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

Erasca

Status and phase: Enrolling; Phase 3

Conditions: Advanced or Metastatic NRAS-mutant Melanoma

Treatments: Drug: Trametinib; Drug: Naporafenib; Drug: Dacarbazine; Drug: Temozolomide

Study type: Interventional

Funder types: Industry

Identifiers

NCT06346067

ERAS-254-02

Details and patient eligibility

About

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).

Full 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.

Enrollment: 470 estimated patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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 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.
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)
5. LVEF <50%
6. Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
7. 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.
8. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

470 participants in 5 patient groups

Stage 1 Dose selection Lead-in Arm 1

Experimental group

Description:

Naporafenib + Trametinib Naporafenib (ERAS-254) 100 mg administered orally twice daily (BID) Trametinib 1 mg once daily (QD)

Treatment:

Drug: Naporafenib

Drug: Trametinib

Stage 1 Dose selection Lead-in Arm 2

Experimental group

Description:

Naporafenib + Trametinib Naporafenib (ERAS-254) 400 mg administered orally twice daily (BID) Trametinib 0.5 mg once daily (QD)

Treatment:

Drug: Naporafenib

Drug: Trametinib

Stage 1 Dose selection Lead-in Arm 3 Trametinib monotherapy

Active Comparator group

Description:

Trametinib 2 mg once daily (QD)

Treatment:

Drug: Trametinib

Stage 2 Arm A

Experimental group

Description:

Naporafenib + Trametinib Naporafenib (ERAS-254) BID oral administration with Trametinib QD at the dose selected in Stage 1

Treatment:

Drug: Naporafenib

Drug: Trametinib

Stage 2 Arm B - Physician's Choice

Active Comparator group

Description:

* 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

Treatment:

Drug: Temozolomide

Drug: Dacarbazine

Drug: Trametinib