Clinical Trial Finder

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) 3. Corrected QT interval using Fridericia's formula (QTcF) at Screening >450 ms based on triplicate average NOTE: criterion does not apply to patients with a right or left bundle branch block 4. LVEF <50% 5. Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible. 6. Patients receiving treatment with medications that are known to be strong inhibitors and/or inducers of cytochrome P450 (CYP)3A; substrates of CYP2C8, CYP2C9, and CYP3A with a narrow therapeutic index and sensitive substrates of CYP3A; 7. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

SEACRAFT-2 is a global, Phase III, open-label, randomized study 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 unresectable or metastatic NRAS mutant melanoma who have progressed on, or are intolerant to, an anti-programmed death-1 ligand 1 (PD 1/L1)-based regimen. The study will consist of 2 stages: dose optimization in Stage 1 and the Phase 3 portion in Stage 2. A total of approximately 470 eligible patients will be randomized to receive study drug(s) in this study across 2 stages.

Arms

Experimental: Stage 1 Dose selection Lead-in Arm 1

Naporafenib + Trametinib Naporafenib (ERAS-254) 100 mg administered orally twice daily (BID) Trametinib 1 mg once daily (QD)

Experimental: Stage 1 Dose selection Lead-in Arm 2

Naporafenib + Trametinib Naporafenib (ERAS-254) 400 mg administered orally twice daily (BID) Trametinib 0.5 mg once daily (QD)

Active Comparator: Stage 1 Dose selection Lead-in Arm 3 Trametinib monotherapy

Trametinib 2 mg once daily (QD)

Experimental: Stage 2 Arm A

Naporafenib + Trametinib Naporafenib (ERAS-254) BID oral administration with Trametinib QD at the dose selected in Stage 1

Active Comparator: Stage 2 Arm B - 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 PO QD

Interventions

Drug: - Naporafenib

Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor

Drug: - Dacarbazine

Dacarbazine IV - Day 1

Drug: - Temozolomide

Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle

Drug: - Trametinib

Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.