This study will test an experimental drug called ZE74-0282 in people with certain blood disorders caused by a specific mutation called JAK2 V617F. The main goals are to find the right dose level, to see how safe and tolerable different doses are, how the drug moves through the body, and whether it shows early signs of anti-tumor activity. Participants will receive ZE74-0282 in one of several dose groups. The study is open-label, meaning both the doctor and the participant know which treatment is given. It will take place at multiple centers across different countries. Blood tests and regular check-ups will be done to monitor side effects and measure the effect on the disease.

This is a Phase 1, open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of ZE74-0282 in patients with JAK2 V617F mutated hematologic malignancies who have received prior therapy or have declined available treatment options.

The study will be conducted in two parts:

Part 1 (Dose Escalation): Sequential cohorts of patients will receive escalating doses of ZE74-0282 to determine the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE). Safety, tolerability, and PK will be assessed at each dose level.

Part 2 (Dose Expansion): Additional patients will be enrolled into several expansion cohorts at the MTD/RDE to further evaluate safety, tolerability, and preliminary anti-tumor activity in specific disease subtypes.

The study is expected to enroll approximately 60 patients. Adverse events will be graded according to CTCAE v6.0. Anti-tumor activity will be assessed using disease-specific response criteria.

Inclusion Criteria:

1. Patient is ≥18 years of age at the time of obtaining informed consent.

2. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

3. 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.

4. All AEs related to prior therapies (chemotherapy/systemic therapies, radiation, surgery) must have resolved to Grade 1 or baseline except for:

   1. Alopecia (Grade ≤2)
   2. Sensory neuropathy (Grade ≤2)
   3. Other AEs that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the patient.

5. Adequate hematologic function including

6. Organ function/reserve as per the following laboratory criteria:

   1. Hepatic: Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) ≤ 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.
   2. Renal: Adequate renal function as defined by calculated creatinine clearance >45 mL/min for the local laboratory.

7. 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.

8. Pregnancy:

   1. 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.
   2. 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.

9. Contraception and Gamete Donation:

   1. 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.
   2. 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.

10. 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.

Exclusion Criteria:

1. Clinical signs/symptoms of leukostasis or thrombophilia require urgent therapy (phereses).
2. Known active infection with Human Immunodeficiency Virus (HIV), hepatitis B or hepatitis C. Patients with a history of positive serology for hepatitis B or C require a negative Polymerase chain reaction (PCR) test for virus to go onto therapy.
3. Disseminated intravascular coagulopathy with active, unmanageable bleeding or signs of thrombosis.
4. Patients who have received an investigational agent (for any indication) <14 days prior the first dose of ZE74-0282; an investigational agent is one for which there is no approved indication by the United States (US) FDA or by the applicable regulatory authority in the country where the study is being conducted. Additionally, the first dose of ZE74-0282 should not occur before the shorter of 28 days or a period of 5 half-lives of the investigational drug; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment.
5. Systemic antineoplastic or radiotherapy <14 days prior to the first day of ZE74-0282 administration (Hydroxyurea is allowed prior to study to control counts and may be given during study until completion of cycle 2.
6. Female patients who are pregnant, lactating, or planning to become pregnant or initiate breastfeeding.
7. Patients with psychological, familial, social, or geographic factors, other significant medical condition, laboratory abnormality that otherwise preclude them from giving informed consent, following the protocol, potentially hamper compliance with study treatment and follow-up or would confound the interpretation of the results of the study.
8. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction with evidence of residual abnormalities, stroke or transient ischemic attack within 6 months prior to enrollment (Troponin (regular or high sensitivity) leak alone not included if no residual dysfunction),
9. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
10. Patients with uncontrolled infection requiring parenteral therapy shall not be enrolled until infection is treated and brought under control (to minimum of requirement of oral antibiotics).
11. Currently participating in or has planned participation in a study of another investigational agent or device.
12. Active prior or concurrent malignancy. Such patients for whom the natural history of the malignancy or its treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational schedule are eligible for this study, if approved in writing by the sponsor. Examples of such malignancies include basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and early-stage prostate cancer undergoing watchful waiting. Patients with a completely treated prior malignancy and no evidence of disease for >2 years prior to the first dose of ZE74-0282 are eligible.
13. Patient for whom MRI OR CT imaging of spleen can not be performed on the same imaging platform throughout the study