This is a first-in-human, open-label, multi-center Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of PRT12396 in participants with high-risk polycythemia vera (PV) and myelofibrosis (MF), and to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion (RDE\[s\]). The study consists of a dose-escalation phase followed by a dose-expansion phase to further evaluate selected dose level(s).
Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including contraception requirements), and other study procedures.
Confirmed diagnosis of PV or MF according to WHO 2016 or revised ICC/WHO 2022 criteria
Documented presence of a JAK2 V617 mutation
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
History of another malignancy within 3 years prior to enrollment, except for malignancy considered cured with low risk of recurrence.
Clinically significant anemia due to nutritional deficiency or hemolytic disorders.
Active or uncontrolled infection requiring systemic therapy or hospitalization.
Any other medical or psychiatric conditions that, in the Investigator's judgment, would increase risk or interfere with study participation or interpretation of results.
Sequential
PRT12396
DrugPRT12396 is an investigational oral capsule administered twice daily at the assigned dose level or RDE. Capsules are swallowed whole with water and may be taken one hour before or two hours after meals.
Dose limiting toxicity (DLT) of PRT12396
Incidence of dose limiting toxicities, defined according to protocol-specified criteria
Incidence and severity of Adverse events
Incidence and severity of treatment-emergent adverse events (AEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 6.0
Adverse Events Leading to Dose Modifications or Discontinuation
Incidence of AEs leading to dose reductions, dose interruptions, treatment discontinuations, and clinically significant laboratory abnormalities
Maximum tolerated dose (MTD) and Recommended Dose(s) for Expansion (RDE[s]) of PRT12396
Determination of the maximum tolerated dose (MTD) and recommended dose(s) for expansion (RDE\[s\]) based on evaluation of DLTs, safety, and tolerability data
Hematologic Response Rate (PV)
Proportion of participants with polycythemia vera (PV) achieving best overall hematologic response (complete hematologic response or partial hematologic response) from the overall response assessments by Investigator
Duration of Hematologic Response (PV)
Duration of hematologic response in PV participants, defined as the time from first documented response (best overall hematologic response) to disease progression or death, whichever comes first
Hematocrit Control Without Phlebotomy Requirements (PV)
Proportion of PV participants achieving and maintaining hematocrit control without phlebotomy, time to first phlebotomy, and frequency of phlebotomy
Spleen Response (MF)
Assessment of spleen response including proportion achieving protocol-specified reduction in spleen volume, time to spleen response, duration of spleen response, and reduction in palpable spleen length
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