]
    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)

  9. PK parameter: Tmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2) [ Time Frame: up to 3 years ]
    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).

  10. 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) [ Time Frame: up to 3 years ]
    To assess the effect of siremadlin in combination with venetoclax plus azacitidine in MRD



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05155709


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, California
UCLA Medical Center Recruiting
Los Angeles, California, United States, 90095
Contact    310-825-9111      
Principal Investigator: Caspian Oliai         
United States, Colorado
Rocky Mountain Cancer Centers RMCC - Aurora Recruiting
Longmont, Colorado, United States, 80501
Contact: Bobbie Donnachaidh    303-418-7600    bobbie.donnachaidh@usoncology.com   
Principal Investigator: Christopher Benton         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Nicole Tong    503-346-7894    tongni@ohsu.edu   
Principal Investigator: Elie Traer         
United States, Texas
Texas Oncology Sammons Cancer Center Sammons Cancer Center (SC) Recruiting
Dallas, Texas, United States, 78246
Contact: Valdez Ericka R       ericka.valdez@usoncology.com   
Principal Investigator: Moshe Levy         
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030-4099
Contact    713-794-5783      
Principal Investigator: Naval Daver         
United States, Virginia
Virginia Cancer Specialists Recruiting
Fairfax, Virginia, United States, 22031
Contact: Karina Castillo Grady    703-280-5390    Karina.CastilloGrady@usoncology.com   
Principal Investigator: Mitul Gandhi         
Australia, Western Australia
Novartis Investigative Site Recruiting
Perth, Western Australia, Australia, 6000
Hong Kong
Novartis Investigative Site Recruiting
Hong Kong, Hong Kong
Hungary
Novartis Investigative Site Recruiting
Budapest, Hungary, 1085
Israel
Novartis Investigative Site Recruiting
Beer-Sheva, Israel, 8457108
Novartis Investigative Site Recruiting
Jerusalem, Israel, 91031
Novartis Investigative Site Recruiting
Jerusalem, Israel, 9112001
Italy
Novartis Investigative Site Recruiting
Bologna, BO, Italy, 40138
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20162
Malaysia
Novartis Investigative Site Recruiting
Alor Setar, Kedah, Malaysia, 05460
Novartis Investigative Site Recruiting
Kuala Lumpur, Malaysia, 59100
Novartis Investigative Site Recruiting
Selangor, Malaysia, 68000
Switzerland
Novartis Investigative Site Recruiting
Bern, Switzerland, 3010
Novartis Investigative Site Recruiting
Lausanne, Switzerland, 1011
Turkey
Novartis Investigative Site Recruiting
Ankara, Yenimahalle, Turkey, 06200
Novartis Investigative Site Recruiting
Izmir, Turkey, 35340
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT05155709    
Other Study ID Numbers: CHDM201I12201
2021-001165-21 ( EudraCT Number )
First Posted: December 14, 2021    Key Record Dates
Last Update Posted: January 23, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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

URL: https://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Acute myeloid leukemia
AML
Azacitidine
venetoclax
p53
MDM2
siremadlin
HDM201
unfit adult AML participants
newly diagnosed unfit AML
presenting with high-risk clinical features
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors