Advanced Solid Tumor, Metastatic Solid Tumor, Non-small Cell Lung Cancers, SMARCA4 Gene Mutation
Conditions
Keywords
Advanced Solid Tumors, BRG1, BRM, Metastatic Solid Tumors, Non-Small Cell Lung Cancers, NSCLC, PRT3789, SMARCA2 Degrader, SMARCA4, Docetaxel
Brief summary
This is a Phase 1 dose-escalation study of PRT3789, a SMARCA2 degrader, in participants with advanced or metastatic solid tumors with loss of SMARCA4 due to truncating mutation and/or deletion. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) of PRT3789 monotherapy and in combination with docetaxel, describe any dose limiting toxicities (DLTs), define the dosing schedule, and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) to be used in subsequent development of PRT3789.
Detailed description
This is an open-label, multi-center, dose-escalation, first in human, Phase 1 study of PRT3789 as monotherapy and in combination with docetaxel, a SMARCA2 degrader, evaluating participants with advanced or metastatic solid tumors with loss of SMARCA4 due to truncating mutation and/or deletion. The study will evaluate escalating doses of PRT3789 until the MTD or RP2D is determined. Taking into account pharmacokinetic and pharmacodynamic data from the preceding dose levels, the dose may be escalated until a dose limiting toxicity is identified. Approximately 186 participants will be enrolled in monotherapy, dose escalation, backfill, and combination cohorts.
Interventions
DRUGPRT3789
PRT3789 will be administered by intravenous infusion
DRUGDocetaxel
Docetaxel will be administered by intravenous infusion
Sponsors
Prelude Therapeutics
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 * Histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy with any mutation of SMARCA4 (dose escalation and combination cohorts) and loss of function mutation of SMARCA4 (backfill cohorts) by local testing that have either progress on or ineligible for standard of care therapy * Must have measurable or non-measureable (but evaluable) disease per RECIST v1.1 for dose escalation and combination cohorts * Must have measureable diseases per RECIST v1.1 for backfill cohort * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Willing to provide either archival or fresh tumor tissue sample * Adequate organ function (hematology, renal, and hepatic)
Exclusion criteria
* Participants with solid tumors with known concomitant SMARCA2 mutation or loss of protein expression * Clinically significant or uncontrolled cardiac disease, uncontrolled electrolyte disorders, uncontrolled or symptomatic central nervous system (CNS) metastases or leptomeningeal disease * History of another malignancy within 3 years except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancies, or malignancies previously treated with curative intent and not on active therapy or expected to require treatment or recurrence during the study * Concurrent treatment with strong or moderate CYP3A4 inhibitor or inducer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicity (DLT) of PRT3789 monotherapy and in combination with docetaxel | Baseline through Day 21 | Dose limiting toxicities will be evaluated over the 21-day observation period |
| Safety and tolerability of PRT3789 monotherapy and in combination with docetaxel: AEs, CTCAE Assessments | Baseline through approximately 3 years | Safety and tolerability will be evaluated by incidence of DLTs, laboratory measurements, dose interruption, modification, and discontinuation due to adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) |
| Maximum tolerated dose (MTD)/ Recommended phase 2 dose (RP2D) of PRT3789 monotherapy and in combination with docetaxel | Baseline through approximately 3 years | The MTD/RP2D will be established for further investigation in participants with advanced solid tumors |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of PRT3789 monotherapy and in combination with docetaxel: Duration of response (DOR) | Baseline through approximately 3 years | Duration from time of first observed response (CR or PR) to the earliest date of disease progression, as assessed by the investigator per RECIST v1.1, or death due to any cause |
| Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Maximum observed plasma concentration | Baseline through approximately 3 years | Pharmacokinetics will be calculated including the maximum observed plasma concentration |
| Efficacy of PRT3789 monotherapy and in combination with docetaxel: Objective response rate (ORR) | Baseline through approximately 3 years | Best overall response of either complete response (CR) or partial response (PR), as assessed by the investigator per RECIST v1.1 |
| Pharmacodynamic effect of PRT3789 monotherapy and in combination with docetaxel: Target engagement | Baseline through approximately 3 years | Pharmacodynamic effect of PRT3789 monotherapy and in combination with docetaxel demonstrating target engagement by assessment of SMARCA2 protein in peripheral blood mononuclear cells (PBMCs) and tumor tissue |
| Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Area under the curve | Baseline through approximately 3 years | Pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC) |
| Efficacy of PRT3789 monotherapy and in combination with docetaxel: Progression-free survival (PFS) | Baseline through approximately 3 years | Duration from Day 1 to the earliest date of first disease progression, as assessed by the investigator per RECIST v1.1, discontinuation because of disease progression, or death due to any cause |
| Efficacy of PRT3789 monotherapy and in combination with docetaxel: Clinical benefit rate (CBR) | Baseline through approximately 3 years | Best overall response of CR, PR, or durable stable disease (24 weeks or longer duration), as assessed by the investigator per RECIST v1.1 |
Countries
France, Netherlands, Singapore, Spain, United States
Outcome results
None listed