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

Sponsor

Erasca, Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05907304

Collaborator

(none)

115

Enrollment

Arm

28.1

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Advanced or Metastatic Solid Tumors	Drug: Naporafinib Drug: Trametinib	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

115 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Nov 1, 2025

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Naporafenib + Trametinib

Naporafenib (ERAS-254) 200 mg twice daily (BID) Trametinib 1 mg once daily (QD)

Drug: Naporafinib

Naporafenib (ERAS-254) 200 mg twice daily (BID) of an experimental Pan-Raf inhibitor

Other Names:

LXH254

ERAS-254

Drug: Trametinib

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

Other Names:

Mekinist

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Willing and able to provide written informed consent
Age ≥ 12 years
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.
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.
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.
ECOG performance status 0, 1 or 2
Presence of at least 1 measurable lesion according to RECIST v1.1
Able to swallow oral medication.

Exclusion Criteria:

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