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

Study Identifier:
DISC-0974-102
CT.gov Identifier:
NCT05320198
EudraCT Identifier:
N/A
EU Trial (CTIS) Number:
N/A
Study Contact Information:
(210) 593-5651 or [email protected]
Will Be Recruiting

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Study Summary

This phase 1b/2a open-label study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of DISC-0974 as well as categorize the effects on hematologic response in participants with myelofibrosis or myelodysplastic syndrome and anemia. To asses the safety, tolerability,pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of DISC-0974 in patients with MF andanemia. Anemia was defined as baseline hemoglobin (Hgb) <10 g/dL with or without intermittent transfusion requirement (non-transfusion dependent [nTD]) or transfusion dependent (TD), as defined by the IWG-MRT. Hematologic response was defined for TD as transfusion independence (TI) during any 12-week consecutive period and for nTD as ≥1.5 g/dL Hgb increase from baseline at any time point. Durability was evaluated as mean Hgb ≥1.5 g/dL above baseline during any 12-week period.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Myelodysplastic Syndrome
Unmapped
Myeloproliferative Neoplasms
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental: Phase 1b: Dose Escalation In the Phase 1b (dose-escalation) portion of the study, DISC-0974 will be administered subcutaneously every 4 weeks. Drug: DISC-0974 DISC-0974 is administered subcutaneously. Experimental: Phase 2a: Expansion In the Phase 2a (expansion) portion of the study, DISC-0974 will be administered subcutaneously every 4 weeks. Drug: DISC-0974 DISC-0974 is administered subcutaneously. EHA 2024: DISC-0974 was administered subcutaneously monthly for a total of 6 doses. Dose escalation was based on a Bayesian optimal interval design with accelerated titration. DISC-0974 was administered subcutaneously monthly for 6 doses. ASH 2024 The trial was comprised of both patients receiving concomitant JAK inhibitor therapy (n=13) and not receiving JAK inhibitor therapy (n=22). DISC-0974 was administered subcutaneously at 14 mg (n=1), 28 mg (n=7), 50 mg (n=12), 75 mg (n=9), or 100 mg (n=6) every 4 weeks for up to 6 treatments.
Study Status
Indicates the current recruitment status or the expanded access status
Will Be Recruiting

Requirements information
Inclusion 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: 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.
  • 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:
  • Androgens
  • EPO
  • Cladribine
  • Immunomodulators (lenalidomide, thalidomide)
  • Luspatercept/sotatercept
  • 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. 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
  • Stable dosing of MF-directed therapy:
  • Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.
  • Interferon alpha stable dosing for at least 12 weeks prior to Screening.
  • JAK 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.
  • If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-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.
  • TSAT <75% (local lab acceptable) at or within 2 weeks of Screening.
  • 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 ≥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 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 or Gilbert's syndrome, with approval from Sponsor.
  • If 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:
  • Stable hormonal contraceptive (≥3 months; female partner)
  • Intrauterine device in place for at least 3 months (female partner)
  • Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
  • Confirmed successful vasectomy
  • If 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:
  • Stable hormonal contraceptive (≥3 months)
  • Intrauterine device in place for at least 3 months
  • Tubal ligation or single male partner with vasectomy
  • 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-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.
  • Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:
  • Androgens
  • EPO-stimulating agents
  • Luspatercept
  • Sotatercept (ACE-011)
  • Imetelstat
  • Granulocyte colony-stimulating factor (G CSF) OR granulocyte-macrophage CSF (GM CSF).
  • Systemic 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.
  • Anemia:
  • Baseline 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
  • Medical history of ≤24 units of PRBC for MDS and anemia
  • ECOG performance score ≤2
  • Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening
  • TSAT <75% (local lab acceptable) at or within 2 weeks of Screening
  • 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 1 of the following highly effective methods of contraception during the study and for at least 8 weeks after the last study drug dose:
  • Stable hormonal contraceptive (≥3 months; female partner)
  • Intrauterine device in place for at least 3 months (female partner)
  • Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
  • Confirmed successful vasectomy
  • If 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:
  • Stable hormonal contraceptive (≥3 months)
  • Intrauterine device in place for at least 3 months
  • Tubal ligation or single male partner with vasectomy
  • 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 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 of the skin
  • 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 3 months prior to Screening
  • Known allergic reaction to any study drug excipient
  • 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, 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, 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, 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%
  • Current treatment with hypomethylating agent or other acute myeloid leukemia (AML)-like combination chemotherapy or planned use within 6 months after Screening
  • Prior treatment with >3 anemia-directed therapies (unless otherwise approved by Sponsor) including:
  • Luspatercept
  • Sotatercept (ACE-011)
  • EPO-stimulating agent
  • Imetelstat
  • 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:
  • Basal or squamous cell carcinoma of the skin
  • Carcinoma in situ of the cervix or the breast
  • Histologic 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
  • Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 6 months prior to Screening
  • Known allergic reaction to any study drug excipient
  • 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

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START New Jersey
East Brunswick, NJ, United States, 08816
Investigator
Bruno Fang
Status
Will Be Recruiting
Condition(s) Treated at Site
Myelodysplastic Syndrome
Unmapped
Myeloproliferative Neoplasms