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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02124772
Registration number
NCT02124772
Ethics application status
Date submitted
24/04/2014
Date registered
28/04/2014
Date last updated
14/07/2021
Titles & IDs
Public title
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
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Scientific 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 Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Children and Adolescents With Cancers Harboring V600 Mutations
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Secondary ID [1]
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2013-003596-35
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Secondary ID [2]
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116540
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Cancer
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Condition category
Condition code
Cancer
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Other cancer types
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Neurological
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Other neurological disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Trametinib
Treatment: Drugs - Dabrafenib
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)
Treatment: Drugs: Trametinib
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).
Treatment: Drugs: Dabrafenib
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).
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy
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Assessment method [1]
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Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.
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Timepoint [1]
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From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months
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Primary outcome [2]
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Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy)
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Assessment method [2]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib.
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Timepoint [2]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [1]
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Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib
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Assessment method [1]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.
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Timepoint [1]
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pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [2]
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Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
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Assessment method [2]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
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Timepoint [2]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [3]
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Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
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Assessment method [3]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.
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Timepoint [3]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [4]
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Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Trametinib When Administered Alone and in Combination With Dabrafenib
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Assessment method [4]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.
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Timepoint [4]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [5]
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Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Trametinib When Administered Alone and in Combination With Dabrafenib
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Assessment method [5]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. The duration of the dosing interval (tau) was 24 hours for trametinib.
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Timepoint [5]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [6]
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Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib
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Assessment method [6]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.
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Timepoint [6]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [7]
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Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib
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Assessment method [7]
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Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib.
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Timepoint [7]
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pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [8]
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Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib
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Assessment method [8]
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Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.
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Timepoint [8]
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From the day of the first dose of the combination up to 30 days after the last dose, up to maximum duration of 53 months
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Secondary outcome [9]
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Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
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Assessment method [9]
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Response evaluations were assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for subjects with solid tumors except neuroblastomas, primary central nervous system tumors (gliomas) or plexiform neurofibromas (PNs).
Response evaluations for subjects with neuroblastomas could have included: measureable disease (by CT/MRI alone) assessed according to RECIST v1.1, evaluable disease assessed for meta-iodobenzylguanidine (MIBG) response, and biochemical (urine HVA/VMA) with bone marrow involvement assessed by Hematoxylin and Eosin staining of bilateral bone marrow biopsies and aspirates.
Response evaluations for glioma subjects was assessed using Response Assessment in Neuro Oncology (RANO) criteria with solid tumors through MRI scans.
Response evaluations of PNs were assessed using volumetric determination and Dombi criteria through MRI scans.
The number of participants in each response category is reported in the table.
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Timepoint [9]
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From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
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Secondary outcome [10]
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Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
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Assessment method [10]
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Objective response rate (ORR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR) or partial response (PR) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.
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Timepoint [10]
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From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
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Secondary outcome [11]
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Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
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Assessment method [11]
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Clinical Benefit Rate (CBR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR), partial response (PR) or stable disease (SD) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.
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Timepoint [11]
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From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
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Secondary outcome [12]
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Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model
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Assessment method [12]
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The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Apparent clearance (CL/F) of trametinib estimated with the PopPK model is summarized in this record.
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Timepoint [12]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [13]
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Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model
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Assessment method [13]
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The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Apparent central volume (Vc/F) of trametinib estimated with the PopPK model is summarized in this record.
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Timepoint [13]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [14]
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Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model
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Assessment method [14]
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The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. The absorption rate constants (Ka1 and Ka2) estimated with the PopPK model are summarized in this record.
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Timepoint [14]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [15]
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Significant Covariates Estimated With a PopPK Model
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Assessment method [15]
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The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Sex and weight are significant covariates on apparent clearance (CL/F), and weight is also a significant covariate on apparent intercompartmental clearance (Q/F). Use of dabrafenib, yes or no, is a covariate on the relative bioavailability of trametinib, reflecting the effect of dabrafenib on the PK of trametinib.
The estimates of these covariates (effect of weight on CL/F, effect of sex on CL/F, effect of weight on Q/F, effect of combination with dabrafenib on relative bioavailability F1) calculated with the PopPK model are summarized in this record.
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Timepoint [15]
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pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.
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Secondary outcome [16]
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Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib
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Assessment method [16]
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Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.
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Timepoint [16]
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pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [17]
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Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib
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Assessment method [17]
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Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
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Timepoint [17]
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pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [18]
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Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib
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Assessment method [18]
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Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.
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Timepoint [18]
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pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [19]
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Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Dabrafenib When Administered in Combination With Trametinib
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Assessment method [19]
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Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.
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Timepoint [19]
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pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [20]
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Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Dabrafenib When Administered in Combination With Trametinib
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Assessment method [20]
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Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. The duration of the dosing interval (tau) was 12 hours for dabrafenib.
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Timepoint [20]
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pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [21]
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Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib
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Assessment method [21]
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Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.
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Timepoint [21]
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pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [22]
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Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib
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Assessment method [22]
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Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of dabrafenib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 12 h for dabrafenib.
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Timepoint [22]
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pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
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Secondary outcome [23]
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Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire
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Assessment method [23]
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For subjects = 12 years of age who received the trametinib oral solution, the subject completed a form to evaluate the various properties of the solution (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the solution, their caregiver (e.g. parent or guardian) evaluated the solution with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.
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Timepoint [23]
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After the first dose of trametinib oral solution and no later than Day 8 (±3 days)
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Secondary outcome [24]
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Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire
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Assessment method [24]
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For subjects = 12 years of age who received the dabrafenib suspension, the subject completed a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the suspension, their caregiver (e.g. parent or guardian) evaluated the suspension with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.
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Timepoint [24]
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After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days)
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Eligibility
Key inclusion criteria
- General Eligibility Criteria (All Parts)
- Written informed consent - a signed informed consent and/or assent (as age
appropriate) for study participation including PK sampling will be obtained according
to institutional guidelines.
- Male or female between one month and <18 years of age (inclusive) at the time of
signing the informed consent form (Part C and Part D between 12 months and <18 years
of age, inclusive).
- Must have a disease that is relapsed/refractory to all potentially curative standard
treatment regimens or must have a current disease for which there is no known curative
therapy, or therapy proven to prolong survival with an acceptable quality of life.
- Prior therapy: The subject's disease (i.e. cancer, neurofibromatosis type 1 [NF-1]
with plexiform neurofibroma [PN], or Langerhans cell histocytosis [LCH]) must have
relapsed after or failed to respond to frontline curative therapy or there must not be
other potentially curative treatment options available. Curative therapy may include
surgery, radiation therapy, chemotherapy, or any combination of these modalities. All
subjects must have recovered to grade <=1 from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to enrollment. Prior therapy
includes; myelosuppressive chemotherapy, differentiating agents/ biologic response
modifiers (small molecules, antibodies, viral therapies) (anti-cancer agent),
non-myelosuppressive anticancer agents, investigational agent, radiation therapy, stem
cell transplantation or infusion, number of prior treatment regimens, colony
stimulating factors, corticosteroids.
- Performance score of >=50% according to the Karnofsky/Lansky performance status scale.
- Females of child-bearing potential must be willing to practice acceptable methods of
birth control. Additionally, females of childbearing potential must have a negative
serum pregnancy test within 7 days prior to start of study drugs, throughout treatment
period and for 4 months after last dose of study drugs.
- Must have adequate organ function as defined by the following values: renal function -
24 hr creatinine clearance (revised Schwartz formula), or radioisotope glomerular
filtration rate (GFR) >=60 milliliter (mL) per minute per 1.73 meter square
(mL/min/1.73m^2); or a serum creatinine <=upper limit of normal (ULN) for age and
gender; liver functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN
for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes of enrollment
and toxicity monitoring the ULN for ALT will be 45 unit per liter (U/L); cardiac
function - corrected QT (QTcB) interval <480 milliseconds (msec), left ventricular
ejection fraction (LVEF) >=lower limit of normal (LLN) by ECHO.
- Able to swallow and retain enterally (per oral [PO] or nasogastric or gastric tube)
administered medication and does not have any clinically significant gastrointestinal
abnormalities that may alter absorption such as malabsorption syndrome or major
resection of the stomach or bowels.
- Adequate Blood Pressure Control defined as: Blood pressure <= the 95th percentile for
age, height, and gender.
- French subjects: In France, a subject will be eligible for inclusion in this study
only if either affiliated to or a beneficiary of a social security category.
- Specific Eligibility Criteria, Part A
- Subjects must meet general eligibility criteria.
- For the initial dose escalation to identify the maximum tolerable or PK target dose,
age between 2 years and <18 years (inclusive) at the time of signing the informed
consent form. Children < 2 years of age will be enrolled once the age specific
expansion cohorts are open.
- Histologically confirmed solid tumors, which may include but are not limited to
rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors,
osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, primary
brain tumors, NF-1 associated PF and LCH. In subjects with brain stem gliomas the
requirement for histological confirmation can be waived if a biopsy was not performed.
For plexiform neurofibromas, histologic confirmation of tumor is not necessary in the
presence of consistent clinical and radiological findings, but should be considered if
malignant degeneration of a PN is clinically suspected.
- Measurable or evaluable tumors. Subjects with neuroblastoma that is only detectable by
Meta-iodobenzylguanidine (MIBG) scan are eligible. Subjects with neuroblastoma that is
only detected by bone marrow aspirate/biopsy or elevated homovanillic acid /
vanillylmandelic acid (HVA/VMA) are not eligible.
- Adequate bone marrow function defined as absolute neutrophil count (ANC)
>=1000/microliter, hemoglobin >=8.0 gram per deciliter (g/dL) (may receive red blood
cell transfusions), platelets >=75,000/ microliter (transfusion independent, defined
as not receiving platelet transfusions within a 7 day period prior to enrollment).
- Specific Eligibility Criteria, Part B
- Subjects must meet general eligibility criteria. The specific eligibility criteria
listed here will apply to subjects enrolling to different cohorts of Part B.
- Tumor tissue (archived or fresh) is required and must be available to be shipped to
GSK or site specific laboratory.
- Solid tumor cohort (B1) specific criteria
- B1: Refractory or relapsed neuroblastoma
- B2: Recurrent or unresectable low grade gliomas with BRAF tandem duplication with
fusion
- B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that
are unresectable and medically significant.
- B4: BRAF V600 mutant tumors.
- Specific Eligibility Criteria, Part C - Subjects must meet general eligibility
criteria.
- Tumors that have been documented by CLIA or equivalent certified laboratory test to
harbor BRAF V600 mutation at diagnosis or relapse
- Measurable or evaluable disease
- Adequate bone marrow function
- Specific Eligibility Criteria, Part D - Subjects must meet general eligibility
criteria
- Measurable or evaluable disease
- Recurrent or refractory BRAFV600 mutant LGG or LCH tumors
- Adequate bone marrow function
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Minimum age
1
Month
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Maximum age
17
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Lactating or pregnant female.
- History of another malignancy including resected non-melanomatous skin cancer.
- Subjects with NF-1 associated optic pathway tumors are excluded if they are actively
receiving therapy for the optic pathway tumor or do not meet criteria for PN or
malignant solid tumor.
- Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya).
- Subjects with NF-1 actively receiving therapy for the optic pathway tumor.
- Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis
(only applicable to Part B).
- Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures.
- Any prohibited medication(s), currently used or expected to be required.
- Any medications for treatment of left ventricular systolic dysfunction.
- Part B, Part C and Part D only: Previous treatment with dabrafenib or any BRAF
inhibitor, trametinib or another MEK inhibitor, or and Extracellular signal-regulated
kinase inhibitor (exception: prior treatment with sorafenib is permitted). Patients
who have received prior dabrafenib or another BRAF inhibitor may enrol into Part B4.
Patients who have had prior dabrafenib or BRAF inhibitor therapy may enroll in Part C
or Part D if they have had prior benefit to dabrafenib or BRAF inhibitor monotherapy,
as determined by the investigator.
- Administration of an investigational study treatment within 30 days preceding the
first dose of study treatment(s) in this study.
- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study treatment or excipients that contraindicate their
participation.
- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, or liver metastases).
- History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the
prior 3 months.
- History of heparin-induced thrombocytopenia.
- History of interstitial lung disease or pneumonitis.
- History of or current evidence of retinal vein occlusion (RVO).
- For subjects with solid tumors that are not primary central nervous system (CNS)
tumors or NF-1 associated plexiform neurofibromas subjects with symptomatic or
untreated leptomeningeal or brain metastases or spinal cord compression are excluded.
NOTE: Subjects previously treated for these conditions that have had stable CNS
disease (verified with consecutive imaging studies) for >3 months, are asymptomatic
and are not currently taking corticosteroids, or are on stable dose or decreasing of
corticosteroids for at least 7 days prior to enrolment are permitted.
- A history of known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.
Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.
- Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous
anti-cancer therapy, except alopecia.
- Presence of active gastrointestinal (GI) disease or other condition that will
interfere significantly with the absorption of drugs.
- A history or evidence of cardiovascular risk including: a QT interval corrected for
heart rate using the Bazett's formula (QTcB) >=480 msec; a history or evidence of
current clinically significant uncontrolled arrhythmias (clarification: Subjects with
atrial fibrillation controlled for >30 days prior to dosing are eligible); a history
of acute coronary syndromes (including myocardial infarction or unstable angina),
coronary angioplasty, or stenting within 6 months prior to randomization; a history or
evidence of current >=Class II congestive heart failure as defined by the New York
Heart Association (NYHA) guidelines; subjects with intra-cardiac defibrillators;
abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects
with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on
study). Subjects with moderate valvular thickening should not be entered on study.
Subjects with prosthetic valves can be considered eligible provided they meet the
criteria as stated above; Treatment refractory hypertension defined as a blood
pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg (or
above 95th age-specific percentile listed in protocol), which cannot be controlled by
anti-hypertensive therapy.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
15/01/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
29/12/2020
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Sample size
Target
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Accrual to date
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Final
139
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
0
0
Novartis Investigative Site - Westmead
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Recruitment postcode(s) [1]
0
0
2145 - Westmead
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Recruitment outside Australia
Country [1]
0
0
United States of America
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State/province [1]
0
0
Arizona
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Country [2]
0
0
United States of America
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State/province [2]
0
0
California
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Country [3]
0
0
United States of America
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State/province [3]
0
0
District of Columbia
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Country [4]
0
0
United States of America
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State/province [4]
0
0
Maryland
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Country [5]
0
0
United States of America
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State/province [5]
0
0
Massachusetts
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Country [6]
0
0
United States of America
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State/province [6]
0
0
Minnesota
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Country [7]
0
0
United States of America
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State/province [7]
0
0
New York
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Country [8]
0
0
United States of America
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State/province [8]
0
0
Ohio
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Country [9]
0
0
United States of America
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State/province [9]
0
0
Pennsylvania
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Country [10]
0
0
United States of America
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State/province [10]
0
0
Tennessee
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Country [11]
0
0
Canada
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State/province [11]
0
0
Ontario
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Country [12]
0
0
France
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State/province [12]
0
0
Paris Cedex 05
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Country [13]
0
0
France
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State/province [13]
0
0
Villejuif Cedex
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Country [14]
0
0
United Kingdom
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State/province [14]
0
0
Surrey
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Country [15]
0
0
United Kingdom
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State/province [15]
0
0
London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief 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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02124772
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
0
0
Novartis Pharmaceuticals
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Address
0
0
Novartis Pharmaceuticals
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Country
0
0
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Phone
0
0
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Fax
0
0
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Email
0
0
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Contact person for public queries
Name
0
0
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Address
0
0
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Country
0
0
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Phone
0
0
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Fax
0
0
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Email
0
0
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02124772
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