Phase 2 Study of Oral Epetraborole in Adults With Polycythemia Vera

Prior treatment

• History of clinically significant arterial or venous thrombosis (eg, deep vein thrombosis or splenic vein thrombosis) within 24 weeks prior to Day 1
• History of major bleeding events and/or a requirement for blood transfusion therapy due to bleeding in the 6 months prior to Day 1
• Prior, concomitant, or planned therapy with ruxolitinib
• Received any investigational drug within 6 weeks prior to Day 1 or 5 half-lives (whichever is longer) prior to Day 1 or has not recovered from adverse effects of prior administration of any investigational agent
• Prior exposure to epetraborole; drug intolerance or hypersensitivity to any compound from the same class as epetraborole
• History of prior drug-induced pneumonitis
• Current skin malignancy or history of clinically significant skin cancer within 5 years prior to Day 1
• Any major surgical procedure requiring general anesthesia within 1 month prior to Day 1 or planned elective surgery during the trial
• Prior or concomitant therapy within 4 weeks prior to Day 1, or expected during the trial, with the following:
  • Drugs known to consistently produce myelosuppression: oxazolidinone antibiotics , chloramphenicol, mTORC inhibitors
  • Drugs that can inhibit ADH: some H2-receptor antagonists (eg, cimetidine, famotidine, ranitidine), pyrazoles (fomepizole)
  • Drugs that inhibit ALDH: disulfiram, isoniazid, ketoconazole, certain cephalosporins , first-generation sulfonylureas

Other illness

• Severe hepatic impairment at Screening as evidenced by clinical signs of cirrhosis or end-stage hepatic disease
• Known primary or secondary immunodeficiency defined as the following:
  • Primary immunodeficiency: rare, inherited genetic disorders, leading to frequent, severe, or unusual infections, autoimmune issues, and a higher cancer risk
  • Secondary immunodeficiency: acquired deficiencies, including those from chemotherapy/immunosuppressive drugs, certain cancers (like leukemia/lymphoma), severe malnutrition, major burns/trauma, and other chronic conditions. These are common and result from environmental influences or diseases, unlike primary ones that are genetic.

Lab values

• Platelets \>1000 × 109/L, WBC count \>25 × 109/L; or presence of any blast cells in peripheral blood at Screening
• Liver disease or liver injury at Screening as evidenced by:
  • ALT or AST \>3 × ULN
  • Total bilirubin \>2 × ULN
• eGFR \<30 mL/min/1.73 m2 at Screening
• Known history of:
  • Hepatitis B or C infection
  • HIV infection plus either an active AIDS-defining illness or a known CD4 count \<200/mm3 within 12 months prior to Day 1
• Any other condition, prior therapy, or clinically significant co-morbidity at Screening that would, in the Investigator's opinion, interfere with the participant's ability to participate in the entire trial, pose a risk to the participant, or constitute a potentially confounding medical condition, including the following:
  • Uncontrolled hypertension \>160/100 mmHg
  • Uncontrolled diabetes mellitus (HbA1c level of ≥9%)
  • NYHA Class III/IV heart failure
  • Severe coronary artery disease, including unstable angina or myocardial infarction in the 12 months prior to Screening, or likely to require invasive procedure(s) to manage their CAD during the trial
  • Symptomatic CVD or recent stroke within 12 months prior to Screening or active CVD with symptomatic transient events
  • Non-cutaneous malignancy requiring treatment

Other

• Meets the criteria for post-PV myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (Tefferi, 2023)
• Diagnosis of secondary polycythemia

• Willing and able to read and provide written informed consent prior to the performance of any trial-specific procedures and willing to follow the protocol requirements
• Aged 18 to 75 years (inclusive) at Screening
• A confirmed diagnosis of PV according to ICC (Thiele, 2023), including Hgb/Hct level, EPO level, and JAK2 mutation status assessed by analysis of peripheral blood sampling
• Documented positive JAK2 V617F (exon 14) or JAK2 exon 12 mutation
• Hct \<45% at Screening
• Has records of all phlebotomies performed for at least 28 weeks (preferably up to 52 weeks) prior to Day 1
• Phlebotomy-dependent, defined as at least 3 phlebotomies during the 28 weeks prior to Day 1, including a phlebotomy within 8 weeks prior to Screening
• Either receiving OR not receiving cytoreductive therapy for PV, as follows:
  • Participants who are not currently receiving cytoreductive therapy must have either never received it or been discontinued from it for at least 24 weeks prior to Day 1 and any AEs due to cytoreductive therapy have either recovered or are ≤ Grade 1 prior to Day 1
  • Participants currently receiving cytoreductive therapy with HU, interferon, or busulfan must have received such therapy for at least 24 weeks prior to Day 1 and have been on a stable or decreasing dose for at least 8 weeks prior to Day 1, and with no planned change in dose during the trial
• ECOG score of 0, 1, or 2
• If FOCP
  • Must not be currently breastfeeding
  • If sexually active with a male partner: Must be either sexually abstinent or agree to use at least 2 medically accepted, effective methods of birth control from Screening through at least 1 week after the last dose of trial intervention
  • Must have a negative urine pregnancy test at Screening and on Day 1; the Day 1 urine test will be confirmed by a serum pregnancy test.
• Male participants who are sexually active with an FOCP must agree to use an effective barrier method of contraception from Screening through at least 1 week after the last dose of trial intervention
• Agrees to not donate sperm (males) or ova (females) from Screening through at least 1 week after the last dose of trial intervention