Study of DISC-0974 in Participants With Myelofibrosis and Anemia

Study Overview
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Brief Summary
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This phase 1b/2a open-label study will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of DISC-0974 as well as categorize the effects on anemia response in subjects with myelofibrosis and anemia.

Official Title
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A Phase 1b/2a Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DISC-0974 in Participants With Myelofibrosis and Anemia

Conditions
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Myelofibrosis; Anemia, Anemia, Myelofibrosis, Myelofibrosis Due to and Following Polycythemia Vera, Primary Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis

Intervention / Treatment
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* Drug: DISC-0974


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older at the time of signing the informed consent (ICF). For Phase 1b: Dynamic International Prognostic Scoring System (DIPSS) score of 3 to 4 (intermediate-2 risk) or ≥ 5 (high-risk) primary MF, post-PV MF, and/or post-ET MF, as confirmed in the most recent local bone marrow biopsy report, according to World Health Organization (WHO) 2016 criteria. Washout of at least 28 days prior to Screening of the following treatments: androgens, erythropoietin, cladribine, immunomodulators (lenalidomide, thalidomide), interferon alpha-2a or any other MF-directed therapy. Systemic corticosteroids are permitted for non-hematological conditions if stable or decreasing dose for ≥ 28 days prior to Screening and receiving an equivalent to ≤ 10 mg prednisone for the 28 days immediately prior to Screening. Anemia: For Phase 1b: Hemoglobin (Hgb) < 10 g/dL on ≥ 3 assessments over 84 days prior to Screening, without RBC transfusion, or Hgb < 10 g/dL and receiving RBC transfusions periodically but not meeting criteria for TD participant as defined for the TD cohort. The baseline Hgb value for these participants is the lowest Hgb level during the 84 days prior to Screening, or RBC transfusion dependence, defined as an RBC transfusion frequency of ≥ 6 units packed RBCs (PRBC) over the 84 days immediately prior to Screening. There must not be any consecutive 42-day period without an RBC transfusion in the 84-day period, and the last transfusion must be within 28 days prior to Screening. For Phase 2a: RBC transfusion dependence, defined as an RBC transfusion frequency of ≥ 6 units PRBC over the 84 days immediately prior to Screening. There must not be any consecutive 42-day period without an RBC transfusion in the 84-day period, and the last transfusion must be within 28 days prior to Screening. Stable dose of JAK inhibitor (except momelotinib) and/or hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening. Momelotinib use requires 12 weeks of stable dosing prior to Screening. If subject discontinues JAK inhibitor (including momelotinib) and/or hydroxyurea prior to Screening, a 28-day washout period is required. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening. Transferrin saturation <75% (local lab acceptable). Liver iron concentration by MRI < 7 mg/g dry weight within 3 months of eligibility confirmation. Serum ferritin ≥ 30 μg/L at Screening. Platelet count ≥ 25,000/μL and < 1,000,000/μL; neutrophils ≥ 1,000/μL; and total white blood cell (WBC) count < 50,000/μL at Screening. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula. Aspartate aminotransferase (AST) and alanine transaminase (ALT) < 3.0 x upper limit of normal (ULN) at Screening. Direct bilirubin < 2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis. Exclusion Criteria: Medical History: Hereditary hemochromatosis Hemoglobinopathy or intrinsic RBC defect associated with anemia Total splenectomy Hematopoietic cell transplant within the past 10 years Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding Active immune-mediated hemolytic anemia Symptomatic bleeding, unrelated to surgery, in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of RBCs in the 6 months prior to Screening Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery Malignancy within the past 3 years, other than primary MF, post-ET, or post-PV MF. The following history or concurrent conditions are allowed: basal or squamous cell carcinoma carcinoma in situ of the cervix or the breast histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) A history of completed treatment (medical or surgical) of stage 1-2 cancers may be permitted with prior Sponsor agreement. Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 6 months prior to Screening Known allergic reaction to any study drug excipient, or anaphylaxis to any food or drug A history of anti-drug antibody formation Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction < 35% Active Hepatitis B or C, or human immunodeficiency virus (HIV) with detectable viral load Uncontrolled fungal, bacterial, or viral infection (ongoing signs/symptoms related to the infection, without improvement despite appropriate treatment) Treatment History: Iron chelation therapy in the 28 days prior to Screening Change in anticoagulant therapy regimen within 8 weeks prior to Screening Laboratory Exclusions: Peripheral blood myeloblasts ≥ 10% of WBC differential at most recent evaluation prior to Screening Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Dose Escalation<br>In the Phase 1b (dose-escalation) portion of the study, DISC-0974 will be administered subcutaneously every 4 weeks. | Drug: DISC-0974<br>* DISC-0974 is administered subcutaneously.<br>|
| Experimental: Phase 2a: Expansion<br>In the Phase 2a (expansion) portion of the study, DISC-0974 will be administered subcutaneously every 4 weeks. | Drug: DISC-0974<br>* DISC-0974 is administered subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (Phase 1b only) |  | up to 225 days | 
| Incidence of clinically abnormal vital signs (Phase 1b only) |  | up to 225 days | 
| Incidence of clinically abnormal physical exam (Phase 1b only) |  | up to 225 days | 
| Incidence of clinically abnormal electrocardiograms (Phase 1b only) |  | up to 225 days | 
| Incidence of abnormal laboratory test results (Phase 1b only) |  | up to 225 days | 
| Anemia response, defined per IWG-MRT criteria (Phase 2a only) |  | up to 225 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anemia response defined per IWG-MRT criteria (Phase 1b only) |  | up to 225 days | 
| Change from baseline in concentration of iron laboratory parameters (Phase 1b and 2a) |  | up to 225 days | 
| Change from baseline in concentration of hematologic laboratory parameters (Phase 1b and 2a) |  | up to 225 days | 
| Rate of RBC transfusion per participant month during treatment period (Phase 1b and 2a) |  | up to 225 days | 
| Transfusion response defined per IWG-MRT criteria (Phase 1b and 2a) |  | up to 225 days | 
| Mean change in Hgb (Phase 1b and 2a) |  | up to 225 days | 
| Incidence of treatment-emergent adverse events (Phase 2a only) |  | up to 225 days | 
| Incidence of clinically abnormal vital signs (Phase 2a only) |  | up to 225 days | 
| Incidence of clinically abnormal physical exam (Phase 2a only) |  | up to 225 days | 
| Incidence of clinically abnormal electrocardiogram (Phase 2a only) |  | up to 225 days | 
| Incidence of abnormal laboratory test results (Phase 2a only) |  | up to 225 days | 
| Cmax-Maximum drug concentration measured in plasma (Phase 1b and 2a) |  | up to 225 days | 
| Tmax-Time of maximum drug concentration (Phase 1b and 2a) |  | up to 225 days | 
| AUC-Area under the drug concentration time curve (Phase 1b and 2a) |  | up to 225 days | 
| T½ - Elimination half life of the drug (Phase 1b and 2a) |  | up to 225 days | 
| CL/F-Apparent drug clearance (Phase 1b and 2a) |  | up to 225 days | 
| Vd/F-Apparent volume of distribution of the drug (Phase 1b and 2a) |  | up to 225 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloproliferative Neoplasm, Myeloproliferative Disorders