Advanced or Metastatic NRAS-mutant Melanoma
Conditions
Keywords
Melanoma, NRAS Mutant, Cutaneous Melanoma
Brief summary
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).
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.
Interventions
DRUGNaporafenib
Naporafenib (ERAS-254) is an experimental Pan-Raf inhibitor
DRUGDacarbazine
Dacarbazine IV - Day 1
DRUGTemozolomide
Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle
DRUGTrametinib
Trametinib is an FDA approved anticancer medication that targets MEK1 and MEK2.
Sponsors
Erasca, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2 | Assessed up to 6 months from time of first dose | Incidence and severity of treatment-emergent AEs and serious AEs |
| 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) | Assessed up to 24 months from time of first dose | * Progression free survival (PFS) based on assessment of radiographic imaging per RECIST v1.1 * Survival status |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | Assessed up to 24 months from time of first dose | Incidence and severity of treatment-emergent AEs and serious AEs |
| Duration of Response (DOR) | Assessed up to 24 months from time of first dose] | Based on assessment of radiographic imaging per RECIST version 1.1 |
| Time to Response (TTR) | Assessed up to 24 months from time of first dose] | Based on assessment of radiographic imaging per RECIST version 1.1 |
| Disease Control Rate (DCR) | Assessed up to 24 months from time of first dose] | Based on assessment of radiographic imaging per RECIST version 1.1 |
| Overall Response Rate (ORR) | Assessed up to 24 months from time of first dose | Based on the assessment of radiographic imaging per RECIST version 1.1 |
| Plasma concentration (Cmax):Stage 1 only | Study Day 1 up to Day 29 | Maximum plasma concentration of ERAS-254 and trametinib |
| Area under the curve (AUC):Stage 1 only | Study Day 1 up to Day 29 | Area under the plasma concentration-time curve |
| Quality of Life: To assess disease and treatment-related QOL in patients with NRASm melanoma. | Assessed up to 24 months from time of first dose | 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. |
Countries
Australia, Canada, Czechia, France, Italy, Netherlands, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORJoyce Antal
Clinical Development
Outcome results
None listed