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

    Study type

    TREATMENT

    phase

    Phase

      PHASE3

    trial

    Trial ID

    NCT06346067

    Intervention or treatment

    DRUG: Naporafenib

    DRUG: Dacarbazine

    DRUG: Temozolomide

    DRUG: Trametinib

    Conditions

    • Advanced or Metastatic NRAS-mutant Melanoma

    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

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    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/ArmIntervention/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 MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2Incidence and severity of treatment-emergent AEs and serious AEsAssessed up to 6 months from time of first dose
    Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2Objective response rate (ORR) based on assessment of radiographic imaging RECIST v1.1Assessed up to 6 months from time of first dose
    Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2Maximum plasma concentration of ERAS-254 and trametinibStudy Day 1 up to Day 29
    Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2Time to achieve maximum plasma concentration of ERAS-254 and trametinibStudy Day 1 up to Day 29
    Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2Area under the plasma concentration-time curveStudy 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 statusAssessed up to 24 months from time of first dose

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Adverse EventsIncidence and severity of treatment-emergent AEs and serious AEsAssessed up to 24 months from time of first dose
    Duration of Response (DOR)Based on assessment of radiographic imaging per RECIST version 1.1Assessed up to 24 months from time of first dose]
    Time to Response (TTR)Based on assessment of radiographic imaging per RECIST version 1.1Assessed up to 24 months from time of first dose]
    Disease Control Rate (DCR)Based on assessment of radiographic imaging per RECIST version 1.1Assessed up to 24 months from time of first dose]
    Overall Response Rate (ORR)Based on the assessment of radiographic imaging per RECIST version 1.1Assessed up to 24 months from time of first dose
    Plasma concentration (Cmax):Stage 1 onlyMaximum plasma concentration of ERAS-254 and trametinibStudy Day 1 up to Day 29
    Area under the curve (AUC):Stage 1 onlyArea under the plasma concentration-time curveStudy 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

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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)

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