NCT07529951 Study of ZE74-0282 in Patients With JAK2 V617F- or Calreticulin-Mutated Hematologic Disorders

Eligibility & Interventions

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What to Expect as a Participant

You will actively receive the study intervention — which may be a drug, biologic, device, or procedure.

Phase 1 is the earliest stage of human testing — safety and dosage are the primary focus. Visits are frequent and medical supervision is intensive. You will be among the first people to receive this treatment.

This trial targets 60 participants in total. It began in 2026-06-01 with a primary completion date of 2028-09-30.

Brief Summary

This Phase 1 study will evaluate ZE74-0282 in adults with polycythemia vera or myelofibrosis with a JAK2 V617F or calreticulin mutation who have received prior therapy or have declined prior therapy. The main objectives are to determine the maximum tolerated dose and/or recommended Phase 2 dose, characterize safety and tolerability, describe pharmacokinetics and pharmacodynamics, and assess preliminary anti-disease activity. In Part 1, participants will receive escalating oral doses of ZE74-0282 using a Rolling-6 dose-finding design. Once-daily and twice-daily dosing schedules may be evaluated, including protocol-specified step-up dosing. In Part 2, participants will be randomized to one of two selected expansion doses to further evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary activity. ZE74-0282 is administered as an oral powder for suspension in continuous 28-day treatment cycles.

Eligibility 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 of a JAK2 V617F- or calreticulin-mutated hematologic diagnosis, with later confirmation using the ipsogen JAK2 RGQ PCR Kit for JAK2 V617F or a validated NGS assay for calreticulin mutation, and has received prior therapy or has declined prior therapy. Specifics for disease include: 1. Myelofibrosis (WHO and ICC diagnostic criteria) having received a JAK2 inhibitor or having declined it\*, spleen volume of \>=450 cm3 (by CT or MRI) and MFSAF v4.0 TSS \>10 or \>=2 of 7 MFSAF v4.0 symptom item scores \>3 at Screening. 2. Polycythemia vera (WHO and ICC diagnostic criteria) with standard therapy having received hydroxyurea, ruxolitinib, and/or interferon (or declined it)\* and MPN-SAF TSS \>10 or \>=3 of 10 MPN-SAF TSS item scores \>3 at Screening. * If an approved FDA therapy for these diagnoses is not approved in the local vicinity preventing the patient from having access to it, this eligibility criterion will not apply. For patients who are eligible because they have declined an approved standard-of-care therapy, the Investigator must document in the source records that approved treatment options, including their expected benefits and risks, were discussed with the patient before enrollment. The Investigator must also document that the patient understands that ZE74-0282 is investigational, is not approved in Australia or elsewhere, may not provide benefit, and is not a proven substitute for approved therapy. Understanding should be assessed using open questions/teach-back during the consent discussion. A patient must not be enrolled on the basis of declining approved therapy unless the Investigator is satisfied that the decision is voluntary, informed, and not due to coercion or misunderstanding. 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: 1. ANC \>=1 x 10\^9/L. 2. Platelets \>=50 x 10\^9/L (may not be transfused to meet eligibility). 3. Hemoglobin \>=8 g/dL (80 g/L) (may be transfused). 6. Organ function/reserve as per the following laboratory criteria: 1. Hepatic: AST \<=2.5 x ULN, 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 with approval of the medical monitor. If due to disease, higher values may be approved after discussion with the 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 Fridericia (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 study treatment. They must also refrain from sperm donation from the 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 study treatment. They must also refrain from ova donation from the 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 requiring 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 to the first dose of ZE74-0282; an investigational agent is one for which there is no approved indication by the United States 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 the first dose of study treatment. 5. Systemic antineoplastic therapy or radiotherapy less than 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, or 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 interpretation of the study results. 8. 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 study treatment should not be enrolled. 10. Patients with uncontrolled infection requiring parenteral therapy shall not be enrolled until the infection is treated and brought under control (to a minimum 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. 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 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. Patients for whom MRI or CT imaging of the spleen cannot be performed using the same imaging modality throughout the study are not eligible for participation.

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