A Phase 1/2 Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of ARV-806 in Participants With KRAS G12D Mutated Advanced Solid Tumors

This is a study to evaluate the safety and potential anti-tumor activity of an investigational agent called ARV-806 in Adults with Advanced Cancer having a specific KRAS mutation. This is an open-label study which means that participants and study staff will know that all participants will receive ARV-806. Researchers think that ARV-806 can work by breaking down a specific protein with a mutation that is present in some tumors, which might help prevent or slow tumors from growing. This will be the first time ARV-806 will be used in people. The investigational drug will be given through a vein. This is called intravenous (IV) infusion. This study will include 2 parts. In Part A (Phase 1), different small groups of participants will receive lower to higher doses of ARV-806. Adults with advanced cancers having a specific KRAS mutation will be included. In Part B (Phase 2), participants will be assigned to receive one of up to 2 dose levels decided by the information from Part A. Part B will include participants with advanced pancreatic ductal cancer having a specific KRAS mutation.

Overview

ARV-766 is an investigational oral PROTAC® (Proteolysis Targeting Chimera) protein degrader developed by Arvinas, Inc., targeting the androgen receptor (AR) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). (ir.arvinas.com)

Mechanism of Action

ARV-766 is designed to selectively degrade the androgen receptor, including all clinically relevant resistance-driving point mutations of the AR ligand binding domain (LBD), such as L702H, T878, and H875 mutations. By degrading these AR variants, ARV-766 aims to overcome resistance mechanisms associated with current AR-targeted therapies. (ir.arvinas.com)

Efficacy

In a Phase 1/2 dose escalation and expansion trial involving men with mCRPC who had progressed on standard therapies, ARV-766 demonstrated promising activity:

• PSA Response: 42% of patients with AR LBD mutations achieved a ≥50% reduction in prostate-specific antigen (PSA) levels (PSA₅₀). Notably, 3 out of 5 patients with L702H mutations achieved PSA₅₀. (ir.arvinas.com)

• Tumor Response: Among four RECIST-evaluable patients with AR LBD mutations, one achieved a confirmed partial response, and another had an unconfirmed partial response. (ir.arvinas.com)

Safety

ARV-766 was well-tolerated in the trial:

• Adverse Events: The majority of treatment-related adverse events (TRAEs) were Grade 1 or 2, with no Grade ≥4 TRAEs and no dose-limiting toxicities reported. (ir.arvinas.com)

• Discontinuations and Dose Reductions: Low rates of discontinuation (1 of 47 patients) and dose reductions (2 of 47 patients) were observed. (ir.arvinas.com)

Further Reading

• Arvinas Announces Interim Data from the ARV-766 Phase 1/2 Dose Escalation and Expansion Trial

• Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer

• Androgen Receptor Inhibitors in Treating Prostate Cancer

Last updated: Aug 2025

Inclusion Criteria:

Part A:

* Histological or cytological diagnosis of unresectable or metastatic solid tumor malignancy, AND

* Must have evidence of KRAS G12D mutation in tumor tissue or blood (circulating tumor deoxyribonucleic acid \[ctDNA\]), AND

* Must have received prior standard-of-care (SOC) therapy appropriate for their type and stage of disease and have no other available treatment options with curative intent, or, in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate SOC therapy, AND

* Must have at least 1 measurable lesion

Part B:

* Histological or cytological diagnosis of unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC) with KRAS G12D mutation status confirmed by local testing of tumor tissue using a validated molecular or next-generation sequencing (NGS) testing, AND

* Must be willing to provide archival tumor tissue or willing to undergo pretreatment biopsy, AND

* Must have received at least one prior standard of care systemic therapy for PDAC (systemic therapy received in the neoadjuvant or adjuvant setting is allowed), AND

* Participants must have at least 1 measurable lesion

Part A / Part B:

* Eastern Cooperative Oncology Group performance status of 0 or 1,

* Participants with adequate organ function,

* Participants must accept and follow pregnancy prevention guidance.

Exclusion Criteria:

Part A / Part B:

* Active brain metastases

* Carcinomatous meningitis

* Uncontrolled hypertension despite optimal medical therapy

* Prior treatment with a KRAS G12D or a KRAS G12C targeting therapy (pan-KRAS inhibitor/degrader included)

* Participants with an inability to comply with listed prohibited treatments

* Systemic anticancer therapy within 2 weeks or 5 half-lives (whichever is shorter) or radiation therapy (excluding palliative radiation) within 2 weeks prior to the study intervention treatment. If the last immediate anticancer treatment contained an antibody-based agent(s), then an interval of 28 days or 5 half-lives (whichever is shorter) of the agent(s) is required prior to receiving the study intervention treatment.

* Standard 12-lead electrocardiogram that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results