A Study to Evaluate ARV-6723 Alone and With Pembrolizumab in Participants With Advanced Solid Tumors

Official title

A Phase 1/2 Open-label Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of ARV-6723 Administered as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors

Overview

This is a study to evaluate the safety and potential anti-tumor activity of an investigational drug called ARV-6723, in participants with advanced solid tumors. This is an open-label study which means that participants and study staff will know that all participants will receive ARV-6723. The investigational drug ARV-6723 will be given as an oral tablet on its own and also in combination with other drugs. Researchers think that ARV-6723 can help the body's immune system to better recognize, attack, and destroy cancer cells in adults with advanced solid tumors. ARV-6723 is an investigational drug, and this is the first time ARV-6723 will be used in humans. Depending on the treatment assignment, the investigational drug, ARV-6723, will be given as an oral tablet either on its own (monotherapy) or in combination with pembrolizumab, either through a vein (intravenously or IV) or through an injection beneath the skin (subcutaneously or SQ). This study will include multiple parts: In Part A1 (Phase 1a), different small groups of participants will receive lower to higher doses of ARV-6723 as monotherapy or in combination with standard-dose of pembrolizumab. In Part A2 (Phase 1b), two groups of participants with specific tumor indication(s) (TBD) will receive one of two doses selected based on information from Part A1. Details of Part B will be determined based on information generated from Part A.

Interventions

• Drug ARV-6723
  Oral daily dose of ARV-6723 at an assigned dose.
• Drug Pembrolizumab
  IV infusion or SQ injection Q3W at an assigned dose.
• Drug SOC
  Investigator's choice of SOC drugs.

Primary outcome measures

• Part A1: Number of Dose-Limiting Toxicities (DLTs) of ARV-6723 [Time frame: 21 days from first ARV-6723 administration]
• Part A1: Number of Participants With Adverse Events (AEs) [Time frame: From the first dose of ARV-6723 through at least 28 days after the last dose (up to approximately 4.7 years)]
• Part A2: Number of Participants With AEs [Time frame: From the first dose of ARV-6723 through at least 28 days after the last dose (up to approximately 4.7 years)]
• Part A2: Overall Response Rate (ORR) by computed tomography/magnetic resonance imaging (CT/MRI) Using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) Criteria Per Investigator Assessment [Time frame: Approximately 24 months]
• Part B: ORR by CT/MRI using RECIST v1.1 Criteria Per Investigator Assessment [Time frame: Approximately 24 months]

Secondary outcome measures (12)

• Part A1: Area Under the Plasma or Blood Concentration-Time Profile During a Dosing Interval (AUCtau) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Area Under the Plasma or Blood Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (Clast) (AUClast) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Maximum Plasma or Blood Concentration (Cmax) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Lowest Plasma Concentration Immediately Prior to Dosing(Ctrough) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Apparent Plasma Clearance at Steady State (CL/F) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Time to Maximum Observed Plasma Concentration (Tmax) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Apparent Volume of Distribution Divided by the Bioavailability of the Drug (Vz/F) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Terminal Elimination Half-Life (t½) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Effective Terminal Elimination Half-Life (t½) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Accumulation Ratio (Rac) [Time frame: At predefined intervals throughout the treatment period, up to approximately 9 months after first dose.]
• Part A1: Overall Response Rate (ORR) [Time frame: Approximately 24 months]
• Part A1: Disease Control Rate (DCR) [Time frame: Approximately 24 months]

Eligibility criteria

Inclusion criteria

Part A1 dose escalation and A2 dose optimization: Participants must meet all of the following criteria:

• Have a histologic or cytologic diagnosis of unresectable or metastatic solid tumor malignancy.
• Have previously received at least one prior therapy targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and/or another T-cell co-stimulatory or immune checkpoint pathway, in any treatment setting (including neoadjuvant or adjuvant).
• Have received prior SOC therapy appropriate for their disease type and stage and have no remaining available treatment options with established clinical benefit; or, in the opinion of the investigator, are unlikely to tolerate or derive clinically meaningful benefit from appropriate SOC therapy; or have declined SOC therapy.
• Participants must have demonstrated radiographic progression and have at least 1 measurable lesion per RECIST v1.1 that has not been previously irradiated or has demonstrated progression of disease since radiation therapy.
• ECOG PS 0 or 1 or equivalent. Participants with ECOG PS 2 may be considered upon discussion with the Sponsor Medical Monitor.
• Participants with adequate organ function.

Exclusion criteria

Exclusion Criteria (Part A)

• Active brain metastases (new lesions identified on imaging, existing lesions showing progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)/imaging characteristics or by clinical criteria, lesions requiring active interventions for symptom control).
• Carcinomatous meningitis.
• Known or suspected hypersensitivity to ARV-6723 or pembrolizumab or any of its excipients.
• Active autoimmune disease or history of autoimmune diseases that may relapse.
• History of severe immune-related adverse events (irAE) attributed to prior anti-PD-1/anti-CTLA-4/anti-LAG-3 therapy.
• Prior treatment with any HPK1-targeting agent
• Systemic anti-cancer therapy or radiation therapy within 14 days prior to study treatment start.
• Current use of any prohibited concomitant medication(s) or herbal supplements which cannot be discontinued, prior to start of study intervention and for the duration of the study.
• Baseline (screening) standard 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• Clinical Trial Site — Huntersville
• Clinical Trial Site — San Antonio
• Clinical Trial Site — Fairfax

Identifiers

NCT: NCT07749586 · ARV-6723-101 · 2026-525614-57-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗