A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy

Study Overview
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Brief Summary
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This trial will seek to extend the preliminary findings of efficacy of MBG453 in combination with hypomethylating agents (HMA) by evaluating MBG453 in combination with the HMA azacitidine and the Bcl-2 inhibitor venetoclax.

Detailed Description
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The primary purpose of Part 1 (Safety Run-in) is 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) is to evaluate efficacy of MBG453, when administered in combination with azacitidine and venetoclax in adult patients with newly diagnosed AML, who are not suitable for treatment with intensive chemotherapy. There will be an analyis of the CR rate, after all subjects have completed at least 12 cycles of treatment ( cycle =28Days) or discontinued earlier.

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: MBG453
* Drug: Venetoclax
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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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 30 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 Other protocol-defined Inclusion/Exclusion may apply.

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
Intervention Model: Sequential Assignment
Interventional Model Description: safety -run -in with escalating dose of MBG453 followed by expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBG453+Venetoclax +Azacitidine<br>Patients will receive MBG453 in combination with Venetoclax and Azacitidine | Drug: MBG453<br>* Solution for intravenous infusion<br>* Other names: Sabatolimab;Drug: Venetoclax<br>* Tablet for oral administration<br>Drug: Azacitidine<br>* Solution for subcutaneous injection or intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (Safety run-in patients only) | Assessment of tolerability of MBG in combination with venetoclax and azacitidine | From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days | 
| Percentage of subjects achieving complete remission (CR) | Assessing Complete Remission (CR) Rate (Safety run in (expansion dose Level only) + Expansion) | at least 6 cycles from last patient first treatment up to 100 weeks (each cycle =28 Days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects achieving a complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) | Assessing the complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) Rate | every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment | 
| Time from date of first documented CR or CRi to the date of first documented relapse or death due to any cause | Time to relapse from CR/CRi or death (relapse free survival), whichever occurs first | every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment | 
| Time from the date of the first documented CR to the date of first documented relapse or death due to any cause | Assessing the durability of complete remission (CR) by determining the Relapse Free Survival (RFS) in subjects who achieved CR, whichever occurs first | every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment | 
| Time from start of treatment until death, relapse from CR, or treatment failure, whichever occurs first | Assessing event free survival (EFS). | every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment | 
| Time from start of treatment to death due to any cause (overall survival) | Time to death due to any cause to assess overall survival | date of start of treatment to date of death due to any reason (for up to 48 months from last patient first treatment) | 
| Peak Serum Concentration (Cmax) MBG453 | 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 | Concentration of MBG453 prior to next dosing or after end of treatment | 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 | Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days | 
| Anti-drug Antibody (ADA) prevalence at baseline | Immunogenicity to MBG453 prior to MBG453 exposure | prior to first dose of MGB453 on Cycle 1 Day 8 (cycle =28 Days) | 
| ADA prevalence on-treatment | Immunogenicity to MBG453 on Treatment and after treatment | Throughout study until 150 day safety follow-up | 
| Percentage of MRD-negative subjects in the full study population and in subjects achieving CR or CRi | Rate of MRD-negative subjects | every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment | 
| Rate of subjects who achieve transfusion independence from baseline and while on treatment. | Percentage of subjects who are not dependent on blood transfusions for more than 8 weeks will be determined and related to the total number of patients participating to report percentage | from start of treatment up to 48 months from last patient first treatment | 
| Percentage of subjects achieving a complete remission (CR) or complete remission with partial hematologic blood count recovery (CRh) | Assessing the complete remission (CR) or complete remission with partial hematologic blood count recovery (CRh) Rate | every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment | 
| Time from date of first documented CR or CRh to the date of first documented relapse or death due to any cause | Time to relapse from CR/CRh or death (relapse free survival), whichever occurs first | every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MBG453, Venetoclax, Azacitidine, Phase 2, AML, Acute myeloid Leukemia, Sabatolimab