A Phase 1 Study of PRT12396 in Participants With Select Myeloproliferative Neoplasms

Phase 1RecruitingNCT07469891

Prelude Therapeutics100 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

100

Conditions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 0-2 * 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.

Outcomes

Primary Outcomes

Dose limiting toxicity (DLT) of PRT12396

Incidence of dose limiting toxicities, defined according to protocol-specified criteria

Time frame: Through cycle 1 (4 weeks)

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

Time frame: Through study completion, an average of 2 years

Adverse Events Leading to Dose Modifications or Discontinuation

Incidence of AEs leading to dose reductions, dose interruptions, treatment discontinuations, and clinically significant laboratory abnormalities

Time frame: Through study completion, an average of 2 years

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

Time frame: Through study completion, an average of 2 years

Secondary Outcomes

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

Time frame: Through study completion, an average of 2 years

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

Time frame: Through study completion, an average of 2 years

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

Time frame: Through study completion, an average of 2 years

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

Time frame: Through study completion, an average of 2 years

Change from Baseline in Hemoglobin (MF)

Change from baseline in hemoglobin levels in MF participants

Time frame: Through study completion, an average of 2 years

Change from Baseline in Platelet Count (MF)

Change from baseline in platelet count in MF participants

Time frame: Through study completion, an average of 2 years

Change from Baseline in Absolute Neutrophil Count (MF)

Change from baseline in absolute neutrophil count in MF participants

Time frame: Through study completion, an average of 2 years

Transfusion Independence (MF)

Proportion achieving transfusion independence and duration of transfusion independence as defined by protocol criteria

Time frame: Through study completion, an average of 2 years

Maximum Observed Plasma Concentration (Cmax)

Maximum observed plasma concentration will be calculated using non-compartmental analysis

Time frame: Up to Cycle 4 Day 1 (each cycle is 4 weeks)

Time To Maximum Concentration (Tmax)

Time to maximum concentration will be calculated using non-compartmental analysis

Time frame: Up to Cycle 4 Day 1 (each cycle is 4 weeks)

Area under the plasma concentration versus time curve (AUC)

Area under the plasma concentration-time curve will be calculated using non-compartmental analysis

Time frame: Up to Cycle 4 Day 1 (each cycle is 4 weeks)

Terminal Elimination Half-life (T1/2)

Terminal elimination half-life will be calculated using non-compartmental analysis

Time frame: Cycle 1 Day 1

Steady State Trough Concentrations

Steady state trough concentrations will be calculated using non-compartmental analysis

Time frame: Up to Cycle 4 Day 1 (each cycle is 4 weeks)

Clearance

Clearance will be calculated using non-compartmental analysis

Time frame: Cycle 1 Day 1

Accumulation

Accumulation will be calculated using non-compartmental analysis

Time frame: Up to Cycle 4 Day 1 (each cycle is 4 weeks)

Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

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.

Time frame: Through study completion, an average of 2 years

Patient Global Impression of Change (PGI-C)

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.

Time frame: Through study completion, an average of 2 years

A Phase 1 Study of PRT12396 in Participants With Select Myeloproliferative Neoplasms

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts