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

PHASE3RECRUITING

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).

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

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.

Exclusion criteria

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

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-04-29

Primary completion: 2028-04-01

Study completion finish: 2028-12-01

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT06346067

Intervention or treatment

DRUG: Naporafenib

DRUG: Dacarbazine

DRUG: Temozolomide

DRUG: Trametinib

Conditions

• Advanced or Metastatic NRAS-mutant Melanoma

Image related to Advanced or Metastatic NRAS-mutant Melanoma

Condition: Advanced or Metastatic NRAS-mutant Melanoma
DRUG: Naporafenib and other drugs
Waratah, New South Wales, Australia and more
Sponsor: Erasca, Inc.

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Find a site

Closest Location:

Calvary Mater Newcastle

Research sites nearby

Select from list below to view details:

Calvary Mater Newcastle
Waratah, New South Wales, Australia
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Hollywood Private Hospital
Nedlands, Western Australia, Australia
Tasman Health Care
Southport, Queensland, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

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: Naporafenib Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor
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: Naporafenib Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor
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.
EXPERIMENTAL: Stage 2 Arm A Naporafenib + Trametinib Naporafenib (ERAS-254) BID oral administration with Trametinib QD at the dose selected in Stage 1	DRUG: Naporafenib Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor
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

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome 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

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome 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

Frequently Asked Questions

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References

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