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 Kirsten rat sarcoma viral oncogene homolog (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.

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