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

Purpose

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).

Condition

  • Advanced or Metastatic NRAS-mutant Melanoma

Eligibility

Eligible Ages
Between 18 Years and 99 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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.

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

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
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
    Other names:
    • ERAS-254
    • LXH254
  • Drug: Trametinib
    Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.
    Other names:
    • Mekinist
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
    Other names:
    • ERAS-254
    • LXH254
  • Drug: Trametinib
    Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.
    Other names:
    • Mekinist
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: Naporafenib
    Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor
    Other names:
    • ERAS-254
    • LXH254
  • Drug: Trametinib
    Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.
    Other names:
    • Mekinist
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: Temozolomide
    Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle
    Other names:
    • Temodar
    • TMZ
  • Drug: Trametinib
    Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.
    Other names:
    • Mekinist

Recruiting Locations

University of Kansas Cancer Center
Kansas City, Kansas 66205

More Details

Status
Recruiting
Sponsor
Erasca, Inc.

Study Contact

Erasca Clinical Team
1-858-465-6511
clinicaltrials@erasca.com

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.