A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2)

Study Purpose

Stage 1: To select the optimal dose of naporafenib + trametinib to be studied in Stage 2. Stage 2: To compare progression free survival (PFS) and overall survival (OS) for patients with NRAS-mutant (NRASm) melanoma who are randomized to receive the combination of naporafenib + trametinib to that of patients who are randomized to physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy).

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 99 Years
Gender	All

More 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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06346067
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Erasca, Inc.
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Joyce Antal
Principal Investigator Affiliation	Clinical Development
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Recruiting
Countries	Australia, Canada, Czechia, France, Italy, Netherlands, Spain, United Kingdom, United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Advanced or Metastatic NRAS-mutant Melanoma

Additional Details

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 & Interventions

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.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Mayo Clinic - Arizona, Phoenix, Arizona

Status

Recruiting

Address

Mayo Clinic - Arizona

Phoenix, Arizona, 85054

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