A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With RAS Q61X Mutations (SEACRAFT-1)

An Open-label Study to Assess the Safety and Efficacy of Naporafenib (ERAS-254) Administered With Trametinib in Previously Treated Patients With Locally Advanced Unresectable or Metastatic Solid Tumor Malignancies With RAS Q61X Mutations

To evaluate the efficacy of naporafenib administered with trametinib in patients with rat sarcoma viral oncogene (RAS) Q61X solid tumors

• To evaluate the safety and tolerability of naporafenib administered with trametinib in patients with RAS Q61X solid tumors
• To characterize the pharmacokinetic (PK) profile of naporafenib and trametinib when administered to patients with RAS Q61X solid tumors

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced or Metastatic Solid Tumors
• Intervention / Treatment: Drug: Trametinib; Drug: Naporafenib

Detailed Description

SEACRAFT-1 is an open-label study to assess the safety and efficacy of naporafenib administered with trametinib in previously treated patients with locally advanced unresectable or metastatic RAS Q61X solid tumor malignancies. The study will enroll a total of approximately 100 adult patients; a sub-study will enroll approximately 15 adolescent patients ≥12 and <18 years for a total sample size of approximately 115. Patients with a locally advanced unresectable or metastatic solid tumor malignancy that is not responsive to standard therapies or for which there is no standard therapy are eligible. Patients with primary central nervous system (CNS) tumors are not eligible. Documentation of a RAS Q61X mutation in tumor tissue prior to the first dose of study treatment is required.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Perth, Australia
    • Linear Clinical Research, LTD
  • New South Wales
    • Macquarie Park, New South Wales, Australia
      • Macquarie University
  • Victoria
    • Melbourne, Victoria, Australia
      • St. Vincent's Hospital
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute- Alberta Health Services (AHS)
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • British Columbia Cancer Agency
  • Ontario
    • London, Ontario, Canada
      • London Regional Cancer Center
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• South Korea
  • Goyang-si, South Korea
    • National Cancer Center
  • Gyeonggi-do, South Korea
    • Seoul National University Hospital Bundang
  • Seoul, South Korea
    • Seoul National University Hospital
  • Seoul, South Korea
    • The Catholic University Hospital
  • Busan Gwang'yeogsi
    • Busan, Busan Gwang'yeogsi, South Korea, 48108
      • Inje University Haeundae Paik Hospital
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, South Korea, 06351
      • Samsung Medical Center
• United Kingdom
  • Glasgow, United Kingdom
    • Beatson West of Scotland Cancer Center
  • London
    • City of London, London, United Kingdom, W1G 6AD
      • Sarah Cannon Research Institute - HCA Healthcare
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Cancer Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists - Sarasota
    • St. Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists - St. Petersburg
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Center of Nevada (CCCN)
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners (formerly Tennessee Oncology)
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute
    • Fairfax, Virginia, United States, 22031
      • Next Virginia
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Willing and able to provide written informed consent
2. Age ≥ 12 years
3. A locally advanced or metastatic tumor who has progressed on or for which no standard therapy exists. Patients who are intolerant to standard therapy or who are not a candidate for standard therapy (in the opinion of the Investigator) or who decline standard therapy are also eligible.
4. Documentation of a RAS Q61X mutation (tumor tissue or blood) prior to first dose of study treatment 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. ECOG performance status 0, 1 or 2
7. Presence of at least 1 measurable lesion according to RECIST v1.1
8. Able to swallow oral medication.

Exclusion Criteria:

1. Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor
2. Impairment of GI function or gastrointestinal (GI) disease that may significantly alter the absorption of study treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
3. 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)
4. 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
5. LVEF <50%
6. All primary CNS tumors
7. Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
8. 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;
9. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naporafenib + Trametinib; Naporafenib (ERAS-254) 200 mg twice daily (BID) Trametinib 1 mg once daily (QD)	Drug: Trametinib; Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.; Other Names: Mekinist; Drug: Naporafenib; Naporafenib (ERAS-254) 200 mg twice daily (BID) of an experimental Pan-Raf inhibitor; Other Names: LXH254; ERAS-254

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the efficacy of naporafenib administered with trametinib in patients with rat sarcoma viral oncogene (RAS) Q61X solid tumors	Based on assessment of Objective response rate (ORR) per RECIST version 1.1	Assessed up to 24 months from time of first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Incidence and severity of treatment-emergent AEs and serious AEs	Assessed up to 24 months from time of first dose
Duration of Response (DOR)	Based on assessment of radiographic imaging per RECIST version 1.1	Assessed up to 24 months from time of first dose
Time to Response (TTR)	Based on assessment of radiographic imaging per RECIST version 1.1	Assessed up to 24 months from time of first dose
Plasma concentration (Cmax)	Maximum plasma concentration of ERAS-254 and trametinib	Study Day 1 up to Day 29
Time to achieve Cmax (Tmax)	Time to achieve maximum plasma concentration of ERAS-254 and trametinib	Study Day 1 up to Day 29
Area under the curve (AUC)	Area under the plasma concentration-time curve	Study Day 1 up to Day 29
Overall survival	Survival Status	Assessed up to 24 months from time of first dose
Progression Free Survival (PFS)	Based on assessment of radiographic imaging per RECIST version 1.1	Assessed up to 24 months from time of first dose
Disease Control Rate (DCR)	Based on assessment of radiographic imaging per RECIST version 1.1	Assessed up to 24 months from time of first dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR) for CNS disease in participants	Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM)	Assessed up to 24 months from time of first dose
Overall Response Rate (ORR) for CNS disease in participants	Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM)	Assessed up to 24 months from time of first dose
Disease Control Rate (DCR) for CNS disease in participants	Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM)	Assessed up to 24 months from time of first dose
Pharmacodynamic assessment	DUSP6: changes from baseline in the expression of DUSP-6 mRNA in blood, a marker of MAPK pathway Inhibition.	Assessed up to 24 months from time of first dose

Collaborators and Investigators

• Sponsor: Erasca, Inc.
• Investigators: Study Director: Joyce Antal, MS, Clinical Development

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2023
• Primary Completion (Actual): July 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: May 30, 2023
• First Submitted That Met QC Criteria: June 7, 2023
• First Posted (Actual): June 18, 2023

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 24, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Non-small cell lung cancer; Pancreatic Cancer; Melanoma; Thyroid cancer; Other solid tumors harboring a RAS Q61X mutation; Colorectal Cancer (cohort full)
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Intestinal Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Pancreatic Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lung Neoplasms; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Thyroid Diseases; Skin and Connective Tissue Diseases; Colorectal Neoplasms; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung; Melanoma; Thyroid Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; trametinib; naporafenib
• Other Study ID Numbers: ERAS-254-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No