This is a Phase 1 first-in-human, open-label multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of RLY-8161, an NRAS-selective inhibitor, in participants with advanced NRAS-mutant melanoma and other solid tumors.

This is a Phase 1 first-in-human, open-label multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of RLY-8161, an NRAS-selective inhibitor, in participants with advanced NRAS-mutant melanoma and other solid tumors. This study consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2).

Part 1, dose escalation will explore multiple ascending doses of RLY-8161 in participants with any advanced NRAS-mutant solid tumor until maximum tolerated dose is reached or one or more recommended Phase 2 dose (RP2D) is identified.

Part 2, dose expansion will be at the RP2D(s) identified in Part 1 in NRAS-mutant solid tumors.

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Histologically confirmed diagnosis of unresectable Stage III or IV melanoma or other solid tumor.
• Disease is refractory to standard therapy (including targeted therapy), participant is intolerant of standard therapy, or participant has declined standard therapy.
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• One or more documented primary oncogenic NRAS mutation(s).

Exclusion Criteria:

• Known activating KRAS, HRAS, or BRAF mutation or known alterations in other driver oncogenes.
• Prior treatment with ERK, MEK, RAF, or RAS targeting agents or any agent whose mechanism of action is to inhibit the RAS-MAPK pathway.
• For participants with melanoma: lactate dehydrogenase (LDH) >2×ULN.
• Central nervous system (CNS) metastases that are associated with progressive neurologic symptoms or require ongoing corticosteroids to control the CNS disease.