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)

Phase 3TerminatedNCT04266301

Novartis Pharmaceuticals530 enrolled

Overview

This was a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to azacitidine in adult participants 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 was to compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm where OS was the time from randomization until death due to any cause. Participants were 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 was stratified into 4 groups: intermediate risk MDS, high risk MDS, very high risk MDS and CMML-2. All participants who discontinued both study treatments were to have entered 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 participant was randomized. Participants were receiving treatment until they experienced progression of disease (including transformation to acute leukemia per WHO 2016 classification), experienced unacceptable toxicity or discontinued the study treatment for other reasons. Continuation of study treatment beyond progression (excluding transformation to acute leukemia: continuation in this case was not possible) could have been possible in selected participants.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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

Locations (149)

Yuma Regional Cancer Center

Yuma, Arizona, United States

University of California LA

Los Angeles, California, United States

Yale University School Of Medicine

New Haven, Connecticut, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

University Of Miami

Miami, Florida, United States

Outcomes

Primary Outcomes

Overall Survival (OS) (Primary Efficacy Results)

OS is the time from randomization until death due to any cause.

Time frame: up to approx. 39 months

Overall Survival (OS) (Final Efficacy Results)

OS is the time from randomization until death due to any cause.