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

• ClinicalTrials.gov Identifier: NCT04810611
• Recruitment Status: Terminated
• First Posted: March 23, 2021
• Last Update Posted: May 17, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Myelodysplastic Syndromes	Drug: MBG453; Drug: NIS793; Drug: canakinumab	Phase 1

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 33 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 18, 2021
• Actual Primary Completion Date: April 19, 2024
• Actual Study Completion Date: April 19, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1: MBG453 single agent; Treatment with MBG453 single agent Q4W to confirm safety and tolerability of RD.	Drug: MBG453; Anti-TIM3 monoclonal antibody; Other Name: sabatolimab
Experimental: Arm 2: NIS793 single agent; Treatment with NIS793 single agent Q3W to establish RD in this indication and confirm safety and tolerability.	Drug: NIS793; Anti-TGF-β monoclonal antibody
Experimental: Arm 3: canakinumab single agent; Treatment with single agent canakinumab Q4W to confirm safety and tolerability of RD.	Drug: canakinumab; Anti-IL-1β monoclonal antibody; Other Name: ACZ885
Experimental: Arm 4: MBG453 + NIS793 combination; Treatment with combination of MBG453 and NIS793 Q3W to confirm safety and tolerability of combination RD.	Drug: MBG453; Anti-TIM3 monoclonal antibody; Other Name: sabatolimab; Drug: NIS793; Anti-TGF-β monoclonal antibody
Experimental: Arm 5: MBG453 + canakinumab combination; Treatment with MBG453 + canakinumab combination Q4W to confirm safety and tolerability of combination RD.	Drug: MBG453; Anti-TIM3 monoclonal antibody; Other Name: sabatolimab; Drug: canakinumab; Anti-IL-1β monoclonal antibody; Other Name: ACZ885

Outcome Measures

Primary Outcome Measures :

1. Dose interruption reduction [ Time Frame: 30 Months ]
   Dose tolerability
2. Incidence of DLTs [ Time Frame: 30 Months ]
   Incidence of dose limiting toxicities (DLTs) during the first 2 cycle of treatment during the dose escalation/confirmation part
3. Dose intensity [ Time Frame: 30 Months ]
   Dose tolerability
4. AE and SAE incidence [ Time Frame: 30 months ]
   Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment

Secondary Outcome Measures :

1. Reduction in red blood cell (RBC) / platelet transfusions from baseline in transfusion dependent patients [ Time Frame: Baseline, 30 Months ]
   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.
2. Duration of transfusion independence lasting for >=8 weeks, >=12 weeks, >=16 weeks, >=24 weeks in transfusion dependent patients [ Time Frame: 30 Months ]
   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.
3. Change from baseline in hemoglobin (Hb) in transfusion dependent and transfusion independent patients [ Time Frame: Baseline, 30 Months ]
   Hemoglobin levels over the course of the study will be compared to the patient's baseline level to monitor for improvements in anemia.
4. Change from baseline in platelet count in transfusion dependent and transfusion independent patients [ Time Frame: Baseline, 30 Months ]
   Platelet count over the course of the study will be compared to the patient's baseline count to monitor for improvements in thrombocytopenia.
5. Change from baseline in Absolute Neutrophil Count/White Blood Cells (ANC/WBC) in transfusion dependent and transfusion independent patients [ Time Frame: Baseline, 30 Months ]
   Platelet count over the course of the study will be compared to the patient's baseline count to monitor for improvements in thrombocytopenia.
6. Best Overall Response (BOR) in transfusion dependent and transfusion independent patients [ Time Frame: 30 Months ]
   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.
7. Time to onset of transfusion independence in transfusion dependent patients [ Time Frame: 30 Months ]
   Time to onset of either red cell transfusion independence or platelet transfusion independence.
8. Time to onset of BOR in transfusion dependent and transfusion independent patients [ Time Frame: 30 Months ]
   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.
9. Duration of Response (DOR) in transfusion dependent and transfusion independent patients [ Time Frame: 30 Months ]
   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).
10. Overall Response Rate (ORR) in transfusion dependent and transfusion independent patients [ Time Frame: 30 Months ]
    ORR is the proportion of subjects with a best overall response of either CR or CRh, or mCR or PR.
11. Progression free survival (PFS) in transfusion dependent and transfusion independent patients [ Time Frame: 30 Months ]
    PFS is defined as the time from the start of treatment until death due to any reason, disease progression, or relapse, whichever comes first.
12. Time to progression (TTP) in transfusion dependent and transfusion independent patients [ Time Frame: 30 Months ]
    TTP is the time from the start of treatment to the date of PD, relapse or death due to underlying cancer.
13. Characterize pharmacokinetics for single agents and combinations: Cmax [ Time Frame: 30 Months ]
    Serum concentrations and derived PK parameters
14. Characterize pharmacokinetics for single agents and combinations: Tmax [ Time Frame: 30 Months ]
    Serum concentrations and derived PK parameters
15. Characterize pharmacokinetics for single agents and combinations: Ctrough [ Time Frame: 30 Months ]
    Serum concentrations and derived PK parameters
16. Characterize the prevalence of immunogenicity [ Time Frame: 30 Months ]
    Anti-drug antibody prevalence at baseline and on treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

City Of Hope National Med Center Oncology

Duarte, California, United States, 91010

United States, Florida

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States, 33612

United States, Massachusetts

Massachusetts General Hospital .

Boston, Massachusetts, United States, 02114

United States, Ohio

The Ohio State University Wexner Medical Center .

Columbus, Ohio, United States, 43210

United States, Texas

MD Anderson Cancer Center/University of Texas MD Anderson

Houston, Texas, United States, 77030

Australia, Victoria

Novartis Investigative Site

Prahran, Victoria, Australia, 3181

Israel

Novartis Investigative Site

Tel Aviv, Israel, 6423906

Italy

Novartis Investigative Site

Milano, MI, Italy, 20162

Korea, Republic of

Novartis Investigative Site

Seoul, Korea, Republic of, 03080

Singapore

Novartis Investigative Site

Singapore, Singapore, 119228

Novartis Investigative Site

Singapore, Singapore, 169608

Spain

Novartis Investigative Site

Salamanca, Castilla Y Leon, Spain, 37007

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04810611
• Other Study ID Numbers: CMBG453E12101; 2019-004623-21 ( EudraCT Number )
• First Posted: March 23, 2021
• Last Update Posted: May 17, 2024
• Last Verified: May 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Myelodysplastic; myelodysplastic syndrome; MDS

Additional relevant MeSH terms:

Preleukemia; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms