Phase Ib Study of Select Drug Combinations in Patients With Lower Risk MDS

A Phase Ib, Multicenter, Open-label Platform Study of Select Drug Combinations in Adult Patients With Lower Risk (Very Low, Low, or Intermediate Risk) Myelodysplastic Syndrome

The purpose of this study was to characterize the safety, tolerability and confirm the dose for select single agents and combinations in patients with lower risk (very low, low, and intermediate risk) MDS.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: MBG453; Drug: NIS793; Drug: canakinumab

Detailed Description

This was a phase Ib, multi center, open-label, platform study with multiple treatment arms.

The design of this study was adaptive to allow discontinuation of poorly tolerated or ineffective treatments and to facilitate the introduction of new candidate single agents or combinations. Study design included a dose escalation/confirmation part and a dose expansion.

The planned initial single agent and combination treatment arms were the following:

• Arm 1: MBG453 single agent
• Arm 2: NIS793 single agent
• Arm 3: canakinumab single agent
• Arm 4: MBG453 + NIS793 combination
• Arm 5: MBG453 + canakinumab combination Patients were treated in the dose confirmation/escalation part of the study in Arms 1, 2, 3 and 5. No patients were treated in Arm 4. The study did not progress into the expansion phase.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • MI
    • Milan, MI, Italy, 20162
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03080
    • Novartis Investigative Site
• Spain
  • Castille and León
    • Salamanca, Castille and León, Spain, 37007
      • Novartis Investigative Site
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Novartis Investigative Site
• United States
  • California
    • Duarte, California, United States, 91010
      • City Of Hope National Med Center Oncology
  • Florida
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital .
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center .
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center/University of Texas MD Anderson

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.
2. Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF).

3. Patients must have a diagnosis prior to participation in the study of IPSS-R very low, low, or intermediate risk MDS with ≤10% bone marrow blasts and one or more of the following:

   1. Symptomatic anemia with hemoglobin <10 g/dL that has relapsed after or is refractory to ESAs (or the patient is intolerant to ESAs)
   2. Symptomatic anemia with hemoglobin <10 g/dL) that is ESA-naive with EPO level ≥ 500 /uL
   3. Thrombocytopenia with platelets <30,000/uL or with clinically significant bleeding or bruising and platelets <50,000/uL
   4. Neutropenia with an absolute neutrophil count (ANC) <500/ µL or with recurrent and/or severe infections and an ANC that is <1000/ µL and amenable to response assessments by International Working Group (IWG) response criteria in myelodysplasia (Cheson et al 2006)
4. Patients who are refractory to, intolerant of, or ineligible/unable to receive SOC therapeutic options including lenalidomide
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
6. Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institutions' guidelines and be willing to undergo a bone marrow aspirate and/or biopsy at screening, during and at the end of therapy on this study -

Key Exclusion Criteria:

1. Systemic antineoplastic therapy (including cytotoxic chemotherapy, alpha-interferon, kinase inhibitors or other targeted small molecules, and toxin-immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment.
2. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
3. Patients with chronic myelomonocytic leukemia (CMML) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
4. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or ESAs anytime ≤ 2 weeks (or 5 half-lives, whichever is longer) prior to start of study treatment.
5. Systemic chronic corticosteroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy within 7 days of first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
6. For arms containing canakinumab: Patients with ANC < 500 /µL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: MBG453 single agent; Treatment with MBG453 single agent Q4W to confirm safety and tolerability of RD.	Drug: MBG453; Anti-TIM3 monoclonal antibody; Other Names: sabatolimab
Experimental: Arm 2: NIS793 single agent; Treatment with NIS793 single agent Q3W to establish RD in this indication and confirm safety and tolerability.	Drug: NIS793; Anti-TGF-β monoclonal antibody
Experimental: Arm 3: canakinumab single agent; Treatment with single agent canakinumab Q4W to confirm safety and tolerability of RD.	Drug: canakinumab; Anti-IL-1β monoclonal antibody; Other Names: ACZ885
Experimental: Arm 4: MBG453 + NIS793 combination; Treatment with combination of MBG453 and NIS793 Q3W to confirm safety and tolerability of combination RD.	Drug: MBG453; Anti-TIM3 monoclonal antibody; Other Names: sabatolimab; Drug: NIS793; Anti-TGF-β monoclonal antibody
Experimental: Arm 5: MBG453 + canakinumab combination; Treatment with MBG453 + canakinumab combination Q4W to confirm safety and tolerability of combination RD.	Drug: MBG453; Anti-TIM3 monoclonal antibody; Other Names: sabatolimab; Drug: canakinumab; Anti-IL-1β monoclonal antibody; Other Names: ACZ885

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose interruption reduction	Dose tolerability	30 Months
Incidence of DLTs	Incidence of dose limiting toxicities (DLTs) during the first 2 cycle of treatment during the dose escalation/confirmation part	30 Months
Dose intensity	Dose tolerability	30 Months
AE and SAE incidence	Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment	30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterize pharmacokinetics for single agents and combinations: Cmax	Serum concentrations and derived PK parameters	30 Months
Characterize pharmacokinetics for single agents and combinations: Tmax	Serum concentrations and derived PK parameters	30 Months
Characterize pharmacokinetics for single agents and combinations: Ctrough	Serum concentrations and derived PK parameters	30 Months
Characterize the prevalence of immunogenicity	Anti-drug antibody prevalence at baseline and on treatment.	30 Months
Reduction in red blood cell (RBC) / platelet transfusions from baseline in transfusion dependent patients	The number of red cell or platelet transfusions a patient receives over the course of study treatment will be compared to the patient's baseline transfusion requirements based on the number of transfusions received during the 16-weeks period prior to the start of study treatment.	Baseline, 30 Months
Duration of transfusion independence lasting for >=8 weeks, >=12 weeks, >=16 weeks, >=24 weeks in transfusion dependent patients	Red cell or platelet transfusion independence is defined as no red cell or platelet transfusions with a duration lasting for 8, 12, 16, or 24 weeks.	30 Months
Change from baseline in hemoglobin (Hb) in transfusion dependent and transfusion independent patients	Hemoglobin levels over the course of the study will be compared to the patient's baseline level to monitor for improvements in anemia.	Baseline, 30 Months
Change from baseline in platelet count in transfusion dependent and transfusion independent patients	Platelet count over the course of the study will be compared to the patient's baseline count to monitor for improvements in thrombocytopenia.	Baseline, 30 Months
Change from baseline in Absolute Neutrophil Count/White Blood Cells (ANC/WBC) in transfusion dependent and transfusion independent patients	Platelet count over the course of the study will be compared to the patient's baseline count to monitor for improvements in thrombocytopenia.	Baseline, 30 Months
Best Overall Response (BOR) in transfusion dependent and transfusion independent patients	BOR is the best disease response recorded from the start of the treatment until disease progression/relapse. The subject's BOR will be calculated based on investigator's response evaluations per International Working Group (IWG) criteria.	30 Months
Time to onset of transfusion independence in transfusion dependent patients	Time to onset of either red cell transfusion independence or platelet transfusion independence.	30 Months
Time to onset of BOR in transfusion dependent and transfusion independent patients	Time to onset of BOR is defined as the time between date of start of study treatment to the date of first onset of Partial Response (PR) or better response.	30 Months
Duration of Response (DOR) in transfusion dependent and transfusion independent patients	DOR is defined as the duration from the first documented onset of complete response (CR), complete remission with partial hematologic recovery (CRh), bone marrow CR (mCR) or PR to the date of disease progression (PD) or relapse or death due to myelodysplastic syndrome (MDS).	30 Months
Overall Response Rate (ORR) in transfusion dependent and transfusion independent patients	ORR is the proportion of subjects with a best overall response of either CR or CRh, or mCR or PR.	30 Months
Progression free survival (PFS) in transfusion dependent and transfusion independent patients	PFS is defined as the time from the start of treatment until death due to any reason, disease progression, or relapse, whichever comes first.	30 Months
Time to progression (TTP) in transfusion dependent and transfusion independent patients	TTP is the time from the start of treatment to the date of PD, relapse or death due to underlying cancer.	30 Months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2021
• Primary Completion (Actual): April 19, 2024
• Study Completion (Actual): April 19, 2024

Study Registration Dates

• First Submitted: March 9, 2021
• First Submitted That Met QC Criteria: March 18, 2021
• First Posted (Actual): March 23, 2021

Study Record Updates

• Last Update Posted (Estimated): October 10, 2025
• Last Update Submitted That Met QC Criteria: October 8, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: MDS; myelodysplastic syndrome; Myelodysplastic
• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; canakinumab; sabatolimab; NIS-793
• Other Study ID Numbers: CMBG453E12101; 2019-004623-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No