A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With RAS Q61X Mutations

PHASE1RECRUITING

To evaluate the efficacy of naporafenib administered with trametinib in patients with rat sarcoma viral oncogene (RAS) Q61X solid tumors * To evaluate the safety and tolerability of naporafenib administered with trametinib in patients with RAS Q61X solid tumors * To characterize the pharmacokinetic (PK) profile of naporafenib and trametinib when administered to patients with RAS Q61X solid tumors.

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Study details:

SEACRAFT-1 is an open-label study to assess the safety and efficacy of naporafenib administered with trametinib in previously treated patients with locally advanced unresectable or metastatic RAS Q61X solid tumor malignancies. The study will enroll a total of approximately 100 adult patients; a sub-study will enroll approximately 15 adolescent patients ≥12 and \<18 years for a total sample size of approximately 115. Patients with a locally advanced unresectable or metastatic solid tumor malignancy that is not responsive to standard therapies or for which there is no standard therapy are eligible.

Patients with primary central nervous system (CNS) tumors are not eligible. Documentation of a RAS Q61X mutation in tumor tissue prior to the first dose of study treatment is required.

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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 ≥ 12 years
  • A locally advanced or metastatic tumor who has progressed on or for which no standard therapy exists. Patients who are intolerant to standard therapy or who are not a candidate for standard therapy (in the opinion of the Investigator) or who decline standard therapy are also eligible.
  • Documentation of a RAS Q61X mutation (tumor tissue or blood) prior to first dose of study treatment 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.
  • 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

  • Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor
  • Impairment of GI function or gastrointestinal (GI) disease that may significantly alter the absorption of study treatment (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)
  • Corrected QT interval using Fridericia's formula (QTcF) at Screening >450 ms based on triplicate average NOTE: criterion does not apply to patients with a right or left bundle branch block
  • LVEF <50%
  • All primary CNS tumors
  • Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
  • Patients receiving treatment with medications that are known to be strong inhibitors and/or inducers of cytochrome P450 (CYP)3A; substrates of CYP2C8, CYP2C9, and CYP3A with a narrow therapeutic index and sensitive substrates of CYP3A;
  • 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 : 12 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2023-08-17

    Primary completion: 2025-07-01

    Study completion finish: 2025-11-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE1

    trial

    Trial ID

    NCT05907304

    Intervention or treatment

    DRUG: Naporafenib

    DRUG: Trametinib

    Conditions

    • Advanced or Metastatic Solid Tumors

    Find a site

    Closest Location:

    Macquarie University

    Research sites nearby

    Select from list below to view details:

    • Macquarie University

      Macquarie Park, New South Wales, Australia

    • St. Vincent's Hospital

      Melbourne, Victoria, Australia

    • Linear Clinical Research, LTD

      Perth, Not Specified, 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: Naporafenib + Trametinib
    • Naporafenib (ERAS-254) 200 mg twice daily (BID) Trametinib 1 mg once daily (QD)
    DRUG: Naporafenib
    • Naporafenib (ERAS-254) 200 mg twice daily (BID) of an experimental Pan-Raf inhibitor

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    To evaluate the efficacy of naporafenib administered with trametinib in patients with rat sarcoma viral oncogene (RAS) Q61X solid tumorsBased on assessment of Objective response rate (ORR) per RECIST version 1.1Assessed 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
    Progression Free Survival (PFS)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
    Plasma concentration (Cmax)Maximum plasma concentration of ERAS-254 and trametinibStudy Day 1 up to Day 29
    Time to achieve Cmax (Tmax)Time to achieve maximum plasma concentration of ERAS-254 and trametinibStudy Day 1 up to Day 29
    Area under the curve (AUC)Area under the plasma concentration-time curveStudy Day 1 up to Day 29
    Overall survivalSurvival StatusAssessed 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 RAS Q61X Mutations

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