Active Cancer NIHR-supported project Brain & Nervous System

A randomized, open-label Phase 3 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]

Funder NIHR (part of DHSC)
Recipient organisation NIHR Lancashire Clinical Research Facility
NIHR support Recorded as supported by this research centre
Period Jan 2025 — Apr 2028

In plain English

AI plain-English summary

Around 470 patients with advanced NRAS-mutant melanoma that has stopped responding to standard treatment will receive either a new two-drug combination or one of three existing therapies to see which works better. This matters because NRAS-mutant melanoma is a particularly aggressive form of skin cancer with limited treatment options once standard therapies fail. Current choices—dacarbazine, temozolomide, or trametinib alone—offer modest benefit. The experimental combination pairs naporafenib, which blocks a cancer-driving protein, with trametinib, which targets a different signalling pathway. The study first tests two dose levels of the combination to find the safest and most effective regimen, then compares the chosen dose against physician’s choice of therapy. If the combination proves superior, it could become a new standard treatment for patients with this specific mutation, extending survival and delaying disease progression where few options currently exist. The open-label design means both doctors and patients know which drug is being given, which speeds recruitment and reflects real-world clinical decision-making. The results will directly inform whether the NHS should adopt this targeted therapy for a defined patient group with an otherwise poor prognosis.

View original technical description
This study (SEACRAFT-2) is designed to assess the efficacy and safety of naporafenib administered with trametinib compared to physician’s choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy) in patients with melanoma with metastatic neuroblastoma rat sarcoma mutantion (NRASm) which cannot be removed with surgery who have progressed on, or are intolerant to, standard of care therapy.This is a study which will be conducted on a large number of patients for whom the drug is intended. It is an open-label study, which means that both the subjects and the investigators will have knowledge of the assigned treatment. A total of up to approximately 470 eligible patients will be randomized to receive study drug(s) in this study across 2 stages.Male and female adult (age ?18 years) patients with confirmed Stage III or Stage IV skin melanoma which cannot be removed with surgery and not reacting to local therapy are eligible to participate.The study participants will receive one of the following during Stage 1 of the study:1. Naporafenib 100 mg by mouth, twice daily, administered with trametinib 1 mg by mouth once daily 2. Naporafenib 400 mg by mouth, twice daily, administered with trametinib 0.5 mg by mouth once daily 3. Trametinib single drug therapy, 2 mg by mouth once dailyDuring Stage 2 of the study, participants will receive one of the following:1. Naporafenib twice daily administered with trametinib once daily at the dose selected in Stage 1.2. Physician’s choice:• Dacarbazine 1000 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle OR• Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle OR• Trametinib monotherapy, 2 mg by mouth once daily

Researchers

Ruth Board (Principal Investigator)

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