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-806 is an investigational, intravenous proteolysis-targeting chimera (PROTAC) designed to selectively degrade mutant KRAS G12D, an oncogenic driver common in pancreatic, colorectal, and some lung cancers. A first-in-human, open-label Phase 1/2 trial (ARV-806-101; NCT07023731) is recruiting adults with advanced solid tumors harboring KRAS G12D; the study includes dose escalation and dose expansion cohorts. As of October 7, 2025, no human efficacy or safety results have been reported. (arvinasmedical.com)

Mechanism of action

• Modality: Heterobifunctional small-molecule degrader (PROTAC).
• Target: KRAS G12D oncoprotein.
• Proposed mechanism: ARV-806 binds KRAS G12D and an E3 ubiquitin ligase to promote ubiquitination and proteasomal degradation of KRAS G12D, aiming to suppress downstream RAS/MAPK signaling. The sponsor has described selective KRAS G12D degradation and resultant pathway suppression in preclinical models; specific E3 ligase recruitment for ARV-806 has not been publicly specified. (arvinasmedical.com)

Context: Multiple peer‑reviewed studies have shown that KRAS G12D–targeted PROTACs can selectively degrade KRAS G12D and suppress MAPK signaling in preclinical systems, supporting the plausibility of this approach. These include CRBN‑ or VHL‑recruiting degraders (e.g., CH091138, RP03707, ZJK‑807) and other KRAS G12D degraders presented at AACR. These reports are not ARV‑806 but demonstrate the underlying strategy. (pubmed.ncbi.nlm.nih.gov)

Clinical development status

• Trial: Phase 1/2, open-label, sequential assignment (ARV‑806‑101; NCT07023731).
• Population: Adults with unresectable/metastatic solid tumors with KRAS G12D; Phase 2 includes a pancreatic ductal adenocarcinoma cohort.
• Dosing: Intravenous ARV‑806; schedules under evaluation include weekly or every 2 weeks.
• Key dates/status: IND clearance in 2025, enrollment initiated mid‑2025; recruiting at U.S. sites. No results posted as of August 2025 updates. (ir.arvinas.com)

Efficacy

• No human efficacy data (e.g., response rates) have been reported for ARV‑806 as of October 7, 2025. (fdaaa.trialstracker.net)

Preclinical sponsor disclosures state that ARV‑806 showed high potency and selectivity for KRAS G12D, with robust antitumor activity in KRAS G12D–mutant models; quantitative comparisons versus inhibitors and other degraders have been described in company filings. Independent peer‑reviewed data specific to ARV‑806 have not yet been published. (sec.gov)

Safety

• No human safety data for ARV‑806 have been reported to date. The ongoing Phase 1/2 trial’s primary objectives include safety, tolerability, and pharmacokinetics. (ichgcp.net)

Further reading

• Clinical trial registry entry (overview, eligibility, sites): NCT07023731. (ichgcp.net)
• Sponsor medical page for ARV‑806 (program summary, trial link). (arvinasmedical.com)
• Company updates noting IND clearance and trial initiation in 2025. (ir.arvinas.com)
• Examples of peer‑reviewed KRAS G12D degrader research (not ARV‑806):
• CH091138 (VHL‑based) preclinical characterization. (pubmed.ncbi.nlm.nih.gov)
• RP03707 (CRBN‑based) discovery/characterization. (pubmed.ncbi.nlm.nih.gov)
• ZJK‑807 (CRBN‑based) overcoming resistance. (pubmed.ncbi.nlm.nih.gov)
• AACR 2025 abstract on a KRAS G12D degrader (HDB‑82). (aacrjournals.org)

Notes: The sources above indicate that ARV‑806 is in early clinical testing with no publicly available human results yet; most detailed ARV‑806 information currently comes from the sponsor’s materials and regulatory filings rather than peer‑reviewed publications. (arvinasmedical.com)

Last updated: Oct 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