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Official Title

RALLY-MF: A Phase 1b/2 Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of DISC-0974 in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia

Phase
Phase 1/Phase 2
Sponsor
Disc Medicine, Inc
Enrollment
150
Timeline
Jun 2022 → Sep 2026
About This Study

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.

Eligibility Criteria

Inclusion Criteria

  • 1Participants are eligible for the study if all of the following criteria apply:
  • 2Age 18 years or older at the time of signing the informed consent form (ICF).
  • 3For 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.55
  • 4For Phase 2: In addition to the criteria above, DIPSS score of ≥2 (intermediate 1 risk) may also be included.
  • 5Washout of at least 28 days prior to Screening of the following treatments:
  • 6Androgens
  • 7EPO
  • 8Cladribine
  • 9Immunomodulators (lenalidomide, thalidomide)
  • 10Luspatercept/sotatercept
  • 11Systemic 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.
  • 12Screening can begin before the 28 day washout is completed, but the washout period must be completed prior to collection of Screening blood samples.
  • 13Anemia:
  • 14For 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.
  • 15For Phase 2:
  • 16TD 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
  • 17Stable dosing of MF-directed therapy:
  • 18Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.
  • 19Interferon alpha stable dosing for at least 12 weeks prior to Screening.
  • 20JAK inhibitors require 12 weeks of stable dosing prior to Screening. For the TD high, TD low, and nTD cohorts, JAK inhibitors allowed include momelotinib, pacritinib, fedratinib, and ruxolitinib.
  • 21If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-day washout period is required.
  • 22Eastern Cooperative Oncology Group (ECOG) performance score ≤2.
  • 23Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening.
  • 24TSAT \<75% (local lab acceptable).
  • 25Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review. Required for TD high participants only.
  • 26Serum ferritin ≥50 µg/L at Screening.
  • 27Platelet 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.
  • 28Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.
  • 29Aspartate aminotransferase (AST) and ALT \<3x upper limit of normal (ULN) at Screening.
  • 30Direct 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.
  • 31If male with female sexual partner(s) of childbearing potential, agrees to use 1 of the following highly effective methods of contraception during the study and for at least 8 weeks after the last study drug dose:
  • 32Stable hormonal contraceptive (≥3 months; female partner)
  • 33Intrauterine device in place for at least 3 months (female partner)
  • 34Surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
  • 35Confirmed successful vasectomy
  • 36If female, then EITHER postmenopausal (defined as 12 months of spontaneous amenorrhea, 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels \>40 mIU/ml, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy), surgically sterile, OR agreeable to use 1 of the following highly effective contraception methods (listed below) on Day 1 (or earlier) and for at least 8 weeks after the last dose of study drug:
  • 37Stable hormonal contraceptive (≥3 months)
  • 38Intrauterine device in place for at least 3 months
  • 39Tubal ligation or single male partner with vasectomy
  • 40Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
  • 41Able to understand the study aims, procedures, and requirements, and provide written informed consent.
  • 42Able to comply with all study procedures.
  • 43Participants are eligible for the MDS exploratory cohort if all of the following criteria apply:
  • 44Age 18 years or older at the time of signing the ICF.
  • 45Molecular International Prognostic Scoring System (IPSS-M) classification of very low, low, or intermediate (ie, lower risk) MDS-ringed sideroblasts (RS) negative, MDS/MPN with ringed sideroblasts and thrombocytosis (RS-T), Chronic Myelomonocytic Leukemia (CMML), Atypical Chronic Myeloid Leukemia (aCML), or Myelodysplastic/Myeloproliferative Neoplasms, Unclassifiable (MDS/MPN-U) as confirmed in the most recent local bone marrow biopsy report according to WHO criteria.
  • 46Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:
  • 47Androgens
  • 48EPO-stimulating agents
  • 49Luspatercept
  • 50Sotatercept (ACE-011)
  • 51Imetelstat
  • 52Granulocyte colony-stimulating factor (G-CSF) OR granulocyte-macrophage CSF (GM-CSF)
  • 53Systemic corticosteroids (except for participants on a stable or decreasing dose for ≥28 days prior to randomization for non-hematological conditions 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.
  • 54Anemia:
  • 55Baseline Hgb of \<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 during the 84 days prior to Screening
  • 56Medical history of ≤24 units of PRBC for MDS and anemia
  • 57ECOG performance score ≤2
  • 58Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening
  • 59TSAT \<75% (local lab acceptable)
  • 60Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review
  • 61Serum ferritin ≥50 μg/L at Screening
  • 62Platelet count ≥25,000/μL and \<1,000,000/μL, and total WBC count \<50,000/μL at Screening or otherwise approved by Sponsor
  • 63eGFR ≥30 mL/min/1.73 m2 by the CKD-EPI formula
  • 64AST and ALT \<3x ULN at Screening
  • 65Direct bilirubin \<2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis.
  • 66If male with female sexual partner(s) of childbearing potential, agrees to use 1 of the following highly effective methods of contraception during the study and for at least 8 weeks after the last study drug dose:
  • 67Stable hormonal contraceptive (≥3 months; female partner)
  • 68Intrauterine device in place for at least 3 months (female partner)
  • 69Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
  • 70Confirmed successful vasectomy
  • 71If female, then EITHER postmenopausal (defined as 12 months of spontaneous amenorrhea, 6 months of spontaneous amenorrhea with serum FSH levels \>40 mIU/ml, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy), surgically sterile, OR agreeable to use 1 of the following highly effective contraception methods (listed below) on Day 1 (or earlier) and for at least 8 weeks after the last dose of study drug:
  • 72Stable hormonal contraceptive (≥3 months)
  • 73Intrauterine device in place for at least 3 months
  • 74Tubal ligation or single male partner with vasectomy
  • 75Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
  • 76Able to understand the study aims, procedures, and requirements, and provide written informed consent.
  • 77Able to comply with all study procedures.

Exclusion Criteria

  • 1Participants are excluded from the study if any of the following criteria apply:
  • 2Medical History, Participants with MF and Anemia
  • 3Hereditary hemochromatosis
  • 4Hemoglobinopathy or intrinsic RBC defect associated with anemia
  • 5Total splenectomy
  • 6Hematopoietic cell transplant within the past 2 years or graft vs host disease requiring immunosuppression
  • 7Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding
  • 8Active immune-mediated hemolytic anemia
  • 9Symptomatic 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
  • 10Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery
  • 11Malignancy with the past 3 years, other than primary MF, post ET MF, or post PV MF. The following history or concurrent conditions are allowed:
  • 12basal or squamous cell carcinoma
  • 13carcinoma in situ of the cervix or the breast
  • 14histologic 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
  • 15Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 3 months prior to Screening
  • 16Known allergic reaction to any study drug excipient
  • 17A history of anti-drug antibody formation
  • 18Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction \<35%
  • 19Hepatitis B or C, or human immunodeficiency virus (HIV) with detectable viral load
  • 20Uncontrolled fungal, bacterial, or viral infection (ongoing signs/symptoms related to the infection, without improvement despite appropriate treatment)
  • 21Treatment History, Medical History, Participants with MF and Anemia
  • 22Iron chelation therapy in the 28 days prior to Screening
  • 23Change in anticoagulant therapy regimen within 8 weeks prior to Screening
  • 24Laboratory Exclusions, Medical History, Participants with MF and Anemia
  • 25Peripheral blood myeloblasts ≥10% of WBC differential at most recent evaluation prior to Screening
  • 26Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening
  • 27Miscellaneous, Medical History, Participants with MF and Anemia
  • 28Pregnant or lactating
  • 29Condition or concomitant medication that would confound the ability to interpret study data
  • 30Other 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
  • 31Participation in any other clinical protocol or investigational study that involves administration of experimental therapy and/or therapeutic devices within 30 days prior to Screening
  • 32Participants are excluded from the MDS exploratory cohort if any of the following criteria apply:
  • 33Medical History, Participants with MDS and Anemia
  • 34Secondary 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
  • 35Peripheral blasts ≥5%
  • 36Prior treatment with hypomethylating agent or other acute myeloid leukemia (AML)-like combination chemotherapy
  • 37Prior treatment with \>3 anemia-directed therapies (unless otherwise approved by Sponsor) including:
  • 38Luspatercept
  • 39Sotatercept (ACE-011)
  • 40EPO-stimulating agent
  • 41Imetelstat
  • 42Hereditary hemochromatosis
  • 43Hemoglobinopathy or intrinsic RBC defect associated with anemia
  • 44Total splenectomy
  • 45Hematopoietic cell transplant within the past 10 years
  • 46Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding
  • 47Active immune-mediated hemolytic anemia
  • 48Symptomatic 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
  • 49Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery
  • 50Malignancy within the past 3 years, other than MDS or MDS/MPN without excess blasts. The following history or concurrent conditions are allowed:
  • 51basal or squamous cell carcinoma
  • 52carcinoma in situ of the cervix or the breast
  • 53histologic finding of prostate cancer (T1a or T1b using the TNM clinical staging system) A history of completed treatment (medical or surgical) of stage 1-2 cancers may be permitted with prior Sponsor agreement
  • 54Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 6 months prior to Screening
  • 55Known allergic reaction to any study drug excipient
  • 56A history of antidrug antibody formation
  • 57Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction \<35%
  • 58Active hepatitis B or C, or HIV with detectable viral load
  • 59Uncontrolled fungal, bacterial, or viral infection (ongoing signs/symptoms related to the infection, without improvement despite appropriate treatment)
  • 60Treatment History, Participants with MDS and Anemia
  • 61Iron chelation therapy in the 28 days prior to Screening
  • 62Change in anticoagulant therapy regimen within 8 weeks prior to Screening
  • 63Laboratory Exclusions, Participants with MDS and Anemia
  • 64Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening
  • 65Miscellaneous, Participants with MDS and Anemia
  • 66Pregnant or lactating
  • 67Condition or concomitant medication that would confound the ability to interpret study data
  • 68Other 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
  • 69Participation in any other clinical protocol or investigational study that involves administration of experimental therapy and/or therapeutic devices within 30 days prior to Screening

Locations

17 sites participating in this study

Emory Winship Cancer Institute

Atlanta, Georgia 30322

Recruiting

Anthony Hunter, MD

Mayo Clinic Jacksonville

Jacksonville, Florida 32224

Recruiting

James Foran, MD

Moffitt Cancer Center

Tampa, Florida 33612

Recruiting

Andrew Kuykendall, MD

Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →