Brief 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.
Brief Title
Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia
Categories
Central Contacts
Central Contact Role
Contact
Central Contact Phone
(617) 674 9274
Central Contact Email
clinicaltrials@discmedicine.com
Completion Date
Completion Date Type
Estimated
Conditions
MYELOFIBROSIS; ANEMIA
ANEMIA
MYELOFIBROSIS
MYELOFIBROSIS DUE TO AND FOLLOWING POLYCYTHEMIA VERA
PRIMARY MYELOFIBROSIS
POST-ESSENTIAL THROMBOCYTHEMIA MYELOFIBROSIS
MYELODYSPLASTIC SYNDROMES
Eligibility Criteria
Inclusion Criteria for Participants with MF and Anemia:
Participants are eligible for the study if all of the following criteria apply:
1. Age 18 years or older at the time of signing the informed consent form (ICF).
2. 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.
3. Washout of at least 28 days prior to Screening of the following treatments:
1. Androgens
2. EPO
3. Cladribine
4. Immunomodulators (lenalidomide, thalidomide)
5. Luspatercept/sotatercept
6. 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.
4. 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
5. Stable dosing of MF-directed therapy:
1. Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.
2. Interferon alpha stable dosing for at least 12 weeks prior to Screening.
3. 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.
4. If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-day washout period is required.
6. Eastern Cooperative Oncology Group (ECOG) performance score ≤2.
7. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening.
8. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening.
9. 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.
10. Serum ferritin ≥50 µg/L at Screening.
11. 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.
12. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.
13. Aspartate aminotransferase (AST) and ALT \<3.0x upper limit of normal (ULN) at Screening.
14. 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.
15. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
16. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
17. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
18. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
19. 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:
1. Age 18 years or older at the time of signing the ICF.
2. 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.
3. Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:
1. Androgens
2. EPO-stimulating agents
3. Luspatercept
4. Sotatercept (ACE-011)
5. Imetelstat
6. Granulocyte colony-stimulating factor (G CSF) OR granulocyte-macrophage CSF (GM CSF).
7. 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.
4. Anemia:
1. 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
2. Medical history of ≤24 units of PRBC for MDS and anemia
5. ECOG performance score ≤2
6. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening
7. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening
8. Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review
9. Serum ferritin ≥50 μg/L at Screening
10. Platelet count ≥25,000/μL and \<1,000,000/μL, and total WBC count \<50,000/μL at Screening or otherwise approved by Sponsor.
11. eGFR ≥30 mL/min/1.73 m2 by the CKD-EPI formula
12. AST and ALT \<3x ULN at Screening
13. Direct bilirubin \<2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis.
14. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
15. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
16. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
17. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
18. Able to comply with all study procedures.
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
1. Hereditary hemochromatosis
2. Hemoglobinopathy or intrinsic RBC defect associated with anemia
3. Total splenectomy
4. Hematopoietic cell transplant within the past 2 years, or graft vs host disease requiring immunosuppression
5. Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding
6. Active immune-mediated hemolytic anemia
7. 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
8. Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery
9. Malignancy within the past 3 years, other than primary MF, post ET, or post PV MF. The following history or concurrent conditions are allowed:
1. basal or squamous cell carcinoma of the skin
2. carcinoma in situ of the cervix or the breast
3. 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
10. Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 3 months prior to Screening
11. Known allergic reaction to any study drug excipient
12. A history of anti-drug antibody formation
13. Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction \<35%
14. Hepatitis B or C, or human immunodeficiency virus (HIV) with detectable viral load
15. 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
16. Iron chelation therapy in the 28 days prior to Screening
17. Change in anticoagulant therapy regimen within 8 weeks prior to Screening
Laboratory Exclusions, Participants with MF and Anemia
18. Peripheral blood myeloblasts ≥10% of WBC differential at most recent evaluation prior to Screening
19. Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening
Miscellaneous, Participants with MF and Anemia
20. Pregnant or lactating
21. Condition or concomitant medication that would confound the ability to interpret study data
22. 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
23. 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
1. 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
2. Peripheral blasts ≥5%
3. Current treatment with hypomethylating agent or other acute myeloid leukemia (AML)-like combination chemotherapy or planned use within 6 months after Screening
4. Prior treatment with \>3 anemia-directed therapies (unless otherwise approved by Sponsor) including:
1. Luspatercept
2. Sotatercept (ACE-011)
3. EPO-stimulating agent
4. Imetelstat
5. Hereditary hemochromatosis
6. Hemoglobinopathy or intrinsic RBC defect associated with anemia
7. Total splenectomy
8. Hematopoietic cell transplant within the past 10 years
9. Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding
10. Active immune-mediated hemolytic anemia
11. 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
12. Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery
13. Malignancy within the past 3 years, other than MDS or MDS/MPN without excess blasts. The following history or concurrent conditions are allowed:
1. Basal or squamous cell carcinoma of the skin
2. Carcinoma in situ of the cervix or the breast
3. 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
14. Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 6 months prior to Screening
15. Known allergic reaction to any study drug excipient
16. A history of antidrug antibody formation
17. Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction \<35%
18. Active hepatitis B or C, or HIV with detectable viral load
19. 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
20. Iron chelation therapy in the 28 days prior to Screening
21. Change in anticoagulant therapy regimen within 8 weeks prior to Screening
Laboratory Exclusions, Participants with MDS and Anemia
22. Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening
Miscellaneous, Participants with MDS and Anemia
23. Pregnant or lactating
24. Condition or concomitant medication that would confound the ability to interpret study data
25. 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
26. 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
Participants are eligible for the study if all of the following criteria apply:
1. Age 18 years or older at the time of signing the informed consent form (ICF).
2. 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.
3. Washout of at least 28 days prior to Screening of the following treatments:
1. Androgens
2. EPO
3. Cladribine
4. Immunomodulators (lenalidomide, thalidomide)
5. Luspatercept/sotatercept
6. 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.
4. 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
5. Stable dosing of MF-directed therapy:
1. Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.
2. Interferon alpha stable dosing for at least 12 weeks prior to Screening.
3. 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.
4. If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-day washout period is required.
6. Eastern Cooperative Oncology Group (ECOG) performance score ≤2.
7. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening.
8. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening.
9. 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.
10. Serum ferritin ≥50 µg/L at Screening.
11. 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.
12. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.
13. Aspartate aminotransferase (AST) and ALT \<3.0x upper limit of normal (ULN) at Screening.
14. 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.
15. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
16. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
17. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
18. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
19. 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:
1. Age 18 years or older at the time of signing the ICF.
2. 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.
3. Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:
1. Androgens
2. EPO-stimulating agents
3. Luspatercept
4. Sotatercept (ACE-011)
5. Imetelstat
6. Granulocyte colony-stimulating factor (G CSF) OR granulocyte-macrophage CSF (GM CSF).
7. 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.
4. Anemia:
1. 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
2. Medical history of ≤24 units of PRBC for MDS and anemia
5. ECOG performance score ≤2
6. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening
7. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening
8. Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review
9. Serum ferritin ≥50 μg/L at Screening
10. Platelet count ≥25,000/μL and \<1,000,000/μL, and total WBC count \<50,000/μL at Screening or otherwise approved by Sponsor.
11. eGFR ≥30 mL/min/1.73 m2 by the CKD-EPI formula
12. AST and ALT \<3x ULN at Screening
13. Direct bilirubin \<2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis.
14. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
15. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
16. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
17. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
18. Able to comply with all study procedures.
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
1. Hereditary hemochromatosis
2. Hemoglobinopathy or intrinsic RBC defect associated with anemia
3. Total splenectomy
4. Hematopoietic cell transplant within the past 2 years, or graft vs host disease requiring immunosuppression
5. Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding
6. Active immune-mediated hemolytic anemia
7. 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
8. Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery
9. Malignancy within the past 3 years, other than primary MF, post ET, or post PV MF. The following history or concurrent conditions are allowed:
1. basal or squamous cell carcinoma of the skin
2. carcinoma in situ of the cervix or the breast
3. 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
10. Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 3 months prior to Screening
11. Known allergic reaction to any study drug excipient
12. A history of anti-drug antibody formation
13. Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction \<35%
14. Hepatitis B or C, or human immunodeficiency virus (HIV) with detectable viral load
15. 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
16. Iron chelation therapy in the 28 days prior to Screening
17. Change in anticoagulant therapy regimen within 8 weeks prior to Screening
Laboratory Exclusions, Participants with MF and Anemia
18. Peripheral blood myeloblasts ≥10% of WBC differential at most recent evaluation prior to Screening
19. Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening
Miscellaneous, Participants with MF and Anemia
20. Pregnant or lactating
21. Condition or concomitant medication that would confound the ability to interpret study data
22. 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
23. 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
1. 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
2. Peripheral blasts ≥5%
3. Current treatment with hypomethylating agent or other acute myeloid leukemia (AML)-like combination chemotherapy or planned use within 6 months after Screening
4. Prior treatment with \>3 anemia-directed therapies (unless otherwise approved by Sponsor) including:
1. Luspatercept
2. Sotatercept (ACE-011)
3. EPO-stimulating agent
4. Imetelstat
5. Hereditary hemochromatosis
6. Hemoglobinopathy or intrinsic RBC defect associated with anemia
7. Total splenectomy
8. Hematopoietic cell transplant within the past 10 years
9. Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding
10. Active immune-mediated hemolytic anemia
11. 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
12. Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery
13. Malignancy within the past 3 years, other than MDS or MDS/MPN without excess blasts. The following history or concurrent conditions are allowed:
1. Basal or squamous cell carcinoma of the skin
2. Carcinoma in situ of the cervix or the breast
3. 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
14. Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 6 months prior to Screening
15. Known allergic reaction to any study drug excipient
16. A history of antidrug antibody formation
17. Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction \<35%
18. Active hepatitis B or C, or HIV with detectable viral load
19. 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
20. Iron chelation therapy in the 28 days prior to Screening
21. Change in anticoagulant therapy regimen within 8 weeks prior to Screening
Laboratory Exclusions, Participants with MDS and Anemia
22. Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening
Miscellaneous, Participants with MDS and Anemia
23. Pregnant or lactating
24. Condition or concomitant medication that would confound the ability to interpret study data
25. 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
26. 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
Inclusion Criteria
Inclusion Criteria for Participants with MF and Anemia:
Participants are eligible for the study if all of the following criteria apply:
1. Age 18 years or older at the time of signing the informed consent form (ICF).
2. 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.
3. Washout of at least 28 days prior to Screening of the following treatments:
1. Androgens
2. EPO
3. Cladribine
4. Immunomodulators (lenalidomide, thalidomide)
5. Luspatercept/sotatercept
6. 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.
4. 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
5. Stable dosing of MF-directed therapy:
1. Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.
2. Interferon alpha stable dosing for at least 12 weeks prior to Screening.
3. 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.
4. If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-day washout period is required.
6. Eastern Cooperative Oncology Group (ECOG) performance score ≤2.
7. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening.
8. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening.
9. 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.
10. Serum ferritin ≥50 µg/L at Screening.
11. 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.
12. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.
13. Aspartate aminotransferase (AST) and ALT \<3.0x upper limit of normal (ULN) at Screening.
14. 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.
15. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
16. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
17. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
18. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
19. 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:
1. Age 18 years or older at the time of signing the ICF.
2. 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.
3. Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:
1. Androgens
2. EPO-stimulating agents
3. Luspatercept
4. Sotatercept (ACE-011)
5. Imetelstat
6. Granulocyte colony-stimulating factor (G CSF) OR granulocyte-macrophage CSF (GM CSF).
7. 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.
4. Anemia:
1. 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
2. Medical history of ≤24 units of PRBC for MDS and anemia
5. ECOG performance score ≤2
6. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening
7. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening
8. Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review
9. Serum ferritin ≥50 μg/L at Screening
10. Platelet count ≥25,000/μL and \<1,000,000/μL, and total WBC count \<50,000/μL at Screening or otherwise approved by Sponsor.
11. eGFR ≥30 mL/min/1.73 m2 by the CKD-EPI formula
12. AST and ALT \<3x ULN at Screening
13. Direct bilirubin \<2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis.
14. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
15. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
16. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
17. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
18. Able to comply with all study procedures.
Participants are eligible for the study if all of the following criteria apply:
1. Age 18 years or older at the time of signing the informed consent form (ICF).
2. 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.
3. Washout of at least 28 days prior to Screening of the following treatments:
1. Androgens
2. EPO
3. Cladribine
4. Immunomodulators (lenalidomide, thalidomide)
5. Luspatercept/sotatercept
6. 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.
4. 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
5. Stable dosing of MF-directed therapy:
1. Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.
2. Interferon alpha stable dosing for at least 12 weeks prior to Screening.
3. 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.
4. If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-day washout period is required.
6. Eastern Cooperative Oncology Group (ECOG) performance score ≤2.
7. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening.
8. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening.
9. 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.
10. Serum ferritin ≥50 µg/L at Screening.
11. 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.
12. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.
13. Aspartate aminotransferase (AST) and ALT \<3.0x upper limit of normal (ULN) at Screening.
14. 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.
15. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
16. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
17. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
18. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
19. 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:
1. Age 18 years or older at the time of signing the ICF.
2. 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.
3. Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:
1. Androgens
2. EPO-stimulating agents
3. Luspatercept
4. Sotatercept (ACE-011)
5. Imetelstat
6. Granulocyte colony-stimulating factor (G CSF) OR granulocyte-macrophage CSF (GM CSF).
7. 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.
4. Anemia:
1. 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
2. Medical history of ≤24 units of PRBC for MDS and anemia
5. ECOG performance score ≤2
6. Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening
7. TSAT \<75% (local lab acceptable) at or within 2 weeks of Screening
8. Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review
9. Serum ferritin ≥50 μg/L at Screening
10. Platelet count ≥25,000/μL and \<1,000,000/μL, and total WBC count \<50,000/μL at Screening or otherwise approved by Sponsor.
11. eGFR ≥30 mL/min/1.73 m2 by the CKD-EPI formula
12. AST and ALT \<3x ULN at Screening
13. Direct bilirubin \<2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis.
14. 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:
1. Stable hormonal contraceptive (≥3 months; female partner)
2. Intrauterine device in place for at least 3 months (female partner)
3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
4. Confirmed successful vasectomy
15. 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:
1. Stable hormonal contraceptive (≥3 months)
2. Intrauterine device in place for at least 3 months
3. Tubal ligation or single male partner with vasectomy
16. Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).
17. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
18. Able to comply with all study procedures.
Gender
All
Gender Based
false
Keywords
Myeloproliferative Neoplasm
Myeloproliferative Disorders
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT05320198
Org Class
Industry
Org Full Name
Disc Medicine, Inc
Org Study Id
DISC-0974-102
Overall Status
Recruiting
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Estimated
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
Primary Outcomes
Outcome Description
Assessed by treatment-emergent adverse events
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
Assessed by vital signs through blood pressure (mmHg), heart rate (bpm), respiration rate (breaths/min), and temperature (°C)
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
Assessed by physical examinations
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
Assessed by electrocardiogram (ECG) parameters: heart rate, PR interval, QRS duration, QRS axis, QT interval, and QTcF interval)
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
The blood testing will include a hematology panel, blood chemistry panel, serology/virology panel, biomarker assessments, PK assessments, and Anti-Drug Antibodies
Outcome Measure
Safety and Tolerability of DISC-0974 assessed through blood testing (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
The urine testing will include a urinalysis
Outcome Measure
Safety and Tolerability of DISC-0974 assessed through urine testing (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
Defined as the absence of packed red blood cell (PRBC) transfusions over any rolling 12-week interval during the treatment period with a minimum hemoglobin (Hgb) of 7 g/dL. Participants meeting this criterion will be considered to have a major response to treatment.
Outcome Measure
Transfusion-dependent (TD) high cohort: transfusion independence (Phase 2 only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
Defined as the absence of PRBC transfusions over any rolling 16-week interval during the treatment period with a minimum Hgb of 7 g/dL. Participants meeting this criterion will be considered to have a major response to treatment.
Outcome Measure
TD low cohort: transfusion independence (Phase 2 only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Description
Defined as the composite of the absence of transfusions over any rolling 12-week period and a concomitant mean Hgb increase of ≥1.5 g/dL over baseline. Participants meeting this criterion will be considered to have a major response to treatment.
Outcome Measure
Non-transfusion-dependent (nTD) cohort: anemia response (Phase 2 only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Secondary Outcomes
Outcome Description
Response in nTD participants is defined as ≥2.0 g/dL increase from baseline in Hgb levels. Response in TD participants requires absence of PRBC transfusions during any rolling 12-week period during the treatment period, capped by an Hgb level of ≥8.5 g/dL.
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Anemia response defined per IWG-MRT 2006 criteria (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
TD high and TD low participants will be evaluated for absence of PRBC transfusions for any rolling 12-week interval during the treatment period (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
TD high participants will be evaluated for absence of PRBC transfusions with minimum Hgb of 7 g/dL during any rolling 12-week interval during the treatment period (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
TD low participants will be evaluated for absence of PRBC transfusions with minimum Hgb of 7 g/dL during any rolling 16-week interval during the treatment period (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
nTD participants will be evaluated for ≥1.5 g/dL increase from baseline Hgb levels during the treatment period (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
nTD participants will be evaluated for the composite of the absence of transfusions over any rolling 12-week period and a concomitant mean Hgb increase of ≥1.5 g/dL over baseline (Phase 1b only)
Outcome Description
Proportion of participants with treatment-emergent adverse events
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Incidence of TEAEs following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts (collectively referred to as MDS) and anemia (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Incidence of clinically abnormal vital signs following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Incidence of clinically abnormal physical exam following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Incidence of clinically abnormal electrocardiograms (ECGs) following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Incidence of abnormal laboratory test results following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only)
Outcome Description
Pharmacokinetic parameters include DISC-0974 pre-dose concentrations at different visits
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Pharmacokinetic data of DISC-0974 following repeated SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only)
Outcome Description
Participants who are nTD and achieve a mean Hgb increase ≥1 g/dL from baseline over any rolling 12-week period in the absence of transfusion will be considered to have a minor response to treatment.
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Proportion of participants achieving a mean Hgb increase ≥1 g/dL or ≥2 g/dL from baseline over any rolling 12-week period in absence of PRBC transfusions in each cohort (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
PD markers of mechanism engagement, including exploratory cohorts assessed through serum iron levels (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
PD markers of mechanism engagement, including exploratory cohorts assessed through TSAT levels (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
PD markers of mechanism engagement, including exploratory cohorts assessed through Ferritin levels (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
PD markers of mechanism engagement, including exploratory cohorts assessed through Transferrin levels (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
PD markers of mechanism engagement, including exploratory cohorts assessed through Serum-hepcidin-25 levels (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Hematologic Parameters assessed through Reticulocyte count (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Hematologic Parameters assessed through Hemoglobin levels (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Hematologic Parameters assessed through Reticulocyte Hemoglobin (CHr) (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Hematologic Parameters assessed through Red Blood Cell Count (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Rate of RBC transfusions per participant month during the treatment period for each cohort (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
The number of units of RBC transfusions per participant month during the treatment period for each cohort (Phase 1b and 2)
Outcome Description
Participants who are TD and achieve a reduction in transfusion requirement ≥50% as compared to baseline over any rolling 12-week period during treatment will be considered to have a minor response to treatment.
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Transfusion-dependent cohorts will be evaluated for proportion of participants who reduce their transfusion requirement by ≥50%, as compared to baseline, over any rolling 12-week period during treatment. (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
nTD participants will be evaluated for longest duration of mean Hgb increase of ≥1.5 g/dL from baseline during the treatment period (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Mean change in Hgb over 12-week treatment periods will be evaluated for all cohorts (nTD, TD low, and TD high) (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Maximum duration of RBC-transfusion-independent response for TD participants (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Proportion of participants that require dose escalation in each cohort (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Proportion of participants that improve Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale by at least 3 points in each cohort during the treatment period (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Mean hemoglobin increase of ≥1.5 g/dL over any rolling 12-week interval and an increase in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue of 3 points by the end of study (EOS) for nTD participants (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
TD high cohort will be evaluated for absence of packed red blood cell (PRBC) transfusions a terminal 12-week interval during the treatment period with a minimum hemoglobin (Hgb) of 7 g/dL (Phase 1b and 2)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
TD low cohort: will be evaluated for the absence of PRBC transfusions a terminal 16-week interval during the treatment period with a minimum Hgb of 7 g/dL (Phase 1b and 2)
Outcome Description
Defined as the composite of the absence of transfusions over any rolling 12-week period and a concomitant mean Hgb increase of ≥1.5 g/dL over baseline
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Non-transfusion-dependent (nTD) cohort will be evaluated for anemia response (Phase 1b and 2)
Outcome Description
Assessed by treatment-emergent adverse events
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 2 only)
Outcome Description
Assessed by vital signs through blood pressure (mmHg), heart rate (bpm), respiration rate (breaths/min), and temperature (°C)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 2 only)
Outcome Description
Assessed by physical examinations
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 2 only)
Outcome Description
Assessed by electrocardiogram (ECG) parameters: heart rate, PR interval, QRS duration, QRS axis, QT interval, and QTcF interval)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and Tolerability of DISC-0974 (Phase 2 only)
Outcome Description
The blood testing will include a hematology panel, blood chemistry panel, serology/virology panel, biomarker assessments, PK assessments, and Anti-Drug Antibodies
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and Tolerability of DISC-0974 assessed through blood testing (Phase 2 only)
Outcome Description
The urine testing will include a urinalysis
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and Tolerability of DISC-0974 assessed through urine testing (Phase 2 only)
Outcome Description
Assessed by treatment-emergent adverse events
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy (Phase 2 only)
Outcome Description
Assessed by vital signs through blood pressure (mmHg), heart rate (bpm), respiration rate (breaths/min), and temperature (°C)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy (Phase 2 only)
Outcome Description
Assessed by physical examinations
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy (Phase 2 only)
Outcome Description
Assessed by electrocardiogram (ECG) parameters: heart rate, PR interval, QRS duration, QRS axis, QT interval, and QTcF interval)
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy (Phase 2 only)
Outcome Description
The blood testing will include a hematology panel, blood chemistry panel, serology/virology panel, biomarker assessments, PK assessments, and Anti-Drug Antibodies
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy assessed through blood testing (Phase 2 only)
Outcome Description
The urine testing will include a urinalysis
Outcome Time Frame
From Day 1 to the end of treatment on Day 169
Outcome Measure
Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy assessed through urine testing (Phase 2 only)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Swati Goel
Investigator Email
swgoel@montefiore.org
Investigator Phone
718-920-6310 / 718-920-4137
Investigator Department
Medicine
Investigator Division
Hematology
Investigator Sponsor Organization
External
Study Department
Medicine
Study Division
Hematology
Categories Mesh Debug
Blood Disorders --- ANEMIA
Blood & Bone Marrow Cancers --- MYELODYSPLASTIC SYNDROMES
Blood & Bone Marrow Cancers --- MYELOPROLIFERATIVE DISORDERS
Blood Disorders --- HEMATOLOGIC DISEASES
MeSH Terms
PRIMARY MYELOFIBROSIS
ANEMIA
MYELODYSPLASTIC SYNDROMES
MYELOPROLIFERATIVE DISORDERS
BONE MARROW DISEASES
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES