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

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

This trial seeked to extend the preliminary findings of efficacy by evaluating MBG453 in combination with hypomethylating agents (HMA) and also Bcl-2 inhibitor venetoclax.

The primary purpose of Part 1 (Safety Run-in) was 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) was to evaluate efficacy of MBG453, when administered in combination with azacitidine and venetoclax in adult patients with newly diagnosed AML, who were not suitable for treatment with intensive chemotherapy.

Originally, there was an analysis planned of the complete response (CR) rate, after all subjects had completed at least 12 cycles of treatment (each cycle = 28 Days) or discontinued earlier. As Novartis decided to end the development of this compound, this primary analysis was skipped and only the final study analysis presented here. At the final analysis timepoint, there was only 1 patient who didn't completed the 12 cycles of treatment or discontinued earlier.

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 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