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

Myelodysplastic Syndromes Clinical Trial

Official title:

A Phase Ib, Multicenter, Open-label Platform Study of Select Drug Combinations in Adult Patients With Lower Risk (Very Low, Low, or Intermediate Risk) Myelodysplastic Syndrome

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04810611
• Other study ID #: CMBG453E12101
• Secondary ID: 2019-004623-21
• Status: Terminated
• Phase: Phase 1
• Start date: June 18, 2021
• Est. completion date: April 19, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 33
• Est. completion date: April 19, 2024
• Est. primary completion date: April 19, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• MBG453
Anti-TIM3 monoclonal antibody
• NIS793
Anti-TGF-ß monoclonal antibody
• canakinumab
Anti-IL-1ß monoclonal antibody

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Prahran	Victoria
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Milano	MI
Korea, Republic of	Novartis Investigative Site	Seoul
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
United States	Massachusetts General Hospital .	Boston	Massachusetts
United States	The Ohio State University Wexner Medical Center .	Columbus	Ohio
United States	City Of Hope National Med Center Oncology	Duarte	California
United States	MD Anderson Cancer Center/University of Texas MD Anderson	Houston	Texas
United States	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Israel,  Italy,  Korea, Republic of,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose interruption reduction	Dose tolerability	30 Months
Primary	Incidence of DLTs	Incidence of dose limiting toxicities (DLTs) during the first 2 cycle of treatment during the dose escalation/confirmation part	30 Months
Primary	Dose intensity	Dose tolerability	30 Months
Primary	AE and SAE incidence	Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment	30 months
Secondary	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.	Baseline, 30 Months
Secondary	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.	30 Months
Secondary	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.	Baseline, 30 Months
Secondary	Change from baseline in platelet count in transfusion dependent and transfusion independent patients	Platelet count over the course of the study will be compared to the patient's baseline count to monitor for improvements in thrombocytopenia.	Baseline, 30 Months
Secondary	Change from baseline in Absolute Neutrophil Count/White Blood Cells (ANC/WBC) in transfusion dependent and transfusion independent patients	Platelet count over the course of the study will be compared to the patient's baseline count to monitor for improvements in thrombocytopenia.	Baseline, 30 Months
Secondary	Best Overall Response (BOR) in transfusion dependent and transfusion independent patients	BOR is the best disease response recorded from the start of the treatment until disease progression/relapse. The subject's BOR will be calculated based on investigator's response evaluations per International Working Group (IWG) criteria.	30 Months
Secondary	Time to onset of transfusion independence in transfusion dependent patients	Time to onset of either red cell transfusion independence or platelet transfusion independence.	30 Months
Secondary	Time to onset of BOR in transfusion dependent and transfusion independent patients	Time to onset of BOR is defined as the time between date of start of study treatment to the date of first onset of Partial Response (PR) or better response.	30 Months
Secondary	Duration of Response (DOR) in transfusion dependent and transfusion independent patients	DOR is defined as the duration from the first documented onset of complete response (CR), complete remission with partial hematologic recovery (CRh), bone marrow CR (mCR) or PR to the date of disease progression (PD) or relapse or death due to myelodysplastic syndrome (MDS).	30 Months
Secondary	Overall Response Rate (ORR) in transfusion dependent and transfusion independent patients	ORR is the proportion of subjects with a best overall response of either CR or CRh, or mCR or PR.	30 Months
Secondary	Progression free survival (PFS) in transfusion dependent and transfusion independent patients	PFS is defined as the time from the start of treatment until death due to any reason, disease progression, or relapse, whichever comes first.	30 Months
Secondary	Time to progression (TTP) in transfusion dependent and transfusion independent patients	TTP is the time from the start of treatment to the date of PD, relapse or death due to underlying cancer.	30 Months
Secondary	Characterize pharmacokinetics for single agents and combinations: Cmax	Serum concentrations and derived PK parameters	30 Months
Secondary	Characterize pharmacokinetics for single agents and combinations: Tmax	Serum concentrations and derived PK parameters	30 Months
Secondary	Characterize pharmacokinetics for single agents and combinations: Ctrough	Serum concentrations and derived PK parameters	30 Months
Secondary	Characterize the prevalence of immunogenicity	Anti-drug antibody prevalence at baseline and on treatment.	30 Months