First-in-human use of RLY-8161 in advanced NRAS-mutant solid tumors

A First-in-human Study of RLY-8161 for Treatment of Advanced NRAS-Mutant Melanoma and Other Solid Tumors

This Phase 1 trial will test whether RLY-8161, a drug that selectively targets NRAS mutations, is safe and shows anti-tumor activity in people with advanced NRAS-mutant melanoma or other NRAS-mutant solid tumors.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 35 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Relay Therapeutics, Inc. (industry)
• Locations: 4 sites (Boston, Massachusetts and 3 other locations)
• Trial ID: NCT07584226 on ClinicalTrials.gov

What this trial studies

This Phase 1, first-in-human, open-label multicenter trial tests RLY-8161, an NRAS-selective inhibitor, in participants with advanced NRAS-mutant melanoma and other NRAS-mutant solid tumors. Part 1 uses dose-escalation to identify a maximum tolerated dose or recommended Phase 2 dose with close monitoring of safety, tolerability, pharmacokinetics, and pharmacodynamics. Part 2 expands cohorts at the selected dose(s) to gather preliminary antitumor activity assessed by RECIST v1.1 and to explore biomarker effects. Enrollment requires documented oncogenic NRAS mutation, ECOG 0–1, measurable disease, and prior standard therapy failure, while patients with other driver mutations or prior RAS-MAPK pathway inhibitors are excluded.

Who should consider this trial

Good fit: Ideal candidates are adults with unresectable stage III/IV melanoma or other advanced solid tumors harboring a documented oncogenic NRAS mutation, ECOG 0–1, measurable disease, and disease refractory or intolerant to standard therapy.

Not a fit: Patients with activating KRAS/HRAS/BRAF or other driver mutations, prior treatment with RAS-MAPK pathway inhibitors, symptomatic CNS metastases, or very high LDH (for melanoma) are unlikely to be eligible or to benefit.

Why it matters

Potential benefit: If successful, RLY-8161 could provide a new targeted treatment option that shrinks or controls tumors driven by NRAS mutations for patients with few effective therapies.

How similar studies have performed: Direct, selective NRAS inhibitors are a novel approach with limited human data to date, and prior attempts targeting downstream MEK/ERK pathways showed only modest clinical benefit.

Eligibility criteria

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.

Where this trial is running

Boston, Massachusetts and 3 other locations

• Massachusetts General Hospital — Boston, Massachusetts, United States (RECRUITING)
• START Midwest, LLC — Grand Rapids, Michigan, United States (RECRUITING)
• Memorial Sloan Kettering Cancer Center — New York, New York, United States (RECRUITING)
• NEXT Virginia — Fairfax, Virginia, United States (RECRUITING)

Study contacts

• Study coordinator: Relay Therapeutics, Inc

Conditions: NRAS Mutation, NRAS-mutant Advanced Melanoma, NRAS-mutant Solid Tumors, NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS Q61H, NRAS G12D