IRB Study Number 23-940
Status Recruiting
Institute Taussig Cancer Institute
Description
4.1.1. Primary Objectives:
Phase 1b – Dose Escalation
• To assess the safety and tolerability of DISC-0974 following repeated SC doses in primary MF, post-ET MF, or post-PV MF (collectively referred to as MF) and anemia
Phase 2a - Expansion
• To characterize the effects of DISC-0974 on anemia response at the recommended Phase 2 dose (RP2D) in MF and anemia
4.1.2. Secondary Objectives (Phases 1b and 2a):
• To characterize the repeat-dose PK of DISC-0974
• To characterize the relationship between DISC-0974 dose level and key biological indicators of mechanism engagement on iron and hematologic parameters
Inclusion Criteria
Age 18 years or older at the time of signing the informed consent (ICF).
For Phase 1b: 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 WHO 2016 criteria.45 For Phase 2: In addition to the criteria above, DIPSS score of 1 to 2 (intermediate-1 risk) may also be included.
Washout of at least 28 days prior to Screening of the following treatments: androgens, erythropoietin, cladribine, immunomodulators (lenalidomide, thalidomide), interferon alpha-2a. 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. Screening can begin before the 28-day washout is completed, but the washout period must be completed prior to collection of Screening blood samples.
Anemia: For Phase 1b: 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 (see Section 6.3). 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 PRBCs 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 PRBCs 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 and/or hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening. If subject discontinues JAK inhibitor 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/1.73 m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.
Aspartate aminotransferase (AST) and alanine transaminase (ALT) < 3.0x 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.
If male with female sexual partner(s) of childbearing potential, agrees he and partner(s) will use one of the following acceptable methods of birth control during the study and for 30 days after the last study drug dose:
a. abstinence
b. stable hormonal contraceptive in conjunction with a barrier method (e.g., condom [male or female] or diaphragm)
c. intrauterine device, in place for at least 3 months
d. surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation
- If female of childbearing potential, defined as prior menarche, no hysterectomy, no bilateral oophorectomy, not postmenopausal [at least 12 months natural, spontaneous amenorrhea], must commit to one of the following methods of acceptable birth control during the study and for at least 8 weeks after the last study drug dose:
a. abstinence
b. stable hormonal contraceptive in conjunction with a barrier method (e.g., condom [male or female] or diaphragm)
c. intrauterine device, in place for at least 3 months
Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2) AND Baseline (Day 1).
Able to understand the study aims, procedures, and requirements, and provide written informed consent.
Able to comply with all study procedures.
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 with the past 3 years, other than primary MF, post-ET MF, or post-PV MF. The following history or concurrent conditions are allowed:
a. basal or squamous cell carcinoma
b. carcinoma in situ of the cervix or the breast
c. 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:
Concurrent or planned treatment with momelotinib during the study period
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
Miscellaneous:
Pregnant or lactating
Condition or concomitant medication that would confound the ability to interpret study data
Other medical or psychiatric condition or laboratory finding not specifically noted above that, in the judgment of the Investigator or Sponsor, would put the participant at unacceptable risk or otherwise preclude the participant from participating in the study
Participation in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices within 30 days prior to Screening
