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

Conditions

• Cancer

Eligibility Criteria

Sex

ALL

Age

1 Month - 17 Years

Healthy Volunteers

Not accepted

Interventions

• Trametinib — DRUG
  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 — DRUG
  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).

Study Details

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.

Key Dates

Start date

Jan 15, 2015

Status verified

Jun 2021

Primary completion

Dec 29, 2020

Completion

Dec 29, 2020

Study Design

Enrollment

139 participants (actual)

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Arms

• Experimental: Part A - TMT 0.0125 mg/kg/day
  Participants treated with trametinib 0.0125 mg/kg/day
• Experimental: Part A - TMT 0.025 mg/kg/day
  Participants treated with trametinib 0.025 mg/kg/day
• Experimental: Part A - TMT 0.032 mg/kg/day
  Participants under 6 years of age treated with trametinib 0.032 mg/kg/day
• Experimental: Part A - TMT 0.04 mg/kg/day
  Participants treated with trametinib 0.04 mg/kg/day
• Experimental: Part B - Neuroblastoma
  Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day
• Experimental: Part B - LGG fusion
  Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day
• Experimental: Part B - NF-1 with PN
  Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day
• Experimental: Part B - BRAF V600 mutant solid tumor
  Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day
• Experimental: Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D
  Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for \<12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects)
• Experimental: Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D
  Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
• Experimental: Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D
  Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)
• Experimental: Part D - LGG
  Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
• Experimental: Part D - LCH
  Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Primary Outcome Measure

Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy [ Time Frame: From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months ]

Locations (10)

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