Clinical trial NCT05552469: Dose Optimization and Expansion Study of DFV890 in Adult Patients With Myeloid Diseases
Official title: A Phase 1b, Open Label, Multi-center, Dose Optimization and Dose Expansion Study to Assess the Safety and Efficacy of DFV890 in Adult Patients With Myeloid Diseases
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Myeloid Diseases
Keywords: MDS
CMML
NLRP3
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
inflammasome
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-09-23
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study CDFV890G12101 is an open-label, phase 1b, multicenter study with a randomized two-dose optimization part, and a dose expansion part consisting of two groups evaluating DFV890 in patients with myeloid diseases. The purpose of this study is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy and recommended dose for single agent DFV890 in patients with lower risk (LR: very low, low or intermediate risk) myelodysplastic syndromes (LR MDS) and lower risk chronic myelomonocytic leukemia (LR CMML).

Detailed description: This research study is to find out if study treatment DFV890 is safe and tolerable, and can help patients who were diagnosed with a myeloid disease such as: very low, low or intermediate risk myelodysplastic syndromes (MDS) and very low, low or intermediate risk chronic myelomonocytic leukemia (CMML). The study seeks to determine the optimal dose of DFV890 that is safe and efficacious in patients with myeloid disease. The effectiveness and safety/tolerability of the study treatment is not yet confirmed in this disease setting.

Eligible patients meeting all study entry requirements will be required to provide a sample from their bone marrow at screening and at select study timepoints. All enrolled patients will be dosed for a minimum of twenty-four weeks (6 cycles of treatment) unless they experience side effects related to the study treatment requiring dose interruption/discontinuation, worsening of the disease, and/or if treatment is discontinued at the discretion of the investigator or the patient.

Eligibility criteria: Key Inclusion Criteria:

1. Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF)
2. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
3. Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institutions guidelines and must be willing to undergo a bone marrow aspirate.
4. Patients must have one of the following for eligibility into the study:

   1. In dose optimization and expansion: IPSS-R defined very low, low or intermediate risk Myelodysplastic Syndrome (LR MDS) who failed to respond to or did not tolerate ESAs or luspatercept or HMAs and patients with del 5q who failed to respond to or did not tolerate lenalidomide; or
   2. In dose optimization and expansion: IPSS-R defined very low, low or intermediate risk Chronic Myelomonocytic Leukemia (LR CMML) who failed to respond to or did not tolerate hydroxyurea or HMAs.

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 28 days or 5 half-lives, whichever is longer, and recovered from the toxicities before the first dose of study treatment. For patients that received antibodies the washout period is 4 weeks prior to study treatment.
2. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
3. Patients who have previously been treated with agents that have the same mechanism of action as DFV890 as defined in Table 6-8, list of prohibited medications (e.g., drugs targeting the NLRP3 inflammasome pathway and the IL-1 pathway (canakinumab and anakinra)).
4. Use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents anytime ≤ 1 week (or 5 half lives, whichever is longer) prior to start of study treatment.
5. Patients receiving:

   1. concomitant medications that are known to be modulators of cytochrome P450 enzymes CYP2C9 and/or CYP3A (specifically strong or moderate inducers of CYP2C9, strong inducers of CYP3A enzymes, strong inhibitors of CYP2C9 and/or strong or moderate dual inhibitors of CYP2C9/CYP3A); and
   2. patients, who are poor CYP2C9 metabolizers receiving concomitant medications known to be strong or moderate inhibitors of CYP3A, whose concomitant medications cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to start of study treatment and for duration of the study. See Section 6.8 and list of prohibited drugs in Appendix 8 for more details.

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Incidence of Dose-limiting Toxicities (DLTs)
timeFrame: 28 days
measure: Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 13 months
measure: Incidence of dose interruptions, discontinuations and reductions
timeFrame: 12 months
Secondary outcomes:
measure: Reduction in red blood cell (RBC) / platelet transfusions from baseline for transfusion-dependent (TD) patients
timeFrame: Baseline, 12 months
measure: Percentage of patients developing transfusion independence (TI) for ≥8 weeks, ≥12 weeks, ≥16 weeks or ≥24 weeks for TD patients
timeFrame: Baseline, 8 weeks, 12 weeks, 16 weeks and 24 weeks
measure: Best overall response (BOR) per 2006 IWG criteria for MDS and CMML
timeFrame: Baseline, 12 months
measure: Hematological improvement per 2006 IWG criteria for MDS and CMML
timeFrame: 12 months
measure: Time to onset of transfusion independence
timeFrame: 12 months
measure: Duration of response (DOR)
timeFrame: 12 months
measure: Change from baseline in hemoglobin (Hb)
timeFrame: Baseline, 12 months
measure: Change from baseline in platelet count
timeFrame: Baseline, 12 months
measure: Change from baseline in Absolute Neutrophil Count/White Blood Cells (ANC/WBC)
timeFrame: Baseline, 12 months
measure: Overall response rate (ORR)
timeFrame: 12 months
measure: Progression free survival (PFS)
timeFrame: 12 months
measure: Time to progression (TTP)
timeFrame: 12 months
measure: For CMML: reduction in spleen volume
timeFrame: Baseline, 12 months
measure: For CMML: MPN-SAF total symptom score (TSS)
timeFrame: Baseline, 12 months
measure: Maximum plasma concentration (Cmax) of DFV890
timeFrame: 15 days
measure: Area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of DFV890
timeFrame: 15 days
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel CCC At JH
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: Weill Cornell Medicine NY-Presb
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Ctr
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Ctr
state: Tennessee
city: Houston
country: United States
facility: Univ of TX MD Anderson Cancer Cntr
state: Texas
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Velbert
country: Germany
facility: Novartis Investigative Site
state: North Rhine-Westphalia
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
References: