Clinical trial NCT04266301: Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)
Official title: A Randomized, Double-blind, Placebo-controlled Phase III Multi-center Study of Azacitidine With or Without MBG453 for the Treatment of Patients With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Keywords: MBG453
Phase III
TIM-3
azacitidine
myelodysplastic syndrome
MDS
chronic myelomonocytic leukemia
CMML-2
Sabatolimab
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-02-12
Enrollment: 530
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind
Primary purpose: TREATMENT

Brief summary: This is a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to azacitidine in adult subjects with intermediate, high or very high-risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) who are not eligible for intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) according to medical judgment by the investigator.

The purpose of the current study is to assess clinical effects of MBG453 in combination with azacytidine in adult subjects with IPSS-R intermediate, high, very high risk MDS and CMML-2.

Detailed description: This is a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo controlled study of MBG453 or placebo added to azacitidine in adult subjects with intermediate, high or very high-risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2).

The primary objective of this study is to compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm where OS is the time from randomization until death due to any cause.

Subjects will be randomized in a 1:1 ratio to treatment arms as follow: MBG453 800 mg IV Q4W plus azacitidine, Placebo IV Q4W plus azacitidine The randomization will be stratified into 4 groups: intermediate risk MDS, high risk MDS, very high risk MDS and CMML-2.

All subjects who discontinue both study treatments will enter a long-term post-treatment follow-up including response and PRO assessments, and/or survival follow-up for up to 5 years after the last subject was randomized.

Subjects will be treated until they experience progression of disease (including transformation to acute leukemia per WHO 2016 classification), experience unacceptable toxicity or discontinue the study treatment for other reasons.

Continuation of study treatment beyond progression (excluding transformation to acute leukemia: continuation in this case is not possible) may be possible in selected subjects.

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

  * Very high (\> 6 points)
  * High (\> 4.5 - ≤ 6 points)
  * Intermediate (\> 3 - ≤ 4.5 points) Or Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia -2 based on WHO 2016 classification (Arber et al 2016, including persistent monocytosis) by local investigator assessment with WBC \< 13 x 109/L at time of initial diagnosis
* Indication for azacitidine treatment according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
* Not eligible at time of screening for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions, including assessment of individual clinical factors such as age, comorbidities and performance status
* Not eligible at 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, including assessment of individual clinical factors such as age, comorbidities, performance status, and donor availability
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

* Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune checkpoint inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines is allowed except if the drug was administered within 4 months prior to randomization
* Previous first-line treatment for intermediate, high, very high risk myelodysplastic syndromes (based on IPSS-R) or CMML with any antineoplastic agents including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitibine and azacitidine. However, previous treatment with hydroxyurea or leukopheresis to reduce WBC count is allowed prior to randomization.
* Investigational treatment received within 4 weeks or 5 half-lives of this investigational treatment, whatever is longer, prior to randomization. In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomization is necessary to allow randomization.
* Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3
* Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia, primary or secondary myelofibrosis based on WHO 2016 classification (Arber et al 2016)
* Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification (Arber et al 2016)
* History of organ or allogeneic hematopoietic stem cell transplant

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Primary outcomes:
measure: Overall Survival
timeFrame: Up to 5 years after last patient randomized
Secondary outcomes:
measure: Key secondary endpoint 1: Time to definitive deterioration of fatigue using Functional Assessment of Cancer Therapy (FACIT)-Fatigue score
timeFrame: Up to 5 years after last patient randomized
measure: Key secondary endpoint 2: Red Blood Cell transfusion-free intervals
timeFrame: Up to 5 years after last patient randomized
measure: Key secondary endpoint: Percent of subjects with at least 3 point confirmed improvement from baseline in FACIT-fatigue scoresscore
timeFrame: Up to 5 years after last patient randomized
measure: Key secondary endpoint 4: Percent of subjects with at least 10 point confirmed improvement from baseline in physical functioning using European Or ganization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: Up to 5 years after last patient randomized
measure: Key secondary endpoint 5: Percent of subjects with at least 10 point confirmed improvement from baseline in emotional functioning using EORTC-QLQ-C30
timeFrame: Up to 5 years after last patient randomized
measure: Percentage of subjects with either CR, or mCR, or PR, or HI in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment
timeFrame: Up to 5 years after last patient randomized
measure: Percentage of subjects with SD in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment
timeFrame: Up to 5 years after last patient randomized
measure: Progression Free Survival (PFS)
timeFrame: Up to 5 years after last patient randomized
measure: Leukemia-free survival
timeFrame: Up to 5 years after last patient randomized
measure: Number of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization
timeFrame: Up to 5 years after last patient randomized as per IWG-MDS criteria
measure: Percentage of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization
timeFrame: Up to 5 years after last patient randomized
measure: Pharmacokinetics of MBG453 (parameter Cmax)
timeFrame: At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug
measure: Pharmacokinetics of MBG453 (parameter AUC)
timeFrame: At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug
measure: Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment
timeFrame: At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug
measure: Change from baseline in the European Quality of Life (EuroQol) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score over time
timeFrame: Up to 5 years after last patient randomized
measure: Change from baseline in the European Quality of Life (EuroQoL) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Visual Analogue Scale over time
timeFrame: Up to 5 years after last patient randomized
measure: Change from baseline to C12D1 of Global Health Status/Quality of Life scores using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30)
timeFrame: Up to cycle 12 day 1 (C12D1)(1 cycle = 28 days)
Other outcomes:
Locations:
city: Yuma
country: United States
facility: Yuma Regional Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: University of California LA
state: California
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami
country: United States
facility: University Of Miami
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
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facility: Massachusetts General Hospital
state: Massachusetts
city: Hackensack
country: United States
facility: Hackensack University Medical Ctr
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Medicine NY-Presb
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Ctr
state: New York
city: Charlottesville
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facility: University of Virginia
state: Virginia
city: Pilar
country: Argentina
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city: Roeselare
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state: SC
city: Sao Paulo
country: Brazil
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state: SP
city: Sao Paulo
country: Brazil
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state: SP
city: Calgary
country: Canada
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state: Alberta
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state: Ontario
city: Vina del Mar
country: Chile
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state: Guangdong
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Shenzhen
country: China
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state: Guangdong
city: Wuhan
country: China
facility: Novartis Investigative Site
state: Hubei
city: Wuhan
country: China
facility: Novartis Investigative Site
state: Hubei
city: Suzhou
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state: Jiangsu
city: Chang Chun
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state: Jilin
city: Chengdu
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state: Sichuan
city: Hangzhou
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state: Zhejiang
city: Beijing
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city: Beijing
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city: Jinan
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city: Tianjin
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city: Praha 2
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state: Czech Republic
city: Hradec Kralove
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city: Dresden
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city: Alexandroupolis
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city: Kolkata
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city: Genova
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city: Sendai city
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state: Nagasaki
city: Osaka Sayama
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state: Tokyo
city: Osaka
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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country: Netherlands
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city: Muscat
country: Oman
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city: Lisboa
country: Portugal
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city: Porto
country: Portugal
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city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
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city: Singapore
country: Singapore
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city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Hualien
country: Taiwan
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Liouying Township
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Edirne
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Pendik Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Samsun
country: Turkey
facility: Novartis Investigative Site
city: Portsmouth
country: United Kingdom
facility: Novartis Investigative Site
state: Hants
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
state: Scotland
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: