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PRT3789

PRT3789 is an experimental cancer medicine being studied for people with advanced or metastatic solid tumors that have a SMARCA4 gene change. Current studies are testing PRT3789 alone and together with other cancer treatments like docetaxel chemotherapy or pembrolizumab (KEYTRUDA®) immunotherapy. These trials mainly look at safety (side effects), the best dose to use, and early signs of how well the treatment may work. [1][2]

Table of Contents

What is PRT3789?

In these clinical trials, PRT3789 is described as a SMARCA2 degrader (also called a “SMARCA2 targeted protein degrader”), meaning it is designed to reduce the SMARCA2 protein in the body. The studies focus on cancers that have problems with SMARCA4, such as loss of SMARCA4 caused by certain harmful mutations or deletion, because these cancers may depend on related pathways involving SMARCA2. [1][2]

Who is being studied in the PRT3789 trials?

The trials enroll people with advanced solid tumor or metastatic solid tumor and a SMARCA4 Gene Mutation. “Advanced” generally means the cancer is far along, and “metastatic” means it has spread to other parts of the body. [1][2]

Specific cancers listed across the studies include Non-small Cell Lung Cancers (NSCLC) and Esophageal Cancer (in the Phase 2 combination study). These trials are not limited to only one tumor type, as long as the tumor is a solid tumor and has the SMARCA4 mutation criteria described. [1][2]

How PRT3789 is given (route and schedules)

PRT3789 is given by intravenous infusion, meaning the medication is delivered directly into a vein. This method allows the study team to control how the drug is administered and to collect timed blood samples for pharmacokinetic testing. [1]

In the PRT3789 plus pembrolizumab study, PRT3789 is administered once weekly for 3 weeks, and pembrolizumab is given at 200 mg by IV infusion over 30 minutes every 3 weeks. This describes how the combination schedule is structured in that trial. [2]

Phase 1 trial: PRT3789 alone and with docetaxel (NCT05639751)

This is a Phase 1, open-label, multi-center, first-in-human, dose-escalation study of PRT3789 given alone and also given together with docetaxel. Phase 1 trials mainly focus on learning about safety and finding an appropriate dose to use in later studies. [1]

The study includes participants with advanced or metastatic solid tumors that have loss of SMARCA4 due to a truncating mutation and/or deletion. “Truncating mutation” is a gene change that can make a protein too short to work properly, and “deletion” means genetic material is missing. [1]

The trial evaluates increasing doses of PRT3789 until the study determines the maximum tolerated dose or selects a recommended phase 2 dose. The decision is based on safety findings (including dose-limiting toxicities) along with PK and PD information from earlier dose levels. [1]

The trial plans to enroll approximately 186 participants across monotherapy dose escalation, backfill, and combination cohorts. “Cohorts” are subgroups of participants treated in a specific way (for example, a particular dose or combination). [1]

Phase 2 trial: PRT3789 with pembrolizumab/KEYTRUDA® (NCT06682806)

This is a Phase 2, open-label, multi-center study testing PRT3789 in combination with pembrolizumab in people with advanced, recurrent, or metastatic solid tumors with a SMARCA4 mutation. Phase 2 trials continue to evaluate safety and look more closely at how well the treatment works. [2]

The study describes PRT3789 as a first-in-class SMARCA2 targeted protein degrader and pembrolizumab as a potent humanized IgG4 monoclonal antibody that binds to the PD-1 receptor. “Monoclonal antibody” is a type of immune-based medicine designed to attach to a specific target in the body. [2]

This trial has two parts: Part 1 is a safety run-in to establish the PRT3789 dose used with pembrolizumab, and Part 2 is the main study. The main study’s primary endpoints include objective response rate and duration of response based on investigator assessment using RECIST v1.1. [2]

The study expects to enroll about 46 to 60 patients across Part 1 and Part 2, depending on the selected/cleared dose from the safety run-in. [2]

What outcomes do these trials measure?

Across the studies, a major focus is identifying dose-limiting toxicities and measuring safety using adverse event reporting and CTCAE grading. In the Phase 1 trial, dose-limiting toxicities are evaluated during a 21-day observation period. [1][2]

To look for early signs that treatment may help, the trials measure objective response rate using RECIST v1.1, where responses include complete response and partial response. These are scan-based categories that describe whether tumors disappear or shrink by a defined amount. [1][2]

The studies also track how long benefits may last using outcomes like duration of response and progression-free survival. The Phase 1 trial includes progression-free survival and clinical benefit rate (including durable stable disease for 24 weeks or longer), and the Phase 2 trial includes progression-free survival and overall survival. [1][2]

  • Clinical benefit can include tumor shrinkage (CR/PR) or stable disease that lasts at least 24 weeks, which means the cancer does not grow significantly for that period. [1][2]

  • Progression-free survival is the time from starting the study treatment until the cancer is documented to worsen (progress) or the patient dies, based on the study rules. [1][2]

  • Overall survival (included in the Phase 2 trial) is the time from first dose until death from any cause. [2]

Safety monitoring and side effect grading

Both trials evaluate safety by recording adverse events and grading them using NCI CTCAE. CTCAE is a standardized way to classify and grade side effects so results can be compared across patients and studies. [1][2]

Safety is also assessed by whether side effects cause dose interruption, dose modification, or stopping treatment. In the Phase 1 trial, this is part of safety and tolerability evaluation over the study duration; in the Phase 2 trial, dose modification due to adverse events is a specific outcome. [1][2]

The Phase 2 combination study additionally lists “key clinical laboratory parameters” that are monitored for changes and CTCAE grade shifts, including ALT, AST, bilirubin, creatinine, hemoglobin, platelet count, neutrophil count, lymphocyte count, and leukocyte count. These labs help the team watch for signs of organ stress (like liver or kidney changes) and blood/immune cell changes. [2]

PK and PD: how researchers study drug levels and drug effects

Both studies measure pharmacokinetics (PK), which describes drug levels in the blood over time. Reported PK outcomes include the maximum observed plasma concentration and area under the curve, and in the Phase 2 trial also include time of maximum concentration and half-life using standard non-compartmental methods. [1][2]

The Phase 1 study also evaluates pharmacodynamics (PD) and target engagement by assessing SMARCA2 protein in PBMCs (immune cells taken from blood) and in tumor tissue. This is intended to show whether PRT3789 is affecting its intended target in the body. [1]

Topic What the trials say
Drug being studied PRT3789 (a SMARCA2 degrader / SMARCA2 targeted protein degrader)
Who is it for (in these trials) People with advanced or metastatic solid tumors with SMARCA4 mutation/loss (including NSCLC; and in one study, esophageal cancer)
How it is given IV infusion; in the pembrolizumab combination study, once weekly for 3 weeks
Combinations studied PRT3789 alone; PRT3789 + docetaxel (Phase 1); PRT3789 + pembrolizumab/KEYTRUDA® (Phase 2)
Main safety goals DLTs, adverse events graded by NCI CTCAE, dose interruptions/modifications/discontinuations; establishing MTD/RP2D (Phase 1) and combination dose (Phase 2 run-in)
Main activity (effectiveness) goals ORR and DOR (both studies), plus PFS and clinical benefit measures; OS is included in the Phase 2 study
Drug measurements PK (Cmax, AUC; also Tmax and half-life in the Phase 2 study) and PD/target engagement (SMARCA2 protein in PBMCs and tumor tissue in Phase 1)
Study size (approx.) Phase 1: ~186 participants; Phase 2: ~46–60 participants

FAQ

  • What is PRT3789 and how is it described in these studies? PRT3789 is described as a SMARCA2 degrader (also called a SMARCA2 targeted protein degrader). This means it is designed to reduce (degrade) the SMARCA2 protein in the body. It is being studied in people whose cancers have loss of SMARCA4 due to specific harmful (truncating) mutations and/or gene deletion.
  • What cancers are being studied with PRT3789? The trials include people with advanced or metastatic solid tumors that have a SMARCA4 mutation. Specific examples listed include non-small cell lung cancer (NSCLC) and esophageal cancer (in the combination study with pembrolizumab).
  • How is PRT3789 given in these clinical trials? In these trials, PRT3789 is given by intravenous (IV) infusion, meaning it is delivered into a vein. In the pembrolizumab combination study, PRT3789 is given once weekly for 3 weeks.
  • What combinations with PRT3789 are being tested? One Phase 1 study tests PRT3789 alone and in combination with docetaxel (a chemotherapy medicine), both given by IV infusion. Another Phase 2 study tests PRT3789 together with pembrolizumab (KEYTRUDA®), an immunotherapy medicine that targets the PD-1 receptor.
  • What are the main goals researchers measure in these trials? Key goals include safety and tolerability (how manageable side effects are), dose-limiting toxicities (DLTs), and finding the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Researchers also look for signs of benefit such as objective response rate (tumor shrinkage measured by RECIST v1.1), duration of response, progression-free survival, and other outcomes, plus pharmacokinetics (how the drug moves through the body) and pharmacodynamics/target engagement (whether it affects SMARCA2 protein levels in blood cells and tumor tissue).

Ongoing Clinical Trials on PRT3789

  • Study of PRT3789 and Pembrolizumab for Patients with Advanced Solid Tumors, Esophageal Cancer, or NSCLC with SMARCA4 Mutation

    Not recruiting

    1 1 1
    Investigated drugs:
    France Germany Spain

Glossary

  • Advanced solid tumor: A cancer that started in an organ (a 'solid' cancer, not a blood cancer) and is far along, often meaning it is difficult to remove with surgery or has grown significantly. These trials include people with advanced disease.
  • Metastatic: Cancer that has spread from where it started to other parts of the body.
  • SMARCA4 mutation (including truncating mutation) and/or deletion: A change in the SMARCA4 gene. A 'truncating' mutation is a type of harmful change that can make a protein too short to work properly. A 'deletion' means part or all of the gene is missing. The Phase 1 trial focuses on tumors with loss of SMARCA4 from these types of changes.
  • SMARCA2 degrader / SMARCA2 targeted protein degrader: A drug designed to lower (degrade) the SMARCA2 protein in cells. PRT3789 is described this way in both studies.
  • Phase 1 study: An early clinical trial stage mainly focused on safety, side effects, and finding the best dose. The Phase 1 PRT3789 study includes dose-escalation to find safe dose levels.
  • Phase 2 study: A clinical trial stage that continues to monitor safety and also looks more closely at how well the treatment works in a specific group of patients. The Phase 2 study tests PRT3789 with pembrolizumab.
  • Open-label: A study design where both the research team and participants know which treatment is being given (there is no blinding).
  • Multi-center: A study run at more than one hospital or clinic.
  • Dose-escalation: A method where small groups of participants receive increasing doses to help find the safest dose and understand side effects.
  • Dose-limiting toxicity (DLT): A side effect serious enough that it prevents increasing the dose further. In the Phase 1 trial, DLTs are evaluated during a 21-day observation period; in the Phase 2 trial they are a key measure during the safety run-in.
  • Maximum tolerated dose (MTD): The highest dose that can be given with acceptable side effects.
  • Recommended Phase 2 dose (RP2D): The dose chosen (often based on safety plus drug level and biologic effect data) to move forward into Phase 2 testing.
  • Safety and tolerability: Safety refers to the type and severity of side effects. Tolerability means how manageable those side effects are, including whether people need dose interruptions, dose changes, or stopping treatment.
  • Adverse event (AE): Any unwanted medical problem that happens during a study, whether or not it is clearly caused by the study drug.
  • NCI CTCAE: A standard system (National Cancer Institute Common Terminology Criteria for Adverse Events) used to grade and report side effects in clinical trials.
  • Objective response rate (ORR): The percentage of patients whose tumors shrink by a defined amount. In these trials, ORR includes complete response (CR) or partial response (PR) measured using RECIST v1.1.
  • Complete response (CR): Disappearance of all signs of cancer on scans and exams, based on the study’s response rules (RECIST v1.1).
  • Partial response (PR): A meaningful decrease in tumor size on scans, based on the study’s response rules (RECIST v1.1).
  • RECIST v1.1: A standardized set of rules using imaging (like CT scans) to measure tumors and define responses such as CR, PR, and progression.
  • Progression-free survival (PFS): The time from starting treatment until the cancer grows/spreads (progresses) or the patient dies from any cause, depending on the study definition.
  • Duration of response (DOR): How long a tumor response (CR or PR) lasts before the cancer grows again or the patient dies from any cause, depending on the study definition.
  • Clinical benefit rate / clinical benefit response: A measure that includes patients who have CR or PR, or who have stable disease that lasts at least 24 weeks (durable stable disease).
  • Overall survival (OS): The time from the first dose in the study until death from any cause.
  • Pharmacokinetics (PK): How the body absorbs, distributes, and clears a drug. These studies measure values such as maximum concentration (Cmax), area under the curve (AUC), time to maximum concentration (Tmax), and half-life (T1/2).
  • Maximum observed plasma concentration (Cmax): The highest measured level of the drug in the blood (plasma) after dosing.
  • Area under the curve (AUC): A summary measure of total drug exposure in the blood over time.
  • Tmax: The time it takes after dosing to reach the highest blood level (Cmax).
  • Half-life (T1/2): The time it takes for the blood level of a drug to drop by about half.
  • Pharmacodynamics (PD) / target engagement: How the drug affects the body and whether it hits its intended target. In the Phase 1 study, target engagement is assessed by measuring SMARCA2 protein in PBMCs and tumor tissue.
  • Peripheral blood mononuclear cells (PBMCs): A group of immune cells taken from a blood sample. The trial measures SMARCA2 protein in these cells to see if PRT3789 is affecting its target.
  • Docetaxel: A chemotherapy drug given by IV infusion. One trial studies PRT3789 alone and with docetaxel.
  • Pembrolizumab (KEYTRUDA®): An immunotherapy drug described as a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor. It is given by IV infusion (200 mg over 30 minutes every 3 weeks) in the Phase 2 combination trial.
  • PD-1 receptor: A protein on immune cells that can act like a 'brake' on the immune response. Pembrolizumab binds PD-1 as part of its mechanism described in the study.
  • Intravenous (IV) infusion: A way to give medicine directly into a vein over a period of time.

References