A Dose finding Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of ZE74-0282 in Select JAK2 V617F Mutated Hematologic Disorders

Inclusion Criteria25

• Patient is greater than or equal to 18 years of age at the time of obtaining informed consent.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Patient has histological confirmation JAK2 V617F mutated hematologic diagnosis with later confirmation using ipsogen® JAK2 RGQ PCR Kit) with prior therapy or who have declined them. Specifics for disease include:
• a. Myelofibrosis having received a JAK2 inhibitor or having declined it, spleen volume of 450 cm2 (by spleen or MRI) and TSS > 10 or 3 of 7 TSS scores >3
• b. polycythemia vera with standard therapy having received hydroxyurea, ruxolitinib, and/or interferon (or declined it)
• All AEs related to prior therapies (chemotherapy/systemic therapies, radiation, surgery) must have resolved to Grade 1 or baseline except for:
• a. Alopecia (Grade less than or equal to 2)
• b. Sensory neuropathy (Grade less than or equal to 2)
• c. Other AEs that have resolved to Grade less than or equal to 2 that, according to the clinical judgment of
• the investigator, do not constitute a safety risk to the patient.
• Adequate hematologic function including
• a. ANC greater than or equal to 1 x 109/L
• b. Platelets greater than or equal to 50 x 109/L
• c. Hemoglobin greater than or equal to 8 g/dl (80 g/L) (may be transfused)
• Organ function/reserve as per the following laboratory criteria:
• a. Hepatic: Aspartate aminotransferase (AST) less than or equal to 2.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) less than or equal to 2.5 x ULN, and total bilirubin < 2 x ULN (except for patients with known or suspected Gilbert’s syndrome and with direct bilirubin within normal range) for the local laboratory. If due to disease, higher values may be approved after discussion with medical monitor.
• b. Renal: Adequate renal function as defined by calculated creatinine clearance >45 mL/min for the local laboratory.
• Baseline corrected QT interval by Fredericia (QTcF) < 470 ms. Patients with right, left, or partial bundle branch blocks or pacemaker that may confound interpretation of this reading are not excluded from this provided they lack history of primary arrhythmic events and are cleared by cardiology for enrollment in the trial.
• Pregnancy:
• a. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test result at screening (not applicable to patients who are unable to become pregnant, including those with bilateral oophorectomy and/or hysterectomy). The test must be performed within 72 hours before Day 1 of treatment.
• b. Women of non-child-bearing potential must have at least 12 continuous months of natural (spontaneous) amenorrhea and an appropriate clinical profile (e.g., age appropriate or history of vasomotor symptoms) or have had surgical sterilization (bilateral oophorectomy, hysterectomy, or bilateral tubal ligation) >42 days prior to screening.
• Contraception and Gamete Donation:
• a. Male patients with a WOCBP partner must use 2 forms of acceptable contraception, including 1 barrier method, during their participation in the study and for 120 days following the last dose of the study treatment. They must also refrain from sperm donation from screening visit until 120 days following the last dose of study treatment.
• b. Women of child-bearing potential must use 2 forms of acceptable contraception, including 1 barrier method, during their participation in the study and for 120 days following the last dose of the study treatment. They must also refrain from ova donation from screening visit until 120 days following the last dose of study treatment.
• Written informed consent must be obtained according to local guidelines and signed and dated by the patient prior to the performance of any study specific procedures, sampling, or analyses.