Clinical trial NCT04810611: Phase Ib Study of Select Drug Combinations in Patients With Lower Risk MDS
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Myelodysplastic Syndromes
Keywords: Myelodysplastic
myelodysplastic syndrome
MDS
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-03-23
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Dose interruption reduction
timeFrame: 30 Months
measure: Incidence of DLTs
timeFrame: 30 Months
measure: Dose intensity
timeFrame: 30 Months
measure: AE and SAE incidence
timeFrame: 30 months
Secondary outcomes:
measure: Reduction in red blood cell (RBC) / platelet transfusions from baseline in transfusion dependent patients
timeFrame: Baseline, 30 Months
measure: Duration of transfusion independence lasting for >=8 weeks, >=12 weeks, >=16 weeks, >=24 weeks in transfusion dependent patients
timeFrame: 30 Months
measure: Change from baseline in hemoglobin (Hb) in transfusion dependent and transfusion independent patients
timeFrame: Baseline, 30 Months
measure: Change from baseline in platelet count in transfusion dependent and transfusion independent patients
timeFrame: Baseline, 30 Months
measure: Change from baseline in Absolute Neutrophil Count/White Blood Cells (ANC/WBC) in transfusion dependent and transfusion independent patients
timeFrame: Baseline, 30 Months
measure: Best Overall Response (BOR) in transfusion dependent and transfusion independent patients
timeFrame: 30 Months
measure: Time to onset of transfusion independence in transfusion dependent patients
timeFrame: 30 Months
measure: Time to onset of BOR in transfusion dependent and transfusion independent patients
timeFrame: 30 Months
measure: Duration of Response (DOR) in transfusion dependent and transfusion independent patients
timeFrame: 30 Months
measure: Overall Response Rate (ORR) in transfusion dependent and transfusion independent patients
timeFrame: 30 Months
measure: Progression free survival (PFS) in transfusion dependent and transfusion independent patients
timeFrame: 30 Months
measure: Time to progression (TTP) in transfusion dependent and transfusion independent patients
timeFrame: 30 Months
measure: Characterize pharmacokinetics for single agents and combinations: Cmax
timeFrame: 30 Months
measure: Characterize pharmacokinetics for single agents and combinations: Tmax
timeFrame: 30 Months
measure: Characterize pharmacokinetics for single agents and combinations: Ctrough
timeFrame: 30 Months
measure: Characterize the prevalence of immunogenicity
timeFrame: 30 Months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City Of Hope National Med Center Oncology
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital .
state: Massachusetts
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center .
state: Ohio
city: Houston
country: United States
facility: MD Anderson Cancer Center/University of Texas MD Anderson
state: Texas
city: Prahran
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
Study officials:
References: