Phase Ib Study of Select Drug Combinations in Patients With Lower Risk MDS

Phase 1TerminatedNCT04810611

Novartis Pharmaceuticals33 enrolled

Overview

The purpose of this study was to characterize the safety, tolerability and confirm the dose for select single agents and combinations in patients with lower risk (very low, low, and intermediate risk) MDS.

This was a phase Ib, multi center, open-label, platform study with multiple treatment arms. The design of this study was adaptive to allow discontinuation of poorly tolerated or ineffective treatments and to facilitate the introduction of new candidate single agents or combinations. Study design included a dose escalation/confirmation part and a dose expansion. The planned initial single agent and combination treatment arms were the following: * Arm 1: MBG453 single agent * Arm 2: NIS793 single agent * Arm 3: canakinumab single agent * Arm 4: MBG453 + NIS793 combination * Arm 5: MBG453 + canakinumab combination Patients were treated in the dose confirmation/escalation part of the study in Arms 1, 2, 3 and 5. No patients were treated in Arm 4. The study did not progress into the expansion phase.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Myelodysplastic Syndromes

Interventions

MBG453DRUG

Anti-TIM3 monoclonal antibody

NIS793DRUG

Anti-TGF-β monoclonal antibody

canakinumabDRUG

Anti-IL-1β monoclonal antibody

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Signed informed consent must be obtained prior to participation in the study. 2. Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF). 3. Patients must have a diagnosis prior to participation in the study of IPSS-R very low, low, or intermediate risk MDS with ≤10% bone marrow blasts and one or more of the following: 1. Symptomatic anemia with hemoglobin \<10 g/dL that has relapsed after or is refractory to ESAs (or the patient is intolerant to ESAs) 2. Symptomatic anemia with hemoglobin \<10 g/dL) that is ESA-naive with EPO level ≥ 500 /uL 3. Thrombocytopenia with platelets \<30,000/uL or with clinically significant bleeding or bruising and platelets \<50,000/uL 4. Neutropenia with an absolute neutrophil count (ANC) \<500/ µL or with recurrent and/or severe infections and an ANC that is \<1000/ µL and amenable to response assessments by International Working Group (IWG) response criteria in myelodysplasia (Cheson et al 2006) 4. Patients who are refractory to, intolerant of, or ineligible/unable to receive SOC therapeutic options including lenalidomide 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 6. Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institutions' guidelines and be willing to undergo a bone marrow aspirate and/or biopsy at screening, during and at the end of therapy on this study - Key Exclusion Criteria: 1. Systemic antineoplastic therapy (including cytotoxic chemotherapy, alpha-interferon, kinase inhibitors or other targeted small molecules, and toxin-immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment. 2. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes. 3. Patients with chronic myelomonocytic leukemia (CMML) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) 4. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or ESAs anytime ≤ 2 weeks (or 5 half-lives, whichever is longer) prior to start of study treatment. 5. Systemic chronic corticosteroid therapy (\>10 mg/day prednisone or equivalent) or any immunosuppressive therapy within 7 days of first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed. 6. For arms containing canakinumab: Patients with ANC \< 500 /µL

Locations (13)

City Of Hope National Med Center Oncology

Duarte, California, United States

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Massachusetts General Hospital .

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

Dose interruption reduction

Dose tolerability

Time frame: 30 Months

Incidence of DLTs

Incidence of dose limiting toxicities (DLTs) during the first 2 cycle of treatment during the dose escalation/confirmation part

Time frame: 30 Months

Dose intensity

Dose tolerability

Time frame: 30 Months

AE and SAE incidence

Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment

Time frame: 30 months

Secondary Outcomes

Reduction in red blood cell (RBC) / platelet transfusions from baseline in transfusion dependent patients

The number of red cell or platelet transfusions a patient receives over the course of study treatment will be compared to the patient's baseline transfusion requirements based on the number of transfusions received during the 16-weeks period prior to the start of study treatment.

Time frame: Baseline, 30 Months

Duration of transfusion independence lasting for >=8 weeks, >=12 weeks, >=16 weeks, >=24 weeks in transfusion dependent patients

Red cell or platelet transfusion independence is defined as no red cell or platelet transfusions with a duration lasting for 8, 12, 16, or 24 weeks.

Time frame: 30 Months

Change from baseline in hemoglobin (Hb) in transfusion dependent and transfusion independent patients

Hemoglobin levels over the course of the study will be compared to the patient's baseline level to monitor for improvements in anemia.

Data from ClinicalTrials.gov

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