A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS). (STIMULUS-MDS1)

Novartis

Status and phase: Terminated; Phase 2

Conditions: Myelodysplastic Syndromes

Treatments: Drug: MBG453; Drug: Placebo; Drug: Hypomethylating agents

Study type: Interventional

Funder types: Industry

Identifiers

NCT03946670

CMBG453B12201

2018-004479-11 (EudraCT Number)

Details and patient eligibility

About

This Phase II was 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.

Full description

The 2 primary objectives were as follows:

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

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

This Phase II study was 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.

Enrollment: 127 patients

Sex: All

Ages: 18 to 100 years old

Volunteers: No 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)-. 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

• 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

• 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.

• 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 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.
• 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.
• History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
• 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.
• 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.
• Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
• Live vaccine administered within 30 Days prior to randomization.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

---

127 participants in 2 patient groups, including a placebo group

MBG453 + hypomethylating agents

Experimental group

Description:

Patients are taking MBG453 plus hypomethylating agents

Treatment:

Drug: Hypomethylating agents

Drug: MBG453

Placebo + hypomethylating agents

Placebo Comparator group

Description:

Patients are taking placebo plus hypomethylating agents

Treatment:

Drug: Hypomethylating agents

Drug: Placebo