STIMULUS MDS-US : Sabatolimab Added to HMA in Higher Risk MDS

Single-arm, Open Label, Phase II Study of MBG453 (Sabatolimab) Added to FDA Approved Hypomethylating Agents of Investigator's Choice (IV/SC/Oral) for Patients With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria (US Multi-center) (STIMULUS MDS-US)

Main objective of this study is to describe and evaluate safety and efficacy of MBG453 (sabatolimab) in combination with FDA approved HMAs of investigator's choice (IV Decitabine or Azacitidine /SC Azacitidine /Oral Decitabine (cedazuridine combination (INQOVI))

Study Overview

• Status: Recruiting
• Conditions: Myelodysplastic Syndrome (MDS)
• Intervention / Treatment: Drug: MBG453; Drug: Azacitidine; Drug: Decitabine; Drug: INQOVI (oral decitabine)

Detailed Description

This is a single-arm, non- randomized, open label, phase II multi-center study of intravenous MBG453 (sabatolimab) added to FDA approved Hypomethylating agents of investigator's choice (IV/SC/ Oral) in adult participants with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R criteria.

There are three separate periods of this study:

1. Screening period (signing of written informed consent through Day 1);
2. Core phase for 24 months (with post treatment safety follow-up monitoring for adverse events (AEs) for 30 days following the last dose of azacitidine or decitabine or INQOVI (oral decitabine), or 150 days following the last dose of MBG453 (sabatolimab), whichever is later);
3. Extension phase for efficacy and/or survival status (up to 36 months from last patient enrolling) (with post treatment safety follow-up monitoring for adverse events (AEs) for 30 days following the last dose of azacitidine or decitabine or INQOVI (oral decitabine), or 150 days following the last dose of MBG453 (sabatolimab), whichever is later).

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

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Recruiting
      • Ironwood Cancer and Research Centers
      • Contact: Phone Number: 480-855-2225
      • Principal Investigator: Mikhail I Shtivelband
    • Phoenix, Arizona, United States, 85016
      • Recruiting
      • Arizona Oncology Associates Arizona Oncology Assoc PC
      • Principal Investigator: Sudhir Manda
      • Contact: Phone Number: 520-877-9096
    • Phoenix, Arizona, United States, 85054
      • Active, not recruiting
      • Mayo Clinic Arizona
    • Tucson, Arizona, United States, 85745
      • Recruiting
      • Arizona Oncology Associates .
      • Principal Investigator: Manda Sudhir
    • Tucson, Arizona, United States, 85745
      • Active, not recruiting
      • Arizona Oncology Associates .
  • Colorado
    • Denver, Colorado, United States, 80218
      • Active, not recruiting
      • SCRI- Colorado Blood Cancer Institute
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Active, not recruiting
      • Yale University School Of Medicine .
  • Florida
    • Orlando, Florida, United States, 32803
      • Active, not recruiting
      • Advent Health Orlando
  • Illinois
    • Peoria, Illinois, United States, 61615-7828
      • Recruiting
      • Illinois Cancer Care P.C. IL Cancer Specialists
      • Contact: Phone Number: 847-827-0319
      • Principal Investigator: Leonard Klein
    • Peoria, Illinois, United States, 61615-7828
      • Recruiting
      • Illinois Cancer Care P.C. .
      • Principal Investigator: Leonard Klein
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Active, not recruiting
      • Uni of Massachusetts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Active, not recruiting
      • University of Michigan .
    • Detroit, Michigan, United States, 48201
      • Active, not recruiting
      • Karmanos Cancer Institute Div.of Hematology/Oncology
  • New York
    • New York, New York, United States, 10029-6574
      • Recruiting
      • Mount Sinai Medical Center
      • Principal Investigator: Lewis Silverman
    • New York, New York, United States, 10016
      • Active, not recruiting
      • Tisch Hospital NYU Langone
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Recruiting
      • Messino Cancer Centers
      • Principal Investigator: Christopher Chay
    • Durham, North Carolina, United States, 27710
      • Active, not recruiting
      • Duke Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Active, not recruiting
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • Active, not recruiting
      • University Hospitals of Cleveland
  • Pennsylvania
    • Horsham, Pennsylvania, United States, 19044
      • Recruiting
      • Alliance Cancer Specialists USO
      • Principal Investigator: Joseph Potz
  • Texas
    • Dallas, Texas, United States, 75246
      • Recruiting
      • Texas Oncology-Baylor USO
      • Principal Investigator: Moshe Levy
    • Houston, Texas, United States, 77030
      • Active, not recruiting
      • Uni of TX MD Anderson Cancer Cntr
    • San Antonio, Texas, United States, 78240
      • Active, not recruiting
      • Texas Oncology San Antonio USO

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (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).
• Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) primary or secondary based on 2016 WHO classification (Arber et al 2016) by investigator assessment with one of the following Prognostic Risk Categories, based on the International Prognostic Scoring System (IPSS-R). Note: MDS diagnosis history will be recorded in the CRF:
• Very high (> 6 points)
• High (> 4.5 - ≤ 6 points)
• Intermediate (> 3 - ≤ 4.5 points)
• Not suitable at the time of screening for immediate myeloablative/ chemotherapy or hematopoietic stem cell transplantation based on investigator assessment of age, comorbidities, local guidelines, institutional practice (any or all of these).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• AST and ALT ≤ 3 × upper limit of normal (ULN).
• Total bilirubin ≤ 2 × ULN (except in the setting of isolated Gilbert syndrome).
• Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory).
• Patient is able to communicate with the investigator and has the ability to comply with the requirements of the study procedures.

Exclusion Criteria:

• Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are allowed only if the last dose of the drug was administered more than 4 months prior to enrollment.
• Previous treatment for intermediate, high or very high risk myelodysplastic syndromes (based on IPSS-R) with chemotherapy or other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine or INQOVI (oral decitabine) (patients who had up to 1 cycle of HMAs can be included). However, previous treatment with hydroxyurea is permitted.
• Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia based on WHO 2016 classification (Arber et al 2016).
• Diagnosis of Chronic myelomonocytic leukemia (CMML), or primary or secondary myelofibrosis based on 2016 WHO classification (Arber et al 2016).
• History of organ transplant or allogenic hematopoietic stem cell transplant

• Participants with prior malignancy, except:

  1. Participants with history of lower risk MDS treated by supportive care (e.g. growth factors, TGF-beta agents) or untreated are eligible
  2. Participants with history of lower risk MDS who were treated adequately with lenalidomide and then failed are eligible
  3. Participants with history of adequately treated malignancy for which no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Participants who are receiving adjuvant therapy such as hormone therapy are eligible.
• Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MBG453 (sabatolimab) + HMA; MBG453 + HMA (azacitidine, decitabine, or INQOVI (oral decitabine))	Drug: MBG453; Solution for intravenous infusion; Other Names: sabatolimab; Drug: Azacitidine; Solution for subcutaneous injection or intravenous infusion; Drug: Decitabine; Solution for intravenous infusion; Drug: INQOVI (oral decitabine); Tablet for oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of treatment emergent adverse events and serious adverse events	Adverse events will be assessed at each visit. Any clinically significant laboratory value or vital sign determined by the investigator to meet the definition of an adverse event will be reported.	Baseline up to approximately 36 months plus 30 - 150 day safety follow up dependent on HMA

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission (CR) rate according to International Working Group (IWG) for MDS (2006) * as per investigator assessment by 12 months.	Complete remission with MBG453 (sabatolimab) in combination with HMAs (IV/SC/Oral) in participants with intermediate, high, or very high risk MDS by 12 months	Baseline, by 12 months
Progression free survival in participants with intermediate, high or very high risk MDS	Defined as time from enrollment to disease progression (including transformation to leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment by 24 months and during extension phase to 36 months post LPFV	Baseline, every 12 weeks up to approximately 36 months
Overall Survival	Time from enrollment to death due to any cause	Baseline, every 12 weeks up to approximately 36 months
Leukemia-free survival	Time from enrollment to > 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or death due to any cause	Baseline, every 12 weeks up to approximately 36 months
Percentage of participants with complete response, marrow complete response and/or partial response	Percentage of complete response, marrow complete response, and/or partial response according to IWG-MDS response criteria as per investigator assessment	Baseline, every 12 weeks up to approximately 36 months
Duration of complete remission	Time from the date of the first documented CR to the date of first documented relapse from CR or death due to any cause, whichever occurs first	Baseline, every 12 weeks up to approximately 36 months
Time to complete remission	Time from first treatment to the first documented complete remission	Baseline, every 12 weeks up to approximately 36 months
Percentage of participants with improvement in RBC/platelets transfusion independence	Transfusion independence is defined as less than 3 units of transfusion within any 8 consecutive weeks on study	Baseline, every 12 weeks up to approximately 36 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2022
• Primary Completion (Estimated): January 1, 2024
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: May 5, 2021
• First Submitted That Met QC Criteria: May 5, 2021
• First Posted (Actual): May 7, 2021

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: adult; MDS; TIM-3; phase II; MBG453; decitabine; sabatolimab; azacitidine; oral decitabine; INQOVI; myelodysplastic syndrome (MDS)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Azacitidine
• Other Study ID Numbers: CMBG453B1US01

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 https://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