Status and phase
Conditions
Treatments
About
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 or myelodysplastic syndrome and anemia.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Inclusion Criteria for Participants with MF and Anemia
Participants are eligible for the study if all of the following criteria apply:
Age 18 years or older at the time of signing the informed consent form (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.63
For Phase 2: In addition to the criteria above, DIPSS score of ≥2 (intermediate 1 risk) may also be included.
Washout of at least 28 days prior to Screening of the following treatments:
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 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 2:
TD high transfusion burden cohort: RBC transfusion dependence, defined as an RBC transfusion requirement of 3 to 12 PRBC units over the 84 days immediately prior to Screening
TD low transfusion burden cohort: RBC transfusion dependence, defined as an RBC transfusion requirement of 1 to 2 PRBC units over the 84 days immediately prior to Screening
nTD cohort: Non-transfusion dependence, baseline Hgb <10 g/dL as defined on ≥3 assessments over 84 days prior to Screening, without RBC transfusion
Exploratory cohort: RBC TD or nTD with momelotinib or pacritinib (note: enrollment will commence with momelotinib only; pacritinib enrollment will be considered after initial safety and efficacy review)
Stable dosing of MF-directed therapy:
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 by central review. Required for TD high participants only.
Serum ferritin ≥30 50 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 aminotransferase (ALT) <3x 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 or Gilbert's syndrome, with approval from Sponsor.
If male with female sexual partner(s) of childbearing potential, agrees to use one of the following acceptable methods of contraception during the study and for at least 8 weeks after the last study drug dose:
If female, then EITHER postmenopausal, defined as at least 12 months of natural, spontaneous amenorrhea and serum follicle-stimulating hormone (FSH) >40 mIU/mL at Screening, or at least 6 weeks following surgical menopause (bilateral oophorectomy or hysterectomy); OR agreeable to use highly effective contraception methods (listed below) on Day 1 (or earlier) for at least 8 weeks after the last dose of study drug:
Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
Able to understand the study aims, procedures, and requirements, and provide written informed consent.
Able to comply with all study procedures.
Inclusion Criteria for Exploratory Cohort of Participants with MDS and Anemia
Participants are eligible for the MDS exploratory cohort if all of the following criteria apply:
Age 18 years or older at the time of signing the ICF.
Molecular International Prognostic Scoring System (IPSS-R) classification of very low, low, or intermediate (ie, lower risk) MDS or MDS/MPN with ringed sideroblasts and thrombocytosis (RS-T) as confirmed in the most recent local bone marrow biopsy report according to WHO criteria.
Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:
Anemia:
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 by central review
Serum ferritin ≥50 μg/L at Screening
Platelet count ≥25,000/μL and <1,000,000/μL, and total WBC count <50,000/μL at Screening or otherwise approved by Sponsor
eGFR ≥30 mL/min/1.73 m2 by the CKD-EPI formula
AST and ALT <3x 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 to use one of the following acceptable methods of contraception during the study and for at least 8 weeks after the last study drug dose:
If female, then EITHER postmenopausal, defined as at least 12 months of natural, spontaneous amenorrhea and serum FSH >40 mIU/mL at Screening, or at least 6 weeks following surgical menopause (bilateral oophorectomy or hysterectomy); OR agreeable to use one of the following highly effective contraception methods on Day 1 (or earlier) for at least 8 weeks after the last dose of study drug:
Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
Able to understand the study aims, procedures, and requirements, and provide written informed consent.
Able to comply with all study procedures.
Exclusion Criteria Exclusion Criteria for Participants with MF and Anemia
Participants are excluded from the study if any of the following criteria apply:
Medical History, Participants with MF and Anemia
Hereditary hemochromatosis
Hemoglobinopathy or intrinsic RBC defect associated with anemia
Total splenectomy
Hematopoietic cell transplant within the past 2 years or graft vs host disease requiring immunosuppression
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:
Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 3 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%
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, Medical History, Participants with MF and Anemia
Iron chelation therapy in the 28 days prior to Screening
Change in anticoagulant therapy regimen within 8 weeks prior to Screening Laboratory Exclusions, Medical History, Participants with MF and Anemia
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, Medical History, Participants with MF and Anemia
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 study that involves administration of experimental therapy and/or therapeutic devices within 30 days prior to Screening
Exclusion Criteria for Exploratory Cohort of Participants with MDS and Anemia
Participants are excluded from the MDS exploratory cohort if any of the following criteria apply:
Medical History, Participants with MDS and Anemia
Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation from other diseases
Peripheral blasts ≥5%
Prior treatment with hypomethylating agent or other acute myeloid leukemia (AML)-like combination chemotherapy
Prior treatment with >1anemia-directed therapies including:
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 MDS or MDS/MPN without excess blasts. The following history or concurrent conditions are allowed:
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 antidrug 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 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, Participants with MDS and Anemia
Iron chelation therapy in the 28 days prior to Screening
Change in anticoagulant therapy regimen within 8 weeks prior to Screening Laboratory Exclusions, Participants with MDS and Anemia
Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening Miscellaneous, Participants with MDS and Anemia
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 study that involves administration of experimental therapy and/or therapeutic devices within 30 days prior to Screening
Primary purpose
Allocation
Interventional model
Masking
150 participants in 2 patient groups
Loading...
Central trial contact
Disc Medicine Clinical Trials
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal