Breast Cancer, Hormone-receptor-positive Breast Cancer, HER2-negative Breast Cancer, HR-positive Breast Cancer, HR+/HER2- Breast Cancer, Locally Advanced Breast Cancer, Metastatic Breast Cancer
Conditions
Keywords
Breast Cancer, Hormone-receptor-positive Breast Cancer, HER2-negative Breast Cancer, HR-positive Breast Cancer, HR+/HER2- Breast Cancer, Locally Advanced Breast Cancer, Locally Advanced or Metastatic HR+/HER2- Breast Cancer, Metastatic Breast Cancer, PRT13722, Abemaciclib, Fulvestrant, Imlunestrant, KAT6A
Brief summary
This first-in-human, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of PRT13722, an oral KAT6A protein degrader, in adults with locally advanced or metastatic Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. PRT13722 will be evaluated as monotherapy and in combination with fulvestrant, abemaciclib plus fulvestrant, or imlunestrant to determine recommended dose(s) for expansion (RDE) and evaluate preliminary clinical activity.
Detailed description
This is a first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of PRT13722, a selective oral KAT6A protein degrader, in adults with locally advanced or metastatic HR-positive, HER2-negative breast cancer. The study will evaluate the safety, tolerability, dose-limiting toxicities, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of PRT13722 administered as monotherapy and in combination with fulvestrant, abemaciclib plus fulvestrant, or imlunestrant to determine recommended dose(s) for expansion and evaluate preliminary clinical activity. The study is conducted in three parts: Part 1: Monotherapy dose escalation and backfill cohorts. Part 2: Combination dose-escalation cohorts with fulvestrant, abemaciclib plus fulvestrant, and imlunestrant. Part 3: Combination dose-expansion cohorts to further evaluate safety and preliminary efficacy at the selected dose levels. Up to approximately 240 participants are planned for enrollment across the three parts of the study.
Interventions
DRUGPRT13722
PRT13722 is an investigational oral drug administered once daily at the assigned dose level.
DRUGFulvestrant
Fulvestrant is an approved selective estrogen receptor degrader (SERD) administered on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, then once monthly as an intramuscular injection into the buttocks (gluteal muscle).
DRUGAbemaciclib
Abemaciclib is an approved oral cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor administered twice daily and used in combination with endocrine therapy for HR-positive, HER2-negative breast cancer.
DRUGImlunestrant
Imlunestrant is an approved oral SERD administered once daily.
Sponsors
Prelude Therapeutics Incorporated
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Sequential Assignment
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. * histological or cytological diagnosis of locally advanced or metastatic HR-positive/HER2-negative breast cancer * Disease progression following prior standard therapy and eligible for the assigned study cohort * Measurable or evaluable disease per RECIST v1.1 * Willingness to provide tumor tissue for biomarker analyses * Eastern Cooperative Oncology Group performance status of 0-1 * Negative serum or urine pregnancy test and agree to use highly effective contraception or maintain true abstinence. * Adequate organ function and bone marrow reserves (hematology, renal, and hepatic)
Exclusion criteria
* Untreated, symptomatic, or unstable brain metastases * Symptomatic visceral disease at risk of imminent life-threatening complications * Uncontrolled infection or significant concurrent medical conditions * Clinically significant cardiovascular disease or prolonged QT syndrome * Pregnancy or breastfeeding * Prior treatment with a KAT6-targeting agent * Recent anticancer therapy, radiotherapy, or major surgery * Use of prohibited concomitant medications, including strong CYP3A4 inhibitors or inducers, proton pump inhibitors, P-gp inhibitors or inducers, and breast cancer resistance protein inhibitors * Participation in another interventional clinical study * Any condition that would interfere with study participation or evaluation of study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicity of PRT13722 (Parts 1A and 2) | Through cycle 1 (28 days) | Incidence of dose limiting toxicities, defined according to protocol-specified criteria |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of PRT13722 as monotherapy and in combination (Parts 1A and 2) | Through study completion, an average of 2 years | Safety and tolerability assessed by the number of participants with treatment-emergent adverse events, serious adverse events, adverse events leading to dose modification, treatment interruption, or treatment discontinuation, and clinically significant laboratory abnormalities. Adverse events and selected laboratory abnormalities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 6.0 |
| Preliminary Antitumor Activity: Objective Response Rate (Parts 1B and 3) | Through study completion, an average of 2 years | Proportion of patients with best overall response of either complete response or partial response, as assessed by the investigator per RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preliminary Antitumor Activity: Objective Response Rate (Parts 1A and 2) | Through study completion, an average of 2 years | Proportion of patients with best overall response of either complete response or partial response, as assessed by the investigator per RECIST v1.1 |
| Duration of Response | Through study completion, an average of 2 years | Time from first documented response to disease progression as assessed by the investigator per RECIST v1.1, or death, whichever comes first. |
| Clinical Benefit Response | Through study completion, an average of 2 years | Proportion of patients with a best overall response of complete response, partial response, or durable stable disease (24 weeks or longer), as assessed by the investigator per RECIST v1.1 |
| Progression-Free Survival | Through study completion, an average of 2 years | Time from the date of first dose of investigational product to the date of first documented disease progression, as assessed by the investigator per RECIST v1.1, or death due to any cause |
| Overall Survival | Through study completion, an average of 2 years | Time from the date of first dose of investigational product to death due to any cause |
| Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] of PRT13722 as Monotherapy and in Combination (Parts 1B and 3) | Through study completion, an average of 2 years | Safety and tolerability will be evaluated by incidence of adverse events leading to dose modifications, treatment interruptions, treatment discontinuations, and clinically significant laboratory abnormalities graded according to NCI CTCAE, Version 6.0 |
| Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1 (each cycle is 28 days) | Maximum observed plasma concentration will be calculated using non-compartmental analysis |
| Time To Maximum Concentration (Tmax) | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1 (each cycle is 28 days) | Time to maximum concentration will be calculated using non-compartmental analysis |
| Terminal Elimination Half-life (T1/2) | Cycle 1 Day 1 (each cycle is 28 days) | Terminal elimination half-life will be calculated using non-compartmental analysis |
| Area under the plasma concentration versus time curve (AUC) | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1 (each cycle is 28 days) | Area under the plasma concentration-time curve will be calculated using non-compartmental analysis |
| Steady State Trough Concentrations | Cycle 1 Day 15, and Cycle 2 Day 1 (each cycle is 28 days) | Steady state trough concentrations will be calculated using non-compartmental analysis |
Contacts
CONTACTStudy Contact (Please Do Not Disclose Personal Information)
Outcome results
None listed