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

Acute Myeloid Leukemia Clinical Trial

— STIMULUS-AML1  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04150029
• Other study ID #: CMBG453C12201
• Secondary ID: 2019-000439-14
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 1, 2020
• Est. completion date: July 12, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 90
• Est. completion date: July 12, 2024
• Est. primary completion date: July 12, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Age = 18 years at the date of signing the informed consent form (ICF)

3. 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)

4. .Not planned for hematopoietic stem-cell transplantation (HSCT)

5. .Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3

Exclusion Criteria:

1. Prior exposure to TIM-3 directed therapy

2. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients

3. 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.

4. 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.

5. Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).

6. Live vaccine administered within 30 Days prior to randomization

Other protocol-defined Inclusion/Exclusion may apply.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• MBG453
Solution for intravenous infusion
• Venetoclax
Tablet for oral administration
• Azacitidine
Solution for subcutaneous injection or intravenous infusion

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Clayton	Victoria
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Toulouse
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Leipzig
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Roma	RM
Japan	Novartis Investigative Site	Fukushima city	Fukushima
Japan	Novartis Investigative Site	Yamagata
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Taiwan	Novartis Investigative Site	Kaohsiung
United States	25Uni of Alabama at Birmingham	Birmingham	Alabama
United States	Dana Farber Cancer Institute Dana Farber Cancer Int	Boston	Massachusetts
United States	Levine Cancer Insitute Carolinas Healthcare System	Charlotte	North Carolina
United States	Chattanooga Onc And Hem Assoc PC Tennessee Oncology Chattanooga	Chattanooga	Tennessee
United States	Duke Univ Medical Center .	Durham	North Carolina
United States	MD Anderson Cancer Center/University of Texas MD Anderson	Houston	Texas
United States	Uni of Iowa Hospitals and Clinics Univ of Iowa Hosp and Clinic	Iowa City	Iowa
United States	Yale University School Of Medicine .	New Haven	Connecticut
United States	Memorial Sloan Kettering Dept. of MSKCC	New York	New York
United States	Weill Cornell Medicine NY-Presb .	New York	New York
United States	Mayo Clinic Rochester Dept of Mayo Clinic 2	Rochester	Minnesota
United States	Huntsman Cancer Institute Univ of Utah .	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	Trough Plasma Concentration (Cmin) Venetoclax	Trough concentration of venetoclax on treatment	Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days
Secondary	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)
Secondary	ADA prevalence on-treatment	Immunogenicity to MBG453 on Treatment and after treatment	Throughout study until 150 day safety follow-up
Secondary	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
Secondary	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
Secondary	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
Secondary	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