A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy (STIMULUS-AML1)

A Phase II Multi-center, Single Arm, Safety and Efficacy Study of MBG453 in Combination With Azacitidine and Venetoclax for the Treatment of Acute Myeloid Leukemia (AML) in Adult Patients Unfit for Chemotherapy

This trial seeked to extend the preliminary findings of efficacy by evaluating MBG453 in combination with hypomethylating agents (HMA) and also Bcl-2 inhibitor venetoclax.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: MBG453; Drug: Azacitidine; Drug: Venetoclax

Detailed Description

The primary purpose of Part 1 (Safety Run-in) was to rule out excessive toxicity of MBG453, when administered in combination with azacitidine and venetoclax.

The primary purpose of the combined Part 1 and Part 2 (Safety run-in and Expansion Part) was to evaluate efficacy of MBG453, when administered in combination with azacitidine and venetoclax in adult patients with newly diagnosed AML, who were not suitable for treatment with intensive chemotherapy.

Originally, there was an analysis planned of the complete response (CR) rate, after all subjects had completed at least 12 cycles of treatment (each cycle = 28 Days) or discontinued earlier. As Novartis decided to end the development of this compound, this primary analysis was skipped and only the final study analysis presented here. At the final analysis timepoint, there was only 1 patient who didn't completed the 12 cycles of treatment or discontinued earlier.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Novartis Investigative Site
• France
  • Paris, France, 75475
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Novartis Investigative Site
• Italy
  • MI
    • Milan, MI, Italy, 20162
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
• Japan
  • Fukushima
    • Fukushima, Fukushima, Japan, 960 1295
      • Novartis Investigative Site
  • Yamagata
    • Yamagata, Yamagata, Japan, 990 9585
      • Novartis Investigative Site
• South Korea
  • Seocho gu
    • Seoul, Seocho gu, South Korea, 06591
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • 25Uni of Alabama at Birmingham
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Uni Of Iowa Hospitals And Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medicine NY-Presb
    • New York, New York, United States, 10017
      • Memorial Sloan Kettering
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Insitute Carolinas Healthcare System
    • Durham, North Carolina, United States, 27710
      • Duke Univ Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Onc And Hem Assoc PC
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center University of Texas
  • Utah
    • Salt Lake City, Utah, United States, 84112 0550
      • Huntsman Cancer Institute Univ of Utah

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study.
• Age ≥ 18 years at the date of signing the informed consent form (ICF)
• Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as: age ≥75, ECOG performance Status 2 or 3, or any of the following comomorbitities: severe cardiac comorbities (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%). moderate hepatic impairment (with total Bilirubin >1.5 to 3x ULN) , renal impairment (eGFR≥ 30 ml/min/1.73m^2 to <45 ml/min/1.73m^2), or other comorbidity incompatible with intensive chemotherapy per Investigator assessement and approved by the Novartis Medical monitor)
• Not planned for hematopoietic stem-cell transplantation (HSCT)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3

Exclusion Criteria:

• Prior exposure to TIM-3 directed therapy
• History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients
• Current use or use within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
• Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine.
• Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
• Live vaccine administered within 30 Days prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MBG453+Venetoclax +Azacitidine; Participants received MBG453 in combination with Venetoclax and Azacitidine	Drug: MBG453; Solution for intravenous infusion; Other Names: Sabatolimab; Drug: Azacitidine; Solution for subcutaneous injection or intravenous infusion; Drug: Venetoclax; Tablet for oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only)	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value considered by the Investigator to be at least possibily related to MBG453 as a single contributor or in combination with other component(s) of study treatment that occurs during the DLT observation period and meets any of the criteria as per protolcol.	From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days
Percentage of Participants Achieving Complete Remission (CR) (CR Rate)	CR rate is defined as the percentage of participants achieving a complete remission (CR) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017).	approx. 31 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurable Residual Disease (MRD) - Negativity Rate: Full Study Population	MRD negativity rate was defined as the percentage of participants with MRD negativity, which was defined as an MRD negative sample (frequency of LAIP below 0.1%, as determined by Multi-parameter Flow Cytometry-Measurable residual disease (MFC-MRD) at Central Lab) in participant with remission (i.e., CR or CRi) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017). MRD-negative response was required to be observed at or after morphological remission, and prior to relapse or disease progression.	approx. 31 months
Measurable Residual Disease (MRD) - Negativity Rate in Participants With Best Overall Response (BOR) of CR/CRi and Evaluable MRD	MRD negativity rate was defined as the percentage of participants with MRD negativity, which was defined as an MRD negative sample (frequency of LAIP below 0.1%, as determined by Multi-parameter Flow Cytometry-Measurable residual disease (MFC-MRD) at Central Lab) in participant with remission (i.e., CR or CRi) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017). MRD-negative response was required to be observed at or after morphological remission, and prior to relapse or disease progression.	approx. 31 months
Duration of Complete Remission (CR)	The duration of CR is defined as the time from first achievement of CR to the first documented relapse or progressive disease or death due to any cause, whichever occurs first. The response assessment is as per investigator assessment based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017).	approx. 31 months
Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Incomplete Hematologic Blood Count Recovery (CRi) (CR/CRi Rate)	CR/CRi rate is defined as the percentage pf participants with best overall response of either complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per investigator assessment (based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017)).	approx. 31 months
The Duration of Complete Remission (CR)/Complete Remission With Incomplete Blood Count Recovery (CRi)	The duration of CR/CRi is defined as the time from first achievement of CR or CRi to the first documented relapse or progressive disease or death due to any cause, whichever occurs first. The response assessment is as per investigator assessment based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017).	approx. 31 months
Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Partial Hematologic Blood Count Recovery (CRh) (CR/CRh Rate)	CR/CRh rate is defined as the percentage of participants with best overall response of either complete remission (CR) or complete remission with partial hematologic recovery (CRh) as per derivation based on ELN 2022 (Döhner et al 2022).	approx. 31 months
Duration of CR/CRh	The duration of CR/CRh is defined as the time from date of first documented CR or CRh to the date of first documented relapse or death due to any cause, whichever occurs first. The response assessment is as per derivation based on ELN 2022 (Döhner et al 2022).	approx. 31 months
Event Free Survival (EFS)	EFS is the time from start of treatment until death due to any cause, relapse from complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), or treatment failure, whichever occurs first. Treatment failure was defined as lack of reaching CR until Cycle 8 Day 1 or earlier permanent discontinuation from study without reaching CR, the time to treatment failure was then set to Day 1.	approx. 31 months
Overall Survival (OS)	OS is the time from start of treatment to death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date).	approx. 31 months
Peak Serum Concentration (Cmax) of MBG453	Cmax is the maximal concentration of MBG453.	Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days
Trough Serum Concentration (Cmin) MBG453	Cmin is the minimum concentration of MBG453 (i.e., prior to the next dosing).	Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months
Trough Plasma Concentration (Cmin) Venetoclax	Trough concentration of venetoclax on treatment	0 hr (Pre-dose) of Day 8 of Cycle 1, 3 and 6 ; Cycle =28 days
Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment	Immunogenicity (IG) to MBG453 prior to MBG453 exposure. ADA prevalence (i.e., ADA-positive samples) is the number of ADA-positive samples among the number of participants with a non-missing sample.	at baseline, up to 150 days after last treatment, approx. 24 months
Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment	Percentage of participants having received no RBC/Platelets transfusions during at least 8 consecutive weeks.	approx. 31 months

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): October 25, 2024
• Study Completion (Actual): October 25, 2024

Study Registration Dates

• First Submitted: October 22, 2019
• First Submitted That Met QC Criteria: October 31, 2019
• First Posted (Actual): November 4, 2019

Study Record Updates

• Last Update Posted (Estimated): January 13, 2026
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: AML; Venetoclax; Azacitidine; MBG453; Phase 2; Sabatolimab; Acute myeloid Leukemia
• 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; sabatolimab
• Other Study ID Numbers: CMBG453C12201; 2019-000439-14 (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 expert 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 is currently available according to the 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