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 is 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: Active, not recruiting
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: MBG453; Drug: NIS793; Drug: canakinumab

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

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; Phone Number: +41613241111

Study Locations

• Australia
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• Spain
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, 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
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; 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; 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 indicence	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
Efficacy of single agents and combinations on transfusion dependent patients: Best Overall Response (BOR)	Evaluate change in transfusion burden and hematologic parameters	30 Months
Efficacy of single agents and combinations on transfusion dependent patients: Duration of Response (DOR)	Evaluate change in transfusion burden and hematologic parameters	30 Months
Efficacy of single agents and combinations on transfusion dependent patients: Progression free survival (PFS)	Evaluate change in transfusion burden and hematologic parameters	30 Months
Efficacy of single agents and combinations on transfusion dependent patients: Time to progression (TTP)	Evaluate change in transfusion burden and hematologic parameters	30 Months
Efficacy of single agents and combinations in patients who are transfusion independent: Best Overall Response (BOR)	Evaluate change in hematologic parameters	30 Months
Efficacy of single agents and combinations in patients who are transfusion independent: Duration of Response (DOR)	Evaluate change in hematologic parameters	30 Months
Efficacy of single agents and combinations in patients who are transfusion independent: Progression Free Survival (PFS)	Evaluate change in hematologic parameters	30 Months
Efficacy of single agents and combinations in patients who are transfusion independent: Time to Progression (TTP)	Evaluate change in hematologic parameters	30 Months
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
Efficacy of single agents and combinations on transfusion dependent patients: Overall Response Rate (ORR)	Evaluate change in transfusion burden and hematologic parameters	30 Months
Efficacy of single agents and combinations in patients who are transfusion independent: Overall Response Rate (ORR)	Evaluate change in hematologic parameters	30 Months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2021
• Primary Completion (Estimated): May 16, 2024
• Study Completion (Estimated): May 16, 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): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: MDS; myelodysplastic syndrome; Myelodysplastic
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia
• Other Study ID Numbers: CMBG453E12101

Drug and device information, study documents

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