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
Condition: Cancer
MeSH terms: Neurofibroma; Neurofibromatoses; Neurofibroma, Plexiform
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This was a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label,
      study in pediatric subjects with refractory or recurrent tumors.

      Part A was a repeat dose, dose escalation and expansion phase that identified the recommended
      phase II dose (RP2D) of trametinib monotherapy. Part B evaluated the preliminary activity of
      trametinib monotherapy in 4 disease-specific cohorts of subjects. Part C was aimed to
      determine the safety, tolerability and preliminary activity of the RP2D of trametinib in
      combination with a limited dose escalation of dabrafenib. Part D evaluated the preliminary
      activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of
      subjects.

      The overall goal of this trial was to efficiently establish safe, pharmacologically relevant
      dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants,
      children and adolescents and determine preliminary activity of trametinib monotherapy and
      trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable
      childhood tumors.
    

Detailed description: 
      This was a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label,
      study in pediatric subjects with refractory or recurrent tumors.

      Part A was a repeat dose, dose escalation and expansion phase that identified the recommended
      phase II dose (RP2D) of trametinib monotherapy using a 3 + 3 dose- escalation procedure. The
      starting dose level of trametinib was 0.0125 mg/kg/day, the second dose level was 0.025
      mg/kg/day and the third dose level was 0.040 mg/kg/day. Additionally, in Part A extension an
      intermediate trametinib dose level of 0.032 mg/kg/day was assessed in subjects under 6 years
      of age. In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2
      mg) in any subject.

      Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific
      cohorts of subjects:

      B1: Refractory or relapsed neuroblastoma B2: Recurrent or unresectable low grade glioma (LGG)
      with BRAF tandem duplication with fusion (glioma fusion) B3: Neurofibromatosis Type -1
      associated plexiform neurofibromas (NF-1 with PN) that are unresectable and medically
      significant B4: BRAF V600 mutant tumors In Part B it was used the RP2D of trametinib (0.025
      mg/kg/day) determined in Part A.

      Part C was 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. The
      trametinib dose administered in Part C was based on the trametinib monotherapy RP2D from Part
      A (0.025 mg/kg/day). For the evaluation of combination therapy in this study, the starting
      dose of dabrafenib was 50% of the monotherapy RP2D established in a separate study: 2.63
      mg/kg/day (<12 years old subjects) and 2.25 mg/kg/day (≥12 years old subjects). The second
      dose level of dabrafenib was 100% of the monotherapy RP2D: 5.25 mg/kg/day (<12 years old
      subjects) and 4.5 mg/kg/day (≥12 years old subjects).

      Additionally, in Part C extension, the trametinib dose determined from Part A extension
      (0.032 mg/kg/day) with 100% pediatric RP2D of dabrafenib (5.25 mg/kg/day) was assessed in
      subjects under 6 years of age.

      In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2 mg) in
      any subject and the total daily dabrafenib dose was not to exceed the adult dose (300 mg) in
      any subject.

      Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in two
      disease-specific cohorts of subjects diagnosed with low grade glioma (LGG) and Langerhans
      cell histiocytosis (LCH).

      In Part D it was used the RP2D of the combination treatment determined in Part C (0.025
      mg/kg/day trametinib and the 100% RP2D of dabrafenib) in subjects 6 years to < 18 years of
      age. Additionally, once Part C extension had defined the trametinib RP2D for subjects under 6
      years of age, this dose was used for the remaining subjects enrolled in Part D (0.032
      mg/kg/day trametinib and the 100% RP2D of dabrafenib).

      The overall goal of this trial was to efficiently establish safe, pharmacologically relevant
      dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants,
      children and adolescents and determine preliminary activity of trametinib monotherapy and
      trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable
      childhood tumors.
    

Intervention name(s): Trametinib; Dabrafenib
Intervention type(s): Drug; Drug
Intervention description(s): Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).; Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).
Intervention MeSH terms: Trametinib; Dabrafenib
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: v600-mutation; neuroblastoma; Trametinib; pediatrics; Langerhans Cell Histiocytosis; low grade glioma; plexiform neurofibromas