Home › Trials › NCT06346067

Assessing naporafenib with trametinib for NRAS-mutant melanoma

A Randomized, Open-label Phase III Study in Patients With Previously Treated Unresectable or Metastatic NRAS Mutant Cutaneous Melanoma Comparing the Combination of Naporafenib + Trametinib to Physician's Choice of Therapy (Dacarbazine, Temozolomide or Trametinib Monotherapy) With a Dose Optimization lead-in [SEACRAFT-2]

Phase 3 Interventional Erasca, Inc. · NCT06346067

This study is testing if a new combination of two drugs, naporafenib and trametinib, can help people with advanced NRAS-mutant melanoma who haven't had success with other treatments.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment470 (estimated)
Ages18 Years to 99 Years
SexAll
SponsorErasca, Inc. Industry-sponsored
Drugs / interventionstrametinib
Locations59 sites (Phoenix, Arizona and 58 other locations)
Trial IDNCT06346067 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness and safety of naporafenib combined with trametinib in patients with advanced NRAS-mutant melanoma who have not responded to or are intolerant to previous anti-PD-1/L1 therapies. The study is divided into two stages: the first stage focuses on determining the optimal dosage of the combination treatment, while the second stage compares progression-free survival and overall survival rates between the combination therapy and standard physician's choice of treatment. Approximately 470 patients will be enrolled and randomized to receive either the study drugs or standard therapies.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with unresectable or metastatic NRAS-mutant melanoma who have progressed on or are intolerant to anti-PD-1/L1 therapies.

Not a fit: Patients with melanoma that does not have an NRAS mutation or those who have not received prior anti-PD-1/L1 therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with NRAS-mutant melanoma who have limited treatment choices.

How similar studies have performed: Other studies have shown promising results with similar combination therapies in melanoma, indicating potential for success in this approach.

Eligibility criteria

Show full inclusion / exclusion criteria 
Key Inclusion Criteria:

1. Willing and able to provide written informed consent
2. Age ≥ 18 years
3. Histologically or cytologically confirmed unresectable or metastatic cutaneous (includes acral) melanoma.
4. Documentation of an NRAS mutation (tumor tissue or blood) prior to first dose of study drug(s) as determined locally with an analytically validated assay in a certified testing laboratory.
5. Archival tumor tissue collected within 5 years prior to enrollment must be confirmed to be available at the time of Screening, which may be submitted before or after enrollment for exploratory biomarker analysis.
6. Must have received an anti-PD-1/L1 based regimen (monotherapy or combination). Patient must have documented disease progression either while receiving therapy or within 12 weeks of last dose of the most recent anti-PD-1/L1 based regimen; the patient is eligible if they have received other therapies between the most recent anti-PD-1/L1 based regimen and enrollment.
7. ECOG performance status 0, 1 or 2
8. Presence of at least 1 measurable lesion according to RECIST v1.1
9. Able to swallow oral medication.

Key Exclusion Criteria:

1. Patients with uveal or mucosal melanoma
2. Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor
3. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug(s) (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndrome)
5. LVEF \<50%
6. Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
7. Patients receiving treatment with herbal medicine known to cause liver toxicity, which cannot be discontinued 7 days prior to first dose of study drug(s) and for the duration of the study.
8. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

Where this trial is running

Phoenix, Arizona and 58 other locations

+9 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Advanced or Metastatic NRAS-mutant MelanomaMelanomaNRAS MutantCutaneous Melanoma
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.