Clinical trial NCT04150029: A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy
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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: MBG453
Venetoclax
Azacitidine
Phase 2
AML
Acute myeloid Leukemia
Sabatolimab
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-11-04
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: safety -run -in with escalating dose of MBG453 followed by expansion
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of dose limiting toxicities (Safety run-in patients only)
timeFrame: From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days
measure: Percentage of subjects achieving complete remission (CR)
timeFrame: at least 6 cycles from last patient first treatment up to 100 weeks (each cycle =28 Days)
Secondary outcomes:
measure: Percentage of subjects achieving a complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi)
timeFrame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
measure: Time from date of first documented CR or CRi to the date of first documented relapse or death due to any cause
timeFrame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
measure: Time from the date of the first documented CR to the date of first documented relapse or death due to any cause
timeFrame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
measure: Time from start of treatment until death, relapse from CR, or treatment failure, whichever occurs first
timeFrame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
measure: Time from start of treatment to death due to any cause (overall survival)
timeFrame: date of start of treatment to date of death due to any reason (for up to 48 months from last patient first treatment)
measure: Peak Serum Concentration (Cmax) MBG453
timeFrame: Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days
measure: Trough Serum Concentration (Cmin) MBG453
timeFrame: Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months
measure: Trough Plasma Concentration (Cmin) Venetoclax
timeFrame: Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days
measure: Anti-drug Antibody (ADA) prevalence at baseline
timeFrame: prior to first dose of MGB453 on Cycle 1 Day 8 (cycle =28 Days)
measure: ADA prevalence on-treatment
timeFrame: Throughout study until 150 day safety follow-up
measure: Percentage of MRD-negative subjects in the full study population and in subjects achieving CR or CRi
timeFrame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
measure: Rate of subjects who achieve transfusion independence from baseline and while on treatment.
timeFrame: from start of treatment up to 48 months from last patient first treatment
measure: Percentage of subjects achieving a complete remission (CR) or complete remission with partial hematologic blood count recovery (CRh)
timeFrame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
measure: Time from date of first documented CR or CRh to the date of first documented relapse or death due to any cause
timeFrame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 25Uni of Alabama at Birmingham
state: Alabama
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Iowa City
country: United States
facility: Uni Of Iowa Hospitals And Clinics
state: Iowa
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine NY-Presb
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Insitute Carolinas Healthcare System
state: North Carolina
city: Durham
country: United States
facility: Duke Univ Medical Center
state: North Carolina
city: Chattanooga
country: United States
facility: Chattanooga Onc And Hem Assoc PC
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center University of Texas
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute Univ of Utah
state: Utah
city: Clayton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Yamagata
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: