A Study of TP-0184 to Treat Anemia in Adults With IPSS-R Low or Intermediate Risk MDS

Inclusion Criteria

• •1. A documented diagnosis of lower risk MDS (IPSS-R Low, Intermediate) according to WHO 2016 classification, de novo or secondary..
• •2. Bone marrow biopsy and/or aspirate performed pre-dose to assess disease status and available for review prior to full screening review. If the bone marrow biopsy and/or aspirate is nonproductive or nondiagnostic, the procedure must be repeated. Bone marrow biopsy/aspirate performed ≤ 12 weeks prior to baseline will not need to be repeated if results and a minimum of 6 slides are available.
• •3. Relapse, refractory/resistant, intolerant, or inadequate response to ESA treatment, as defined by the following:
• •* Relapse according to IWG 2006
• •* Refractory/resistant - documented non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (e.g., with G-CSF); ESA regimen must have been either:
• •* Recombinant human erythropoietin (rHu EPO) ≥ 500 IU/wk for at least 8 doses or equivalent; OR
• •* Darbepoetin alpha ≥ 300 μg Q3W for at least 4 doses or equivalent;
• •* Intolerant- documented discontinuation of prior ESA containing regimen, either as single agent or combination (e.g., with G-CSF), at any time after introduction due to intolerance or an adverse event
• •Inadequate response - in the absence of transfusions support, patients under ESA treatment for at least 12 weeks that do not show a rise in hemoglobin of greater than equal to 1 g/dl.
• •4. Patients with 5q deletions are allowed only if they have failed or are intolerant to lenalidomide treatment.
• •o Failure or intolerance to lenalidomide defined as clinical and cytogenetic responses to according to the international working group 2006 MDS: (1) absence of response, or (2) bone marrow progression during treatment with or without prior response, or (3) secondary failure (loss of prior hematological response without bone marrow progression), or (4) intolerance (treatment discontinuation due to adverse events, with or without prior response) based on investigator judgement (Prebet 2017). 7
• •5. Patients previously treated for anemia with or without RBC transfusion support:
• •1. Low transfusion burden (LTb), defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline hemoglobin \< 9.0 g/dL),
• •2. High transfusion burden (HTb), defined as requiring 4 or more red blood cell units in the 8 weeks before treatment
• •6. At least 12 weeks of transfusion history immediately preceding the first dose of TP-0184. This transfusion data must include hemoglobin measured prior to transfusion (pre transfusion Hgb).
• •7. Written, signed consent for trial participation must be obtained from the patient appropriately in accordance with applicable ICH guidelines and local and regulatory requirements prior to the performance of any study specific procedure.
• •8. Must be ≥18 years of age.
• •9. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤ 2.
• •10. Patients with a life expectancy of ≥3 months (90 days) per the treating investigator.
• •11. Patients with adequate major organ functions meeting the following criteria on the basis of laboratory data within 28 days (4 weeks) before screening (if multiple data are available, most recent data during the period):
• •1. Serum creatinine: ≤1.8 x the upper limit of the normal (ULN) range
• •2. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin ≤2.0 x ULN or if the elevated total bilirubin can be attributed to active red blood cell precursor destruction within the bone marrow (i.e., ineffective erythropoiesis). Elevated indirect bilirubin due to post-transfusion hemolysis is allowed.
• •3. Aspartate transaminase (AST) and alanine transaminase (ALT): ≤2.5 x ULN
• •Left ventricular ejection fraction (LVEF) ≥ 45% by echocardiogram or multigated acquisition (MUGA) scan
• •12. All previous therapy with ESAs, G-CSF and GM-CSF must be discontinued ≥ 14 days before Cycle 1 Day 1 dosing.
• •13. Twenty-eight-day (4 weeks) washout period from prior treatment with cytotoxic chemotherapeutic agents, HMAs (hypomethylating agents), ImiDs (immunomodulatory imide drugs), luspatercept and / or investigational drugs before study dosing for the patient begins.
• •14. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 5 days prior to the first dose of TP-0184.
• •15. Non-fertile or agree to use an adequate method of contraception while on study and for 7 months following the study and have a negative pregnancy test (if female of childbearing potential) and not currently nursing; males agree to use an adequate method of contraception while on study and for 4 months following the study.
• •16. Patients must be able to comply with the requirements of the entire study and accessible for treatment and follow-up.
• •17. Patient agrees not to participate in other interventional clinical studies during their participation in this trial, while on study treatment. Patients participating in surveys or observational studies are eligible to participate in this study.