Clinical trial NCT03946670: A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS).
Official title: A Randomized, Double-blind, Placebo-controlled Phase II Multi-center Study of Intravenous MBG453 Added to Hypomethylating Agents in Adult Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Keywords: Sabatolimab
Placebo
Phase II
MBG453
TIM-3
decitabine
azacitidine
myelodysplastic syndrome (MDS)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-05-13
Enrollment: 127
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy.

Detailed description: The 2 primary objectives are as follows:

To determine if MBG453 combined with standard HMA therapy improves complete remission in subjects with intermediate, high, or very high risk MDS.

To determine if MBG453 combined with standard HMA therapy improves progression free survival (PFS) in subjects with intermediate, high or very high risk MDS.

This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine, as per investigators' choice based on local standard of care (SOC)) in adult subjects with IPSS-R intermediate, high or very high risk MDS not eligible for HSCT or intensive chemotherapy. A total of 127 subjects were randomized in a 1:1 ratio to treatment arms as follows:

MBG453 400 mg IV Q2W and decitabine or azacitidine Placebo IV Q2W and decitabine or azacitidine

The randomization was stratified by 2 stratification factors: a) HMA (decitabine or azacitidine) selected by the investigator as per the local SOC and b) IPSS-R prognostic risk categories (intermediate, high or very high) at randomization. Crossover between treatment arms was not permitted at any time during the study.

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. Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) by investigator assessment with one of the following Prognostic Risk Categories, based on the International Prognostic Scoring System (IPSS-R):

   * Very high
   * High
   * Intermediate with at least ≥ 5% bone marrow blast
4. Not eligible at the time of screening, for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
5. Not eligible at the time of screening, for hematopoietic stem-cell transplantation (HSCT) according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

1. Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are allowed except if the drug was administered within 4 months prior to randomization.
2. Previous first-line treatment for higher risk MDS with chemotherapy or any other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine.
3. History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
4. Currently using or used 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.
5. Investigational treatment for MDS received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: 4 months minimum prior to randomization interval is necessary to allow enrollment.
6. Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
7. Live vaccine administered within 30 Days prior to randomization.

Other protocol-defined Inclusion/Exclusion may apply.

Primary outcomes:
measure: Complete Remission (CR) Rate
timeFrame: average of 7 months
measure: Progression Free Survival (PFS)
timeFrame: approximately 32 months
Secondary outcomes:
measure: Overall Survival
timeFrame: Up to 4 years after LPFV
measure: Event Free Survival
timeFrame: Up to 4 years after LPFV
measure: Leukemia-free Survival
timeFrame: Up to 4 yrs after Last Patient First Visit (LPFV)
measure: Response Rate (CR/mCR/PR/HI)
timeFrame: 7 months after Last Patient First Visit (LPFV)
measure: Duration of Complete Remission
timeFrame: Up to 4 yrs after Last Patient First Visit (LPFV)
measure: Time to Complete Remission
timeFrame: 7 months after Last Patient First Visit (LPFV)
measure: Percent of Subjects Who Are Red Blood Cells (RBC)/Platelets Transfusion Independent After Randomization as Per IWG-MDS
timeFrame: Up to 4 years after last randomized patient
measure: Red Blood Cells (RBC)/Platelets Transfusion Independence Duration After Randomization
timeFrame: Up to 4 years after last randomized patient
measure: Serum Concentrations for MBG453
timeFrame: At Day 8 of each cycle (1 cycle = 28 days) until cycle 6 and at day 8 of cycles 9, 12, 18 and 24, and up to 150 day of the safety follow up period
measure: Immunogenicity of MBG453 When Given in Combination of Hypomethylating Agents
timeFrame: Up to 4 years after Last Patient First Visit (LPFV)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center Medical Oncology & Therapeutic
state: California
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New Brunswick
country: United States
facility: The Cancer Institute of New Jersey
state: New Jersey
city: Columbus
country: United States
facility: Ohio State Comprehensive Cancer Center James Cancer Hospital
state: Ohio
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Brasschaat
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Brno Bohunice
country: Czechia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Alexandroupolis
country: Greece
facility: Novartis Investigative Site
state: Evros
city: Larissa
country: Greece
facility: Novartis Investigative Site
state: GR
city: Patras
country: Greece
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Nyiregyhaza
country: Hungary
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Reggio Calabria
country: Italy
facility: Novartis Investigative Site
state: RC
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Gifu shi
country: Japan
facility: Novartis Investigative Site
state: Gifu
city: Isehara
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Kumamoto-city
country: Japan
facility: Novartis Investigative Site
state: Kumamoto
city: Sendai-shi
country: Japan
facility: Novartis Investigative Site
state: Miyagi
city: Nagasaki-city
country: Japan
facility: Novartis Investigative Site
state: Nagasaki
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Santander
country: Spain
facility: Novartis Investigative Site
state: Cantabria
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
city: Samsun
country: Turkey
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: