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

A Randomized, Open-label Phase III Study in Patients With Previously Treated Unresectable or Metastatic NRAS Mutant Cutaneous Melanoma Comparing the Combination of Naporafenib + Trametinib to Physician's Choice of Therapy (Dacarbazine, Temozolomide or Trametinib Monotherapy) With a Dose Optimization lead-in [SEACRAFT-2]

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced or Metastatic NRAS-mutant Melanoma
• Intervention / Treatment: Drug: Dacarbazine; Drug: Trametinib; Drug: Naporafenib; Drug: Temozolomide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 470
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Erasca Clinical Team; Phone Number: 1-858-465-6511; Email: clinicaltrials@erasca.com

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners (formerly Tennessee Oncology)

Participation Criteria

Eligibility Criteria

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

Description

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 6 months 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) 3. 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 4. LVEF <50% 5. Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.

6. 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; 7. 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: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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)	Drug: Trametinib; Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.; Other Names: Mekinist; Drug: Naporafenib; Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor; Other Names: LXH254; ERAS-254
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)	Drug: Trametinib; Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.; Other Names: Mekinist; Drug: Naporafenib; Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor; Other Names: LXH254; ERAS-254
Active Comparator: Stage 1 Dose selection Lead-in Arm 3 Trametinib monotherapy; Trametinib 2 mg once daily (QD)	Drug: Trametinib; Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.; Other Names: Mekinist
Experimental: Stage 2 Arm A; Naporafenib + Trametinib Naporafenib (ERAS-254) BID oral administration with Trametinib QD at the dose selected in Stage 1	Drug: Trametinib; Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.; Other Names: Mekinist; Drug: Naporafenib; Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor; Other Names: LXH254; ERAS-254
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	Drug: Dacarbazine; Dacarbazine IV - Day 1; Other Names: DTIC; Drug: Trametinib; Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.; Other Names: Mekinist; Drug: Temozolomide; Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle; Other Names: Temodar; TMZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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]
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]
Overall Response Rate (ORR)	Based on the assessment of radiographic imaging per RECIST version 1.1	Assessed up to 24 months from time of first dose
Plasma concentration (Cmax):Stage 1 only	Maximum plasma concentration of ERAS-254 and trametinib	Study Day 1 up to Day 29
Area under the curve (AUC):Stage 1 only	Area under the plasma concentration-time curve	Study Day 1 up to Day 29
Quality of Life: To assess disease and treatment-related QOL in patients with NRASm melanoma.	Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire [QLQ]-C30 subscales and PRO CTCAE® symptom items specific to the potential cutaneous toxicities.	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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: March 17, 2024
• First Submitted That Met QC Criteria: March 28, 2024
• First Posted (Actual): April 3, 2024

Study Record Updates

• Last Update Posted (Estimated): April 29, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Melanoma; Cutaneous Melanoma; NRAS Mutant
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Temozolomide; Trametinib; Dacarbazine; Naporafenib
• Other Study ID Numbers: ERAS-254-02

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