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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Drug: Naporafenib
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small cell lung cancer, Thyroid cancer, Colorectal Cancer, Pancreatic Cancer, Other solid tumors harboring a RAS Q61X mutation, Melanoma