Back to resultsA Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy (STIMULUS-AML1)
Primary Purpose
Acute Myeloid Leukemia
Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
MBG453
Venetoclax
Azacitidine
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring MBG453, Venetoclax, Azacitidine, Phase 2, AML, Acute myeloid Leukemia, Sabatolimab
Eligibility Criteria
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.
Sites / Locations
- 25University of Alabama at Birmingham
- Yale University School of Medicine
- University of Iowa Hospitals and Clinics Univ of Iowa Hosp & Clinic
- Dana Farber Cancer Institute Dana Farber Cancer Int
- Mayo Clinic Dept. of Mayo Clinic (2)
- Memorial Sloan Kettering Dept. of MSKCC
- Weill Cornell Medicine NewYork Presbyterian Hospital
- Levine Cancer Insitute Carolinas Healthcare System
- Duke University Medical Center
- Chattanooga Oncology and Hematology Associates PC Tennessee Oncology Chattanooga
- MD Anderson Cancer Center/University of Texas MD Anderson
- Huntsman Cancer Institute Univ of Utah
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
MBG453+Venetoclax +Azacitidine
Arm Description
Patients will receive MBG453 in combination with Venetoclax and Azacitidine
Outcomes
Primary Outcome Measures
Incidence of dose limiting toxicities (Safety run-in patients only)
Assessment of tolerability of MBG in combination with venetoclax and azacitidine
Percentage of subjects achieving complete remission (CR)
Assessing Complete Remission (CR) Rate (Safety run in (expansion dose Level only) + Expansion)
Secondary Outcome Measures
Percentage of subjects achieving a complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi)
Assessing the durability of complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) rate by determining the relapse free survival (RFS) in participants who achieve complete response (CR)
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
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
Time from start of treatment until death, relapse from CR, or treatment failure, whichever occurs first
Assessing event free survival (EFS).
Time from start of treatment to death due to any cause (overall survival)
Time to death due to any cause to assess overall survival
Peak Serum Concentration (Cmax) MBG453
Maximal concentration of MBG453
Trough Serum Concentration (Cmin) MBG453
Concentration of MBG453 prior to next dosing or after end of treatment
Trough Plasma Concentration (Cmin) Venetoclax
Trough concentration of venetoclax on treatment
Anti-drug Antibody (ADA) prevalence at baseline
Immunogenicity to MBG453 prior to MBG453 exposure
ADA prevalence on-treatment
Immunogenicity to MBG453 on Treatment and after treatment
Percentage of MRD-negative subjects in the full study population and in subjects achieving CR or CRi
Rate of MRD-negative subjects
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
Full Information
NCT ID
NCT04150029
First Posted
October 22, 2019
Last Updated
January 20, 2023
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT04150029
Brief Title
A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 1, 2020 (Actual)
Primary Completion Date
March 13, 2026 (Anticipated)
Study Completion Date
March 13, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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 purpose of the current study is to assess clinical effects of MBG453 in combination with hypomethylating agents (HMA) (azacitidine or decitabine) in adult subjects with International Prognostic Scoring System (IPSS-R) intermediate, high, very high risk MDS.
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 one analysis of the CR rate, 7 months after the last randomized subject. PFS will not be tested at this time point.
A maximum of two analyses will be performed for PFS. A PFS interim analysis will be scheduled when approximately 81 PFS events (after 75% of the planned target PFS events with an option to stop for efficacy) have been documented, expected to occur approximately 28 months after the first subject randomized. If PFS is not statistically significant at the IA, the study will continue until the final PFS analysis.
The final PFS analysis will be performed after observing approximately 108 PFS events (or at the latest at 4 years after the last subject is randomized) expected to occur approximately 51 months after the first subject randomized.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
MBG453, Venetoclax, Azacitidine, Phase 2, AML, Acute myeloid Leukemia, Sabatolimab
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
safety -run -in with escalating dose of MBG453 followed by expansion
Masking
None (Open Label)
Allocation
N/A
Enrollment
90 (Actual)
8. Arms, Groups, and Interventions
Arm Title
MBG453+Venetoclax +Azacitidine
Arm Type
Experimental
Arm Description
Patients will receive MBG453 in combination with Venetoclax and Azacitidine
Intervention Type
Drug
Intervention Name(s)
MBG453
Other Intervention Name(s)
Sabatolimab
Intervention Description
Solution for intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Intervention Description
Tablet for oral administration
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
Solution for subcutaneous injection or intravenous infusion
Primary Outcome Measure Information:
Title
Incidence of dose limiting toxicities (Safety run-in patients only)
Description
Assessment of tolerability of MBG in combination with venetoclax and azacitidine
Time Frame
From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days
Title
Percentage of subjects achieving complete remission (CR)
Description
Assessing Complete Remission (CR) Rate (Safety run in (expansion dose Level only) + Expansion)
Time Frame
at least 6 cycles from last patient first treatment up to 100 weeks (each cycle =28 Days)
Secondary Outcome Measure Information:
Title
Percentage of subjects achieving a complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi)
Description
Assessing the durability of complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) rate by determining the relapse free survival (RFS) in participants who achieve complete response (CR)
Time Frame
every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
Title
Time from date of first documented CR or CRi to the date of first documented relapse or death due to any cause
Description
Time to relapse from CR/CRi or death (relapse free survival), whichever occurs first
Time Frame
every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
Title
Time from the date of the first documented CR to the date of first documented relapse or death due to any cause
Description
Assessing the durability of complete remission (CR) by determining the Relapse Free Survival (RFS) in subjects who achieved CR, whichever occurs first
Time Frame
every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
Title
Time from start of treatment until death, relapse from CR, or treatment failure, whichever occurs first
Description
Assessing event free survival (EFS).
Time Frame
every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
Title
Time from start of treatment to death due to any cause (overall survival)
Description
Time to death due to any cause to assess overall survival
Time Frame
date of start of treatment to date of death due to any reason (for up to 48 months from last patient first treatment)
Title
Peak Serum Concentration (Cmax) MBG453
Description
Maximal concentration of MBG453
Time Frame
Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days
Title
Trough Serum Concentration (Cmin) MBG453
Description
Concentration of MBG453 prior to next dosing or after end of treatment
Time Frame
Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months
Title
Trough Plasma Concentration (Cmin) Venetoclax
Description
Trough concentration of venetoclax on treatment
Time Frame
Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days
Title
Anti-drug Antibody (ADA) prevalence at baseline
Description
Immunogenicity to MBG453 prior to MBG453 exposure
Time Frame
prior to first dose of MGB453 on Cycle 1 Day 8 (cycle =28 Days)
Title
ADA prevalence on-treatment
Description
Immunogenicity to MBG453 on Treatment and after treatment
Time Frame
Throughout study until 150 day safety follow-up
Title
Percentage of MRD-negative subjects in the full study population and in subjects achieving CR or CRi
Description
Rate of MRD-negative subjects
Time Frame
every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
Title
Rate of subjects who achieve transfusion independence from baseline and while on treatment.
Description
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 Frame
from start of treatment up to 48 months from last patient first treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
25University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Yale University School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
University of Iowa Hospitals and Clinics Univ of Iowa Hosp & Clinic
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Dana Farber Cancer Institute Dana Farber Cancer Int
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic Dept. of Mayo Clinic (2)
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Memorial Sloan Kettering Dept. of MSKCC
City
New York
State/Province
New York
ZIP/Postal Code
10017
Country
United States
Facility Name
Weill Cornell Medicine NewYork Presbyterian Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Levine Cancer Insitute Carolinas Healthcare System
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28204
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Chattanooga Oncology and Hematology Associates PC Tennessee Oncology Chattanooga
City
Chattanooga
State/Province
Tennessee
ZIP/Postal Code
37404
Country
United States
Facility Name
MD Anderson Cancer Center/University of Texas MD Anderson
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Huntsman Cancer Institute Univ of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112 0550
Country
United States
Facility Name
Novartis Investigative Site
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Facility Name
Novartis Investigative Site
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 1M9
Country
Canada
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1Z6
Country
Canada
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada
Facility Name
Novartis Investigative Site
City
Paris Cedex 10
ZIP/Postal Code
75475
Country
France
Facility Name
Novartis Investigative Site
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigative Site
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20162
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00133
Country
Italy
Facility Name
Novartis Investigative Site
City
Fukushima city
State/Province
Fukushima
ZIP/Postal Code
960 1295
Country
Japan
Facility Name
Novartis Investigative Site
City
Yamagata
ZIP/Postal Code
990 9585
Country
Japan
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Seocho Gu
ZIP/Postal Code
06591
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08036
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Novartis Investigative Site
City
Kaohsiung City
ZIP/Postal Code
83301
Country
Taiwan
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
IPD Sharing URL
https://www.clinicalstudydatarequest.com
Learn more about this trial
A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy
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