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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: MBG453
* Drug: NIS793
* Drug: canakinumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF). 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: Symptomatic anemia with hemoglobin <10 g/dL that has relapsed after or is refractory to ESAs (or the patient is intolerant to ESAs) Symptomatic anemia with hemoglobin <10 g/dL) that is ESA-naive with EPO level ≥ 500 /uL Thrombocytopenia with platelets <30,000/uL or with clinically significant bleeding or bruising and platelets <50,000/uL 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) Patients who are refractory to, intolerant of, or ineligible/unable to receive SOC therapeutic options including lenalidomide Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 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: 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. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes. Patients with chronic myelomonocytic leukemia (CMML) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) 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. 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. For arms containing canakinumab: Patients with ANC < 500 /µL

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic, myelodysplastic syndrome, MDS