Myelofibrosis (MF), Myeloproliferative Neoplasms (MPNs), Polycythemia Vera (PV), Post-Essential Thrombocythemia Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Primary Myelofibrosis (PMF)
Conditions
Keywords
High-Risk Polycythemia Vera (PV), Intermediate-1 or Intermediate-2 Risk Primary MF, High-Risk Primary MF, Post-Polycythemia Vera MF, Post-Essential Thrombocythemia MF, PRT12396, JAK Inhibitor, Myeloproliferative Neoplasms (MPN)
Brief summary
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).
Detailed description
This first-in-human, open-label, multi-center Phase 1 study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of PRT12396 in participants with high-risk polycythemia vera (PV) and myelofibrosis (MF). Eligible MF populations include participants with intermediate-1, intermediate-2, or high-risk primary MF, as well as post-polycythemia vera MF or post-essential thrombocythemia MF, with evidence of disease burden based on splenomegaly. The study is conducted in two parts: Part 1 (dose escalation) evaluates escalating oral doses of PRT12396 to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion (RDE\[s\]). Part 2 (dose expansion) enrolls additional participants at selected dose level(s) to further characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy of PRT12396 in the PV and MF populations. Approximately up to 100 participants are planned for enrollment across both parts of the study.
Interventions
DRUGPRT12396
PRT12396 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.
Sponsors
Prelude Therapeutics Incorporated
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 * Estimate life expectancy of ≥12 weeks per investigator assessment. * Negative serum or urine pregnancy test and agree to use contraception or maintain true abstinence. * Adequate organ function and bone marrow reserves (hematology, renal, and hepatic)
Exclusion criteria
* 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. * Clinically significant or uncontrolled medical conditions, including active infection or cardiovascular disease, that would increase risk or interfere with study participation. * Unresolved toxicity Grade \>1 from prior anticancer therapy, except for alopecia or peripheral neuropathy Grade ≤2. * Pregnancy or breastfeeding * Known sensitivity or contraindication to any component of study, or the excipients of study treatment. * Prior systemic therapy for PV or MF, prior or planned allogeneic hematopoietic stem-cell transplantation, recent major surgery, prior splenectomy or prior splenic irradiation, or use of hematopoietic growth factors within protocol-defined washout periods. * Use of strong or moderate cytochrome P450 (CYP) 3A4 inhibitor or inducer, sensitive CYP3A substrates with narrow therapeutic range, or acid-reducing agents that cannot be discontinued prior to study treatment. * Participation in another interventional clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicity (DLT) of PRT12396 | Through cycle 1 (4 weeks) | Incidence of dose limiting toxicities, defined according to protocol-specified criteria |
| Incidence and severity of Adverse events | Through study completion, an average of 2 years | 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 | Through study completion, an average of 2 years | 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 | Through study completion, an average of 2 years | Determination of the maximum tolerated dose (MTD) and recommended dose(s) for expansion (RDE\[s\]) based on evaluation of DLTs, safety, and tolerability data |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hematologic Response Rate (PV) | Through study completion, an average of 2 years | 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) | Through study completion, an average of 2 years | 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) | Through study completion, an average of 2 years | Proportion of PV participants achieving and maintaining hematocrit control without phlebotomy, time to first phlebotomy, and frequency of phlebotomy |
| Spleen Response (MF) | Through study completion, an average of 2 years | 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 |
| Change from Baseline in Hemoglobin (MF) | Through study completion, an average of 2 years | Change from baseline in hemoglobin levels in MF participants |
| Change from Baseline in Platelet Count (MF) | Through study completion, an average of 2 years | Change from baseline in platelet count in MF participants |
| Change from Baseline in Absolute Neutrophil Count (MF) | Through study completion, an average of 2 years | Change from baseline in absolute neutrophil count in MF participants |
| Transfusion Independence (MF) | Through study completion, an average of 2 years | Proportion achieving transfusion independence and duration of transfusion independence as defined by protocol criteria |
| Maximum Observed Plasma Concentration (Cmax) | Up to Cycle 4 Day 1 (each cycle is 4 weeks) | Maximum observed plasma concentration will be calculated using non-compartmental analysis |
| Time To Maximum Concentration (Tmax) | Up to Cycle 4 Day 1 (each cycle is 4 weeks) | Time to maximum concentration will be calculated using non-compartmental analysis |
| Area under the plasma concentration versus time curve (AUC) | Up to Cycle 4 Day 1 (each cycle is 4 weeks) | Area under the plasma concentration-time curve will be calculated using non-compartmental analysis |
| Terminal Elimination Half-life (T1/2) | Cycle 1 Day 1 | Terminal elimination half-life will be calculated using non-compartmental analysis |
| Steady State Trough Concentrations | Up to Cycle 4 Day 1 (each cycle is 4 weeks) | Steady state trough concentrations will be calculated using non-compartmental analysis |
| Clearance | Cycle 1 Day 1 | Clearance will be calculated using non-compartmental analysis |
| Accumulation | Up to Cycle 4 Day 1 (each cycle is 4 weeks) | Accumulation will be calculated using non-compartmental analysis |
| Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) | Through study completion, an average of 2 years | Patient-reported outcomes assessed using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), evaluated as change from baseline at protocol-specified time points. The MPN SAF TSS is a validated questionnaire in which individual symptoms are scored using a numeric rating scale ranging from 0 to 10, with 0 indicating no symptoms and 10 indicating the worst imaginable symptoms; higher scores indicate greater symptom severity. |
| Patient Global Impression of Change (PGI-C) | Through study completion, an average of 2 years | Participant reported outcomes assessed using the Patient Global Impression of Change (PGI-C), evaluated at protocol-specified time points. The PGI C is a global assessment scale in which participants rate their overall change in condition since baseline using a 7 point ordinal scale ranging from "very much improved" to "very much worse," with lower scores indicating improvement and higher scores indicating worsening of symptoms. |
Countries
Spain, United States
Contacts
CONTACTStudy Contact (Please Do Not Disclose Personal Information)
Outcome results
None listed