A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT04150029
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 90
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description MBG453+Venetoclax +Azacitidine MBG453 Patients will receive MBG453 in combination with Venetoclax and Azacitidine MBG453+Venetoclax +Azacitidine Venetoclax Patients will receive MBG453 in combination with Venetoclax and Azacitidine MBG453+Venetoclax +Azacitidine Azacitidine Patients will receive MBG453 in combination with Venetoclax and Azacitidine
- Primary Outcome Measures
Name Time Method Incidence of dose limiting toxicities (Safety run-in patients only) From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days Assessment of tolerability of MBG in combination with venetoclax and azacitidine
Percentage of subjects achieving complete remission (CR) at least 6 cycles from last patient first treatment up to 100 weeks (each cycle =28 Days) Assessing Complete Remission (CR) Rate (Safety run in (expansion dose Level only) + Expansion)
- Secondary Outcome Measures
Name Time Method Peak Serum Concentration (Cmax) MBG453 Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days Maximal concentration of MBG453
Trough Serum Concentration (Cmin) MBG453 Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months Concentration of MBG453 prior to next dosing or after end of treatment
Anti-drug Antibody (ADA) prevalence at baseline prior to first dose of MGB453 on Cycle 1 Day 8 (cycle =28 Days) Immunogenicity to MBG453 prior to MBG453 exposure
Time from date of first documented CR or CRh to the date of first documented relapse or death due to any cause every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment Time to relapse from CR/CRh or death (relapse free survival), whichever occurs first
Time from start of treatment until death, relapse from CR, or treatment failure, whichever occurs first every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment Assessing event free survival (EFS).
Percentage of MRD-negative subjects in the full study population and in subjects achieving CR or CRi every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment Rate of MRD-negative subjects
Rate of subjects who achieve transfusion independence from baseline and while on treatment. from start of treatment up to 48 months from last patient first 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
Time from start of treatment to death due to any cause (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) Time to death due to any cause to assess overall survival
Trough Plasma Concentration (Cmin) Venetoclax Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days Trough concentration of venetoclax on treatment
ADA prevalence on-treatment Throughout study until 150 day safety follow-up Immunogenicity to MBG453 on Treatment and after treatment
Percentage of subjects achieving a complete remission (CR) or complete remission with partial hematologic blood count recovery (CRh) every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment Assessing the complete remission (CR) or complete remission with partial hematologic blood count recovery (CRh) Rate
Percentage of subjects achieving a complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment Assessing the complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) Rate
Time from date of first documented CR or CRi to the date of first documented relapse or death due to any cause every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment Time to relapse from CR/CRi or death (relapse free survival), whichever occurs first
Time from the date of the first documented CR to the date of first documented relapse or death due to any cause every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment Assessing the durability of complete remission (CR) by determining the Relapse Free Survival (RFS) in subjects who achieved CR, whichever occurs first
Trial Locations
- Locations (13)
25Uni of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Yale University School Of Medicine
🇺🇸New Haven, Connecticut, United States
Uni Of Iowa Hospitals And Clinics
🇺🇸Iowa City, Iowa, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Memorial Sloan Kettering
🇺🇸New York, New York, United States
Weill Cornell Medicine NY-Presb
🇺🇸New York, New York, United States
Levine Cancer Insitute Carolinas Healthcare System
🇺🇸Charlotte, North Carolina, United States
Duke Univ Medical Center
🇺🇸Durham, North Carolina, United States
Chattanooga Onc And Hem Assoc PC
🇺🇸Chattanooga, Tennessee, United States
MD Anderson Cancer Center University of Texas
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute Univ of Utah
🇺🇸Salt Lake City, Utah, United States
Novartis Investigative Site
🇨🇳Kaohsiung, Taiwan