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

NCT06346067 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: ERAS-254-02
• Study Type: interventional
• Target: 78
• Locations: 9 countries
• Sites: 59

Brief Summary

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).

Conditions

Advanced or Metastatic NRAS-mutant Melanoma

Keywords

Melanoma; NRAS Mutant; Cutaneous Melanoma

Outcome Measures

Primary Outcomes (6)

• Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2

  Incidence and severity of treatment-emergent AEs and serious AEs

  Assessed up to 6 months from time of first dose

• Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2

  Objective response rate (ORR) based on assessment of radiographic imaging RECIST v1.1

  Assessed up to 6 months from time of first dose

• Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2

  Maximum plasma concentration of ERAS-254 and trametinib

  Study Day 1 up to Day 29

• Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2

  Time to achieve maximum plasma concentration of ERAS-254 and trametinib

  Study Day 1 up to Day 29

• Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2

  Area under the plasma concentration-time curve

  Study Day 1 up to Day 29

• Stage 2: To compare PFS and OS for patients who are randomized to receive the combination of naporafenib + trametinib to that of patients who receive physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy)

  * Progression free survival (PFS) based on assessment of radiographic imaging per RECIST v1.1 * Survival status

  Assessed up to 24 months from time of first dose

Secondary Outcomes (8)

• Adverse Events

  Assessed up to 24 months from time of first dose

• Duration of Response (DOR)

  Assessed up to 24 months from time of first dose]

• Time to Response (TTR)

  Assessed up to 24 months from time of first dose]

• Disease Control Rate (DCR)

  Assessed up to 24 months from time of first dose]

• Overall Response Rate (ORR)

  Assessed up to 24 months from time of first dose

Other Outcomes (3)

• Duration of Response (DOR) for CNS disease in participants

  Assessed up to 24 months from time of first dose

• Overall Response Rate (ORR) for CNS disease in participants

  Assessed up to 24 months from time of first dose

• Disease Control Rate (DCR) for CNS disease in participants

  Assessed up to 24 months from time of first dose

Study Arms (5)

Stage 1 Dose selection Lead-in Arm 1

EXPERIMENTAL

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

Drug: Naporafenib; Drug: Trametinib

Stage 1 Dose selection Lead-in Arm 2

EXPERIMENTAL

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

Drug: Naporafenib; Drug: Trametinib

Stage 1 Dose selection Lead-in Arm 3 Trametinib monotherapy

ACTIVE COMPARATOR

Trametinib 2 mg once daily (QD)

Drug: Trametinib

Stage 2 Arm A

EXPERIMENTAL

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

Drug: Naporafenib; Drug: Trametinib

Stage 2 Arm B - Physician's Choice

ACTIVE COMPARATOR

* 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

Drug: Dacarbazine; Drug: Temozolomide; Drug: Trametinib

Interventions

Dacarbazine DRUG

Dacarbazine IV - Day 1

Also known as: DTIC

Stage 2 Arm B - Physician's Choice

Temozolomide DRUG

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

Also known as: Temodar, TMZ

Stage 2 Arm B - Physician's Choice

Trametinib DRUG

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

Also known as: Mekinist

Stage 1 Dose selection Lead-in Arm 1; Stage 1 Dose selection Lead-in Arm 2; Stage 1 Dose selection Lead-in Arm 3 Trametinib monotherapy; Stage 2 Arm A; Stage 2 Arm B - Physician's Choice

Naporafenib DRUG

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

Also known as: ERAS-254, LXH254

Stage 1 Dose selection Lead-in Arm 1; Stage 1 Dose selection Lead-in Arm 2; Stage 2 Arm A

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent
• Age ≥ 18 years
• Histologically or cytologically confirmed unresectable or metastatic cutaneous (includes acral) melanoma.
• 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.
• 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.
• 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.
• ECOG performance status 0, 1 or 2
• Presence of at least 1 measurable lesion according to RECIST v1.1
• Able to swallow oral medication.

You may not qualify if:

• Patients with uveal or mucosal melanoma
• Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor
• 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)
• 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)
• LVEF \<50%
• Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
• 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.
• Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

Sponsors & Collaborators

• Erasca, Inc.: lead

Study Sites (59)

Mayo Clinic - Arizona

Phoenix, Arizona, 85054, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

The Melanoma and Skin Care Institute

Englewood, Colorado, 80113, United States

Location

Mayo Clinic - Florida

Jacksonville, Florida, 70121, United States

Location

University of Miami Sylvester Cancer

Miami, Florida, 33136, United States

Location

University of Kansas Cancer Center

Kansas City, Kansas, 66205, United States

Location

Ochsner Clinic Foundation

Jefferson, Louisiana, 70121, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 70121, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

SCRI Oncology Partners (formerly Tennessee Oncology)

Nashville, Tennessee, 37203, United States

Location

Texas Oncology- Austin Midtown

Austin, Texas, 78705, United States

Location

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

The University of Utah - Huntsman Cancer Institute (HCI)

Salt Lake City, Utah, 84112, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502-1871, United States

Location

Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Calvary Mater Newcastle

Waratah, New South Wales, 2298, Australia

Location

Tasman Health Care

Southport, Queensland, 4215, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Peter MacCallum Cancer Institute

Melbourne, Victoria, 3000, Australia

Location

Hollywood Private Hospital

Nedlands, Western Australia, 6009, Australia

Location

Alfred Hospital

Melbourne, 3004, Australia

Location

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, B3J 3R4, Canada

Location

McGill University Health Centre

Montreal, Quebec, H4A3J1, Canada

Location

Masarykuv Onkologicky Ustav-MOU

Brno, 65653, Czechia

Location

Fakultni nemocnice Hradec Kralove

Nový Hradec Králové, 50005, Czechia

Location

Sanatorium Profesora Arenbergera

Prague, 1502, Czechia

Location

Centre Hospitalier Universitaire (CHU) de Bordeaux - Hospitalier Saint-Andre

Bordeaux, 33075, France

Location

CHU Dijon Bourgogne - Hopital Francois Mitterand (Hopital du Bocage)

Dijon, 21079, France

Location

Centre Hospitalier du Mans

Le Mans, 72000, France

Location

CHRU de Lille - Hôpital Claude Huriez

Lille, 59000, France

Location

Centre Hospitalier Lyon-Sud

Lyon, 69310, France

Location

Assistance Publique Hopitaux de Marseille (AP-HM) - Hopital de la Timone

Marseille, 13005, France

Location

Hospital Ambroise Pairs

Paris, 75010, France

Location

APHP - Hopital Saint Louis

Paris, 9001, France

Location

CLCC Institute Gustave Roussy

Villejuif, 94805, France

Location

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele (HSR) (Istituto Scientifico Universitario Sa

Milan, 20132, Italy

Location

IRCCS Istituto Nazionale Tumori Regina Elena

Roma, 00144, Italy

Location

Istituto Dermopatico dell Immacolata IDI-IRCCS

Roma, 00167, Italy

Location

Azienda Sanitaria Universitaria del Friuli Centrale

Udine, 33100, Italy

Location

Isala Ziekenhuis

Amsterdam, 8025, Netherlands

Location

Leids Universitair Medisch Centrum

Leiden, 2333 ZC, Netherlands

Location

Radboud University

Nijmegen, 6525 GA, Netherlands

Location

Hospital Universitari Vall d'Hebron - Vall d'Hebron Institut d'Oncologia (VHIO)

Barcelona, 08035, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital HM Sanchinarro

Madrid, 28050, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, 33011, Spain

Location

Royal Preston Hospital

Preston, Lancashire, PR29H, United Kingdom

Location

Sarah Cannon Research Institute - HCA Healthcare

City of London, London, W1G 6AD, United Kingdom

Location

Royal Devon and Exeter Hospital

Exeter, EX25DW, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

London, SM2 5PT, United Kingdom

Location

Christie Hospital

Manchester, M20 4GJ, United Kingdom

Location

MeSH Terms

Conditions

Melanoma

Interventions

naporafenib; Dacarbazine; Temozolomide; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Joyce Antal

  Clinical Development

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2024
• First Posted: April 3, 2024
• Study Start: April 29, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: February 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (6); CA (2); FR (9); ES (6); US (21); NL (3); CZ (3); GB (5); IT (4)