Clinical Trial: Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subject

Brief Summary: This is a 3-part (Part A, Part B, Part C), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors. Part A is a repeat dose, dose escalation monotherapy study that will identify the recommended phase II dose (RP2D) on the continuous dosing schedule using a 3 + 3 dose-escalation procedure. Part B will evaluate the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Each cohort will enroll at least 10 response-evaluable subjects (evaluable for response is defined as a subject with a pre-dose and at least 1 post-dose disease assessment or clinical assessment of progression of disease). Part C is will be a 3+3 study design to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part C will enroll up to 18 subjects. . The overall goal of this trial is to efficiently establish safe, pharmacologically relevant dose of trametinib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or unresectable childhood tumors.

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome:

  • Safety Assessment of trametinib as assessed by Adverse Events (AEs) [ Time Frame: From screening up to 24 months ]
  • Safety Assessment of trametinib as assessed by electrocardiogram (ECG) [ Time Frame: From screening up to 24 months ]
    Single 12-lead ECGs will be obtained to assess safety
  • Safety Assessment of trametinib as assessed by echocardiogram (ECHO) [ Time Frame: From screening up to 24 months ]
    ECHOs will be performed to assess cardiac ejection fraction and cardiac valve morphology
  • Safety Assessment of trametinib as assessed by changes in laboratory values [ Time Frame: From screening up to 24 months ]
    Laboratory assessments will include Hematology, Clinical Chemistry, Routine Urinalysis and Other screening tests
  • Safety Assessment of trametinib assessed by changes in vital signs [ Time Frame: From screening up to 24 months ]
    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
  • To determine the dose of trametinib that achieves similar exposures (Ctau) to the recommended adult dose [ Time Frame: Days 15 and 22 ]
    Steady state Ctau of trametinib


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • PK Assessment of trametinib [ Time Frame: Day 15 and Day 22 ]
    PK parameters including Ctau (trough concentration), area under the concentration-time curve over a period of time (AUC [0-t]), area under the concentration-time curve over the dosing interval (AUC [0-tau]), apparent clearance following oral dosing (CL/F), maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax) (tmax) and half-life (t1/2) of trametinib will be assessed
  • Safety and tolerability assessments for trametinib for AEs [ Time Frame: From screening up to 24 months ]
  • Safety and tolerability assessments for trametinib for ECG [ Time Frame: From screening up to 24 months ]
    12-lead ECGs will be performed to assess safety and tolerability
  • Safety and tolerability assessments for trametinib for changes in laboratory values [ Time Frame: From screening up to 24 months ]
    Laboratory parameter including chemistry and hematology
  • Safety and tolerability assessments for trametinib for vital signs [ Time Frame: From screening up to 24 months ]
    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
  • Tumor response for trametinib [ Time Frame: From screening up to 24 months ]
    Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)
  • Effect of age and weight on the PK of trametinib [ Time Frame: Day 15 and Day 22 ]
    PK parameter will include CL/F, volume of distribution (V/F), absorption rate (ka), and coefficients for significant covariates
  • PK assessment of trametinib and dabrafenib when administered in combination [ Time Frame: Day 1, Day 15 and Day 22 of Part C ]
    PK parameters include Ctau, AUC (0-t), AUC (0-tau), CL/F, Cmax, tmax, and t1/2
  • Palatability of trametinib in pediatric subjects assessed by palatability questionnaire [ Time Frame: Day 8 ]
    To be completed after the first dose of study drug and no later than Day 8 (+/-3 days). Ssubjects will complete a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste).
  • Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Adverse Events (AEs) [ Time Frame: From screening up to 24 months ]
  • Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by ECGs. [ Time Frame: From screening up to 24 months ]
    12-lead ECGs will be performed to assess safety and tolerability
  • Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Echo. [ Time Frame: From screening up to 24 months ]
  • Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in laboratory values [ Time Frame: From screening up to 24 months ]
    Laboratory parameter including chemistry, hematology and urinalysis.
  • Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in vital sign values [ Time Frame: From screening up to 24 months ]
    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
  • Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by AEs [ Time Frame: From screening up to 24 months ]
  • Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by ECGs [ Time Frame: From screening up to 24 months ]
    12-lead ECGs will be performed to assess safety and tolerability
  • Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by Echo [ Time Frame: From screening up to 24 months ]
  • Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in lab values [ Time Frame: From screening up to 24 months ]
    Laboratory parameter including chemistry, hematology and urinalysis.
  • Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in vital sings [ Time Frame: From sc

    Original Secondary Outcome:

    • PK Assessment of trametinib [ Time Frame: Day 15 and Day 22 ]
      PK parameters including Ctau (trough concentration), area under the concentration-time curve over a period of time (AUC [0-t]), area under the concentration-time curve over the dosing interval (AUC [0-tau]), apparent clearance following oral dosing (CL/F), maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax) (tmax) and half-life (t1/2) of trametinib will be assessed
    • Safety and tolerability assessments for trametinib for AEs [ Time Frame: From screening up to 24 months ]
    • Safety and tolerability assessments for trametinib for ECG [ Time Frame: From screening up to 24 months ]
      12-lead ECGs will be performed to assess safety and tolerability
    • Safety and tolerability assessments for trametinib for changes in laboratory values [ Time Frame: From screening up to 24 months ]
      Laboratory parameter including chemistry and hematology
    • Safety and tolerability assessments for trametinib for vital signs [ Time Frame: From screening up to 24 months ]
      Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
    • Tumor response for trametinib [ Time Frame: From screening up to 24 months ]
      Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)
    • Effect of age and weight on the PK of trametinib [ Time Frame: Day 15 and Day 22 ]
      PK parameter will include CL/F, volume of distribution (V/F), absorption rate (ka), and coefficients for significant covariates


    Information By: GlaxoSmithKline

    Dates:
    Date Received: April 24, 2014
    Date Started: January 2015
    Date Completion: March 2020
    Last Updated: February 23, 2017
    Last Verified: February 2017