STIMULUS-AML1: A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04150029

Collaborator

(none)

Enrollment

Locations

Arm

66.2

Anticipated Duration (Months)

2.8

Patients Per Site

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: MBG453 Drug: Venetoclax Drug: Azacitidine	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

86 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Intervention Model Description:

safety -run -in with escalating dose of MBG453 followed by expansionsafety -run -in with escalating dose of MBG453 followed by expansion

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 1, 2020

Anticipated Primary Completion Date :

Mar 10, 2026

Anticipated Study Completion Date :

Mar 10, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MBG453+Venetoclax +Azacitidine Patients will receive MBG453 in combination with Venetoclax and Azacitidine	Drug: MBG453 Solution for intravenous infusion Other Names: Sabatolimab Drug: Venetoclax Tablet for oral administration Drug: Azacitidine Solution for subcutaneous injection or intravenous infusion

Arm

Intervention/Treatment

Experimental: MBG453+Venetoclax +Azacitidine

Patients will receive MBG453 in combination with Venetoclax and Azacitidine

Drug: MBG453

Solution for intravenous infusion

Other Names:

Sabatolimab

Drug: Venetoclax

Tablet for oral administration

Drug: Azacitidine

Solution for subcutaneous injection or intravenous infusion

Outcome Measures

Primary Outcome Measures

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

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 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 [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
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).
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
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
Trough Plasma Concentration (Cmin) Venetoclax [Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days]
Trough concentration of venetoclax on 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
ADA prevalence on-treatment [Throughout study until 150 day safety follow-up]
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 [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	25University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	UCSF Medical Center	San Francisco	California	United States	94143
3	Yale University School of Medicine	New Haven	Connecticut	United States	06520
4	Georgia Regents University	Augusta	Georgia	United States	30912
5	University of Iowa Hospitals and Clinics Univ of Iowa Hosp & Clinic	Iowa City	Iowa	United States	52242
6	Dana Farber Cancer Institute Dana Farber Cancer Int	Boston	Massachusetts	United States	02215
7	Mayo Clinic Dept. of Mayo Clinic (2)	Rochester	Minnesota	United States	55905
8	Memorial Sloan Kettering Dept. of MSKCC	New York	New York	United States	10017
9	Weill Cornell Medicine NewYork Presbyterian Hospital	New York	New York	United States	10021
10	Levine Cancer Insitute Carolinas Healthcare System	Charlotte	North Carolina	United States	28204
11	Duke University Medical Center	Durham	North Carolina	United States	27710
12	Chattanooga Oncology and Hematology Associates PC Tennessee Oncology Chattanooga	Chattanooga	Tennessee	United States	37404
13	MD Anderson Cancer Center/University of Texas MD Anderson	Houston	Texas	United States	77030
14	Huntsman Cancer Institute Univ of Utah	Salt Lake City	Utah	United States	84112 0550
15	Novartis Investigative Site	Clayton	Victoria	Australia	3168
16	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 1M9
17	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1Z6
18	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
19	Novartis Investigative Site	Paris Cedex 10		France	75475
20	Novartis Investigative Site	Toulouse		France	31059
21	Novartis Investigative Site	Berlin		Germany	13353
22	Novartis Investigative Site	Leipzig		Germany	04103
23	Novartis Investigative Site	Milano	MI	Italy	20162
24	Novartis Investigative Site	Roma	RM	Italy	00133
25	Novartis Investigative Site	Fukushima city	Fukushima	Japan	960 1295
26	Novartis Investigative Site	Yamagata		Japan	990 9585
27	Novartis Investigative Site	Seoul	Seocho Gu	Korea, Republic of	06591
28	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
29	Novartis Investigative Site	Madrid		Spain	28009
30	Novartis Investigative Site	Kaohsiung City		Taiwan	83301
31	Novartis Investigative Site	Taoyuan		Taiwan	33305