Cancer
Conditions
Keywords
v600-mutation, neuroblastoma, Trametinib, pediatrics, Langerhans Cell Histiocytosis, low grade glioma, plexiform neurofibromas
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.
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.
Interventions
DRUGTrametinib
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).
DRUGDabrafenib
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).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 17 Years
Healthy volunteers
No
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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months | 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. |
| Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 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. | 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. |
| 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 | 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. | 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. |
| 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 | 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. | 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. |
| Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 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. | 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. |
| Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 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. | 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. |
| Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | 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 | 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. |
| Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months | 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. |
| Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months | 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. |
| Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months | 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. |
| Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model | 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. | 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. |
| Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model | 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. | 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. |
| Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days. | 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. |
| Significant Covariates Estimated With a PopPK Model | 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. | 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. |
| Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days. | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 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. | 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. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 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. | 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. |
| 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 | 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. | 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. |
| 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 | 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. | 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. |
| Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 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. | 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. |
| Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 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. | 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. |
| Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | After the first dose of trametinib oral solution and no later than Day 8 (±3 days) | 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. |
| Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days) | 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. |
| Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model | 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. | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 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. | 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. |
Countries
Australia, Canada, France, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in 16 investigative sites in 5 countries.
Pre-assignment details
The participants were screened within 14 days prior to enrollment. After screening, the treatment period started on Cycle 1 Day 1.
Participants by arm
| Arm | Count |
|---|---|
| Part A - TMT 0.0125 mg/kg/Day Participants treated with trametinib 0.0125 mg/kg/day | 3 |
| Part A - TMT 0.025 mg/kg/Day Participants treated with trametinib 0.025 mg/kg/day | 19 |
| Part A - TMT 0.032 mg/kg/Day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day | 12 |
| Part A - TMT 0.04 mg/kg/Day Participants treated with trametinib 0.04 mg/kg/day | 16 |
| Part B - Neuroblastoma Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day | 11 |
| Part B - LGG Fusion Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day | 10 |
| 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 | 10 |
| Part B - BRAF V600 Mutant Solid Tumor Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day | 10 |
| 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) | 3 |
| 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) | 9 |
| 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) | 6 |
| 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) | 20 |
| 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) | 10 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 | 1 | 5 | 2 | 1 | 1 | 5 | 0 | 3 | 1 | 3 | 1 |
| Overall Study | Investigator discretion | 0 | 2 | 2 | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 | 1 | 2 | 3 | 0 | 2 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Other | 0 | 7 | 2 | 5 | 4 | 3 | 4 | 1 | 1 | 1 | 1 | 1 | 0 |
| Overall Study | Progressive disease | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal consent | 0 | 1 | 1 | 1 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A - TMT 0.0125 mg/kg/Day | Part A - TMT 0.025 mg/kg/Day | Part A - TMT 0.032 mg/kg/Day | Part A - TMT 0.04 mg/kg/Day | Part B - Neuroblastoma | Part B - LGG Fusion | Part B - NF-1 With PN | Part B - BRAF V600 Mutant Solid Tumor | Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Part D - LGG | Part D - LCH | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized ≥ 12 years | 1 Participants | 6 Participants | 0 Participants | 5 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 5 Participants | 0 Participants | 9 Participants | 1 Participants | 38 Participants |
| Age, Customized 2 - <6 years | 1 Participants | 5 Participants | 11 Participants | 0 Participants | 3 Participants | 4 Participants | 4 Participants | 5 Participants | 0 Participants | 2 Participants | 5 Participants | 2 Participants | 6 Participants | 48 Participants |
| Age, Customized < 2 years | 0 Participants | 4 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 10 Participants |
| Age, Customized 6 - <12 years | 1 Participants | 4 Participants | 0 Participants | 9 Participants | 5 Participants | 5 Participants | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 9 Participants | 3 Participants | 43 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 4 Participants | 4 Participants | 21 Participants |
| Race (NIH/OMB) White | 3 Participants | 16 Participants | 7 Participants | 14 Participants | 9 Participants | 6 Participants | 7 Participants | 5 Participants | 2 Participants | 6 Participants | 4 Participants | 16 Participants | 3 Participants | 98 Participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 6 Participants | 7 Participants | 6 Participants | 5 Participants | 5 Participants | 5 Participants | 0 Participants | 6 Participants | 4 Participants | 10 Participants | 2 Participants | 64 Participants |
| Sex: Female, Male Male | 2 Participants | 12 Participants | 6 Participants | 9 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 3 Participants | 3 Participants | 2 Participants | 10 Participants | 8 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 19 | 0 / 12 | 0 / 16 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 3 | 0 / 9 | 0 / 6 | 0 / 20 | 0 / 10 |
| other Total, other adverse events | 3 / 3 | 19 / 19 | 12 / 12 | 16 / 16 | 11 / 11 | 10 / 10 | 10 / 10 | 10 / 10 | 3 / 3 | 9 / 9 | 6 / 6 | 20 / 20 | 10 / 10 |
| serious Total, serious adverse events | 1 / 3 | 8 / 19 | 3 / 12 | 11 / 16 | 6 / 11 | 6 / 10 | 6 / 10 | 5 / 10 | 1 / 3 | 5 / 9 | 2 / 6 | 8 / 20 | 6 / 10 |
Outcome results
Primary
Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy)
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A and B and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 5.76 ng/mL | Geometric Coefficient of Variation 24.8 |
| Part A - TMT 0.025 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 13.9 ng/mL | Geometric Coefficient of Variation 27.1 |
| Part A - TMT 0.032 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 15.2 ng/mL | Geometric Coefficient of Variation 16.9 |
| Part A - TMT 0.04 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 21.3 ng/mL | Geometric Coefficient of Variation 20.7 |
| Part B - Neuroblastoma | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 15.1 ng/mL | Geometric Coefficient of Variation 36 |
| Part B - LGG Fusion | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 13.2 ng/mL | Geometric Coefficient of Variation 40.4 |
| Part B - NF-1 With PN | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 13.5 ng/mL | Geometric Coefficient of Variation 25.1 |
| Part B - BRAF V600 Mutant Solid Tumor | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 15.8 ng/mL | Geometric Coefficient of Variation 42.8 |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 14.3 ng/mL | Geometric Coefficient of Variation 35.8 |
Primary
Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy
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.
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
Population: All subjects who received at least one dose of trametinib in Part A and B
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 3 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 1 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 1 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 3 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 4 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 8 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 19 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 19 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 13 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 9 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 12 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 5 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 5 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 12 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 12 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 7 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 3 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 14 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 16 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 16 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 11 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 6 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 6 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 14 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 9 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 10 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 2 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 4 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 11 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 3 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 1 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 3 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 6 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 8 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 4 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 2 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 10 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 10 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 6 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 1 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part B - LGG Fusion | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 8 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 1 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 6 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 5 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 3 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 10 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 6 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 10 Participants |
| Part B - NF-1 With PN | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 2 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose interruptions | 8 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | SAEs | 5 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Fatal SAEs | 0 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions or interruptions | 9 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs leading to discontinuation | 5 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related SAEs | 3 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs requiring dose reductions | 7 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | Treatment-related AEs | 10 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy | AEs | 10 Participants |
Secondary
Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model | Ka1 | 0.134 1/hours |
| Part A - TMT 0.0125 mg/kg/Day | Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model | Ka2 | 1.55 1/hours |
Secondary
Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model | 184 liters |
Secondary
Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model | 5.07 liters/hour |
Secondary
Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib
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.
Time frame: 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.
Population: All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 22900 mL/hour | Geometric Coefficient of Variation 191.2 |
| Part A - TMT 0.025 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 20400 mL/hour | Geometric Coefficient of Variation 45.4 |
| Part A - TMT 0.032 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 10100 mL/hour | Geometric Coefficient of Variation 67 |
| Part A - TMT 0.04 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 25400 mL/hour | Geometric Coefficient of Variation 70.5 |
| Part B - Neuroblastoma | Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 12500 mL/hour | Geometric Coefficient of Variation 63 |
| Part B - LGG Fusion | Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 10200 mL/hour | Geometric Coefficient of Variation 41.6 |
| Part B - NF-1 With PN | Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 25100 mL/hour | Geometric Coefficient of Variation 69.3 |
Secondary
Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2750 mL/hour | Geometric Coefficient of Variation 69.4 |
| Part A - TMT 0.025 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1530 mL/hour | Geometric Coefficient of Variation 64.5 |
| Part A - TMT 0.032 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1240 mL/hour | Geometric Coefficient of Variation 25.5 |
| Part A - TMT 0.04 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2040 mL/hour | Geometric Coefficient of Variation 71.5 |
| Part B - Neuroblastoma | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1710 mL/hour | Geometric Coefficient of Variation 55.6 |
| Part B - LGG Fusion | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1910 mL/hour | Geometric Coefficient of Variation 47.8 |
| Part B - NF-1 With PN | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1590 mL/hour | Geometric Coefficient of Variation 65.3 |
| Part B - BRAF V600 Mutant Solid Tumor | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1820 mL/hour | Geometric Coefficient of Variation 42.6 |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1750 mL/hour | Geometric Coefficient of Variation 51.5 |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2590 mL/hour | — |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 3770 mL/hour | — |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2010 mL/hour | Geometric Coefficient of Variation 38.5 |
| Part D - LGG | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 3540 mL/hour | Geometric Coefficient of Variation 54 |
| Part D - LCH | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 3060 mL/hour | Geometric Coefficient of Variation 44.9 |
| Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2180 mL/hour | Geometric Coefficient of Variation 23.9 |
| Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D | Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib | 3810 mL/hour | Geometric Coefficient of Variation 49.6 |
Secondary
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
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.
Time frame: 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.
Population: All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | 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 | 2870 hours*ng/mL | Geometric Coefficient of Variation 116.6 |
| Part A - TMT 0.025 mg/kg/Day | 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 | 4160 hours*ng/mL | Geometric Coefficient of Variation 24.6 |
| Part A - TMT 0.032 mg/kg/Day | 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 | 4040 hours*ng/mL | Geometric Coefficient of Variation 47.9 |
| Part A - TMT 0.04 mg/kg/Day | 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 | 4070 hours*ng/mL | Geometric Coefficient of Variation 46.7 |
| Part B - Neuroblastoma | 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 | 3910 hours*ng/mL | Geometric Coefficient of Variation 37.4 |
| Part B - LGG Fusion | 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 | 4150 hours*ng/mL | Geometric Coefficient of Variation 30.2 |
| Part B - NF-1 With PN | 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 | 3990 hours*ng/mL | Geometric Coefficient of Variation 47.3 |
Secondary
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
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | 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 | 138 hours*ng/mL | Geometric Coefficient of Variation 24.8 |
| Part A - TMT 0.025 mg/kg/Day | 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 | 334 hours*ng/mL | Geometric Coefficient of Variation 27.1 |
| Part A - TMT 0.032 mg/kg/Day | 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 | 364 hours*ng/mL | Geometric Coefficient of Variation 16.9 |
| Part A - TMT 0.04 mg/kg/Day | 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 | 511 hours*ng/mL | Geometric Coefficient of Variation 20.7 |
| Part B - Neuroblastoma | 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 | 362 hours*ng/mL | Geometric Coefficient of Variation 36 |
| Part B - LGG Fusion | 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 | 316 hours*ng/mL | Geometric Coefficient of Variation 40.4 |
| Part B - NF-1 With PN | 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 | 323 hours*ng/mL | Geometric Coefficient of Variation 25.1 |
| Part B - BRAF V600 Mutant Solid Tumor | 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 | 379 hours*ng/mL | Geometric Coefficient of Variation 42.8 |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | 343 hours*ng/mL | Geometric Coefficient of Variation 35.8 |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | 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 | 290 hours*ng/mL | — |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | 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 | 331 hours*ng/mL | — |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 236 hours*ng/mL | Geometric Coefficient of Variation 28.4 |
| Part D - LGG | 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 | 308 hours*ng/mL | Geometric Coefficient of Variation 20 |
| Part D - LCH | 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 | 186 hours*ng/mL | Geometric Coefficient of Variation 23.7 |
| Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 228 hours*ng/mL | Geometric Coefficient of Variation 33.1 |
| Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D | 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 | 286 hours*ng/mL | Geometric Coefficient of Variation 28.4 |
Secondary
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
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.
Time frame: 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.
Population: All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | 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 | 2560 hours*ng/mL | Geometric Coefficient of Variation 157.1 |
| Part A - TMT 0.025 mg/kg/Day | 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 | 4160 hours*ng/mL | Geometric Coefficient of Variation 24.6 |
| Part A - TMT 0.032 mg/kg/Day | 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 | 3910 hours*ng/mL | Geometric Coefficient of Variation 48.8 |
| Part A - TMT 0.04 mg/kg/Day | 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 | 4030 hours*ng/mL | Geometric Coefficient of Variation 46.4 |
| Part B - Neuroblastoma | 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 | 3800 hours*ng/mL | Geometric Coefficient of Variation 35.4 |
| Part B - LGG Fusion | 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 | 3990 hours*ng/mL | Geometric Coefficient of Variation 28.3 |
| Part B - NF-1 With PN | 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 | 3950 hours*ng/mL | Geometric Coefficient of Variation 46.9 |
Secondary
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
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | 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 | 138 hours*ng/mL | Geometric Coefficient of Variation 24.8 |
| Part A - TMT 0.025 mg/kg/Day | 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 | 341 hours*ng/mL | Geometric Coefficient of Variation 28.3 |
| Part A - TMT 0.032 mg/kg/Day | 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 | 364 hours*ng/mL | Geometric Coefficient of Variation 16.9 |
| Part A - TMT 0.04 mg/kg/Day | 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 | 413 hours*ng/mL | Geometric Coefficient of Variation 76.2 |
| Part B - Neuroblastoma | 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 | 362 hours*ng/mL | Geometric Coefficient of Variation 36 |
| Part B - LGG Fusion | 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 | 316 hours*ng/mL | Geometric Coefficient of Variation 40.4 |
| Part B - NF-1 With PN | 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 | 304 hours*ng/mL | Geometric Coefficient of Variation 36.9 |
| Part B - BRAF V600 Mutant Solid Tumor | 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 | 379 hours*ng/mL | Geometric Coefficient of Variation 42.8 |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | 337 hours*ng/mL | Geometric Coefficient of Variation 38.6 |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | 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 | 290 hours*ng/mL | — |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | 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 | 331 hours*ng/mL | — |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 122 hours*ng/mL | Geometric Coefficient of Variation 29 |
| Part D - LGG | 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 | 270 hours*ng/mL | Geometric Coefficient of Variation 35.8 |
| Part D - LCH | 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 | 118 hours*ng/mL | Geometric Coefficient of Variation 53.4 |
| Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 126 hours*ng/mL | Geometric Coefficient of Variation 30.7 |
| Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D | 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 | 255 hours*ng/mL | Geometric Coefficient of Variation 49.2 |
Secondary
Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib
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.
Time frame: 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.
Population: All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 239 ng/mL | Geometric Coefficient of Variation 116.6 |
| Part A - TMT 0.025 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 347 ng/mL | Geometric Coefficient of Variation 24.6 |
| Part A - TMT 0.032 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 337 ng/mL | Geometric Coefficient of Variation 47.9 |
| Part A - TMT 0.04 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 339 ng/mL | Geometric Coefficient of Variation 46.7 |
| Part B - Neuroblastoma | Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 326 ng/mL | Geometric Coefficient of Variation 37.4 |
| Part B - LGG Fusion | Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 346 ng/mL | Geometric Coefficient of Variation 30.2 |
| Part B - NF-1 With PN | Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 332 ng/mL | Geometric Coefficient of Variation 47.3 |
Secondary
Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 12.1 ng/mL | — |
| Part A - TMT 0.025 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 13.8 ng/mL | — |
| Part A - TMT 0.032 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 9.83 ng/mL | Geometric Coefficient of Variation 28.4 |
| Part A - TMT 0.04 mg/kg/Day | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 12.8 ng/mL | Geometric Coefficient of Variation 20 |
| Part B - Neuroblastoma | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 7.76 ng/mL | Geometric Coefficient of Variation 23.7 |
| Part B - LGG Fusion | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 9.50 ng/mL | Geometric Coefficient of Variation 33.1 |
| Part B - NF-1 With PN | Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 11.9 ng/mL | Geometric Coefficient of Variation 28.4 |
Secondary
Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
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.
Time frame: From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
Population: All subjects who received at least one dose of trametinib in Part A and Part B or at least one dose of any component of the combination in Part C and Part D
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 1 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 16 Participants |
| Part A - TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 3 Participants |
| Part A - TMT 0.032 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 2 Participants |
| Part A - TMT 0.032 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 10 Participants |
| Part A - TMT 0.04 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 2 Participants |
| Part A - TMT 0.04 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 4 Participants |
| Part B - Neuroblastoma | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part B - Neuroblastoma | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 1 Participants |
| Part B - Neuroblastoma | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 1 Participants |
| Part B - Neuroblastoma | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 5 Participants |
| Part B - Neuroblastoma | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part B - Neuroblastoma | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 3 Participants |
| Part B - Neuroblastoma | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 1 Participants |
| Part B - LGG Fusion | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 3 Participants |
| Part B - LGG Fusion | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 7 Participants |
| Part B - LGG Fusion | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 0 Participants |
| Part B - LGG Fusion | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part B - LGG Fusion | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part B - LGG Fusion | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part B - LGG Fusion | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part B - NF-1 With PN | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part B - NF-1 With PN | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part B - NF-1 With PN | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 0 Participants |
| Part B - NF-1 With PN | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 2 Participants |
| Part B - NF-1 With PN | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part B - NF-1 With PN | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part B - NF-1 With PN | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 8 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 4 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 5 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 0 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 1 Participants |
| Part B - BRAF V600 Mutant Solid Tumor | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 1 Participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 2 Participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 0 Participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 5 Participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 1 Participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 3 Participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 2 Participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 1 Participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 1 Participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 2 Participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 1 Participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 0 Participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 8 Participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 9 Participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 2 Participants |
| Part D - LGG | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Partial response (PR) | 3 Participants |
| Part D - LGG | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Missing | 1 Participants |
| Part D - LGG | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Stable disease (SD) | 3 Participants |
| Part D - LGG | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Complete response (CR) | 3 Participants |
| Part D - LGG | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Non-CR/Non-PD | 0 Participants |
| Part D - LGG | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Progressive disease (PD) | 0 Participants |
| Part D - LGG | Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | Unknown | 0 Participants |
Secondary
Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
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.
Time frame: From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
Population: All subjects who received at least one dose of trametinib in Part A and Part B or at least one dose of any component of the combination in Part C and Part D
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 33.3 percentage of participants |
| Part A - TMT 0.025 mg/kg/Day | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 15.8 percentage of participants |
| Part A - TMT 0.032 mg/kg/Day | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 33.3 percentage of participants |
| Part A - TMT 0.04 mg/kg/Day | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 25.0 percentage of participants |
| Part B - Neuroblastoma | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 18.2 percentage of participants |
| Part B - LGG Fusion | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 100 percentage of participants |
| Part B - NF-1 With PN | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 80.0 percentage of participants |
| Part B - BRAF V600 Mutant Solid Tumor | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 90.0 percentage of participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 100 percentage of participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 88.9 percentage of participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 83.3 percentage of participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 95.0 percentage of participants |
| Part D - LGG | Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 90.0 percentage of participants |
Secondary
Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib
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.
Time frame: 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
Population: All subjects who received at least one dose of any component of the combination in Part C and Part D
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related AEs | 3 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose interruptions | 1 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs | 3 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs leading to discontinuation | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | SAEs | 1 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related SAEs | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions | 1 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions or interruptions | 1 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Fatal SAEs | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | SAEs | 5 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs leading to discontinuation | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions or interruptions | 7 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs | 9 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related SAEs | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Fatal SAEs | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose interruptions | 6 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related AEs | 9 Participants |
| Part A - TMT 0.025 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions | 3 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related AEs | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | SAEs | 2 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs leading to discontinuation | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose interruptions | 4 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Fatal SAEs | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions or interruptions | 4 Participants |
| Part A - TMT 0.032 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related SAEs | 1 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs | 20 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Fatal SAEs | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs leading to discontinuation | 5 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose interruptions | 16 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions | 6 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions or interruptions | 16 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related AEs | 20 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | SAEs | 8 Participants |
| Part A - TMT 0.04 mg/kg/Day | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related SAEs | 5 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | SAEs | 6 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs | 10 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related SAEs | 3 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Fatal SAEs | 0 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions or interruptions | 8 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose reductions | 1 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs requiring dose interruptions | 8 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | Treatment-related AEs | 10 Participants |
| Part B - Neuroblastoma | Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib | AEs leading to discontinuation | 1 Participants |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib
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.
Time frame: 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.
Population: All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 630 ng/mL | Geometric Coefficient of Variation 235.2 |
| Part A - TMT 0.025 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 1560 ng/mL | Geometric Coefficient of Variation 35.3 |
| Part A - TMT 0.032 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 1440 ng/mL | Geometric Coefficient of Variation 43.3 |
| Part A - TMT 0.04 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 1360 ng/mL | Geometric Coefficient of Variation 55.6 |
| Part B - Neuroblastoma | Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 1490 ng/mL | Geometric Coefficient of Variation 88.1 |
| Part B - LGG Fusion | Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 1840 ng/mL | Geometric Coefficient of Variation 35.2 |
| Part B - NF-1 With PN | Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 1290 ng/mL | Geometric Coefficient of Variation 68.7 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 9.61 ng/mL | Geometric Coefficient of Variation 32.9 |
| Part A - TMT 0.025 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 21.1 ng/mL | Geometric Coefficient of Variation 33.3 |
| Part A - TMT 0.032 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 26.1 ng/mL | Geometric Coefficient of Variation 16.8 |
| Part A - TMT 0.04 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 32.6 ng/mL | Geometric Coefficient of Variation 28.9 |
| Part B - Neuroblastoma | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 26.6 ng/mL | Geometric Coefficient of Variation 39.6 |
| Part B - LGG Fusion | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 22.1 ng/mL | Geometric Coefficient of Variation 41.9 |
| Part B - NF-1 With PN | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 21.6 ng/mL | Geometric Coefficient of Variation 26.1 |
| Part B - BRAF V600 Mutant Solid Tumor | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 27.5 ng/mL | Geometric Coefficient of Variation 31.6 |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 24.2 ng/mL | Geometric Coefficient of Variation 35.6 |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 26.0 ng/mL | — |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 24.5 ng/mL | — |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 23.7 ng/mL | Geometric Coefficient of Variation 36.3 |
| Part D - LGG | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 22.9 ng/mL | Geometric Coefficient of Variation 29.2 |
| Part D - LCH | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 15.6 ng/mL | Geometric Coefficient of Variation 52.5 |
| Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 25.9 ng/mL | Geometric Coefficient of Variation 35.8 |
| Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D | Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 20.0 ng/mL | Geometric Coefficient of Variation 38.1 |
Secondary
Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
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.
Time frame: From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
Population: All subjects who received at least one dose of trametinib in Part A and Part B or at least one dose of any component of the combination in Part C and Part D
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 0 percentage of participants |
| Part A - TMT 0.025 mg/kg/Day | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 5.3 percentage of participants |
| Part A - TMT 0.032 mg/kg/Day | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 8.3 percentage of participants |
| Part A - TMT 0.04 mg/kg/Day | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 0 percentage of participants |
| Part B - Neuroblastoma | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 9.1 percentage of participants |
| Part B - LGG Fusion | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 30.0 percentage of participants |
| Part B - NF-1 With PN | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 0 percentage of participants |
| Part B - BRAF V600 Mutant Solid Tumor | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 50.0 percentage of participants |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 66.7 percentage of participants |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 33.3 percentage of participants |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 66.7 percentage of participants |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 55.0 percentage of participants |
| Part D - LGG | Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 60.0 percentage of participants |
Secondary
Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire
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.
Time frame: After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days)
Population: All subjects who received at least one dose of dabrafenib oral suspension and filled in the palatability questionnaire.~All palatability questionnaire results were combined and reported based on drug dose to better determine the acceptability and palatability of the formulation. There were no results available for participants who received 50% of the RP2D of dabrafenib monotherapy in combination with trametinib because the participants did not fill in the questionnaire.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | No | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | missing | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | No | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | missing | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | missing | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | No | 4 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | missing | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | No | 4 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | No | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | missing | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | missing | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | No | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | missing | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | Yes | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | No | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | missing | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | No | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | missing | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | No | 4 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | missing | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | Yes | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | No | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | Yes | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | missing | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | No | 2 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | No | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | No | 5 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | missing | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | No | 5 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | Yes | 4 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | No | 2 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | missing | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | missing | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | No | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | missing | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | missing | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | missing | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | Yes | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | missing | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | No | 5 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | No | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | missing | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | Yes | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | No | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | Yes | 2 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | No | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | No | 4 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | missing | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | missing | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | missing | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | Yes | 4 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | Yes | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | No | 2 Participants |
Secondary
Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire
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.
Time frame: After the first dose of trametinib oral solution and no later than Day 8 (±3 days)
Population: All subjects who received at least one dose of trametinib oral solution and filled in the palatability questionnaire.~All palatability questionnaire results were combined and reported based on drug dose to better determine the acceptability and palatability of the formulation.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | No | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | No | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | Yes | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | missing | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | missing | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | missing | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | missing | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | missing | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | No | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | missing | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | missing | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | No | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | No | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | No | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | missing | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | No | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | No | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | missing | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | missing | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | No | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | No | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | No | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | Yes | 0 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | missing | 2 Participants |
| Part A - TMT 0.0125 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | missing | 24 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | Yes | 5 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | No | 24 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | No | 19 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | missing | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | Yes | 8 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | No | 16 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | No | 4 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | Yes | 7 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | No | 18 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | missing | 4 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | missing | 4 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | missing | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | Yes | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | No | 26 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | Yes | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | missing | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | missing | 24 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | Yes | 0 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | No | 29 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | Yes | 1 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | missing | 5 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | Yes | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | No | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | Yes | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | missing | 24 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | No | 5 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | No | 3 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | missing | 24 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | Yes | 2 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | missing | 23 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | Yes | 6 Participants |
| Part A - TMT 0.025 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | No | 3 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | No | 19 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | No | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | Yes | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | No | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | missing | 20 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | missing | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | No | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | missing | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | missing | 20 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | missing | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | No | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | missing | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | Yes | 5 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | No | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | Yes | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | No | 13 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | missing | 20 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | missing | 20 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | Yes | 0 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | No | 15 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | No | 18 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | missing | 20 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | Yes | 2 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | Yes | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | No | 13 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | missing | 2 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | Yes | 6 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | No | 14 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | missing | 1 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | Yes | 7 Participants |
| Part A - TMT 0.032 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | No | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | No | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine gritty? | missing | 4 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | Yes | 1 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | No | 3 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | No | 4 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to mix? | missing | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | missing | 1 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | No | 4 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | Yes | 2 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject like the taste of the medicine? | No | 1 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | No | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | No | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine bitter? | missing | 4 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | missing | 4 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sweet? | missing | 4 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | Yes | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to swallow? | missing | 4 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine sour? | No | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | Yes | 1 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | No | 3 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to administer? | missing | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject have difficulty in taking the medicine? | missing | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | Yes | 1 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | No | 3 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Did the subject resist taking the medicine? | missing | 0 Participants |
| Part A - TMT 0.04 mg/kg/Day | Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire | Was the medicine difficult to measure? | missing | 0 Participants |
Secondary
Significant Covariates Estimated With a PopPK Model
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Significant Covariates Estimated With a PopPK Model | Effect of sex on CL/F | 1.24 no units |
| Part A - TMT 0.0125 mg/kg/Day | Significant Covariates Estimated With a PopPK Model | Effect of weight on Q/F | 0.679 no units |
| Part A - TMT 0.0125 mg/kg/Day | Significant Covariates Estimated With a PopPK Model | Effect of combination with dabrafenib on relative bioavailability F1 | 0.876 no units |
| Part A - TMT 0.0125 mg/kg/Day | Significant Covariates Estimated With a PopPK Model | Effect of weight on CL/F | 0.788 no units |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib
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.
Time frame: 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.
Population: All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 2.00 hours |
| Part A - TMT 0.025 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 1.00 hours |
| Part A - TMT 0.032 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 2.00 hours |
| Part A - TMT 0.04 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 2.00 hours |
| Part B - Neuroblastoma | Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 1.00 hours |
| Part B - LGG Fusion | Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 1.00 hours |
| Part B - NF-1 With PN | Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 2.00 hours |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
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.
Time frame: 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.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part A - TMT 0.025 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2.00 hours |
| Part A - TMT 0.032 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part A - TMT 0.04 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2.00 hours |
| Part B - Neuroblastoma | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part B - LGG Fusion | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.50 hours |
| Part B - NF-1 With PN | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part B - BRAF V600 Mutant Solid Tumor | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.50 hours |
| Part D - LGG | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2.00 hours |
| Part D - LCH | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 1.00 hours |
| Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D | Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib | 2.00 hours |
Secondary
Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib
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.
Time frame: pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
Population: All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 88.9 ng/mL | Geometric Coefficient of Variation 99.6 |
| Part A - TMT 0.025 mg/kg/Day | Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 28.6 ng/mL | Geometric Coefficient of Variation 203.5 |
| Part A - TMT 0.032 mg/kg/Day | Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 8.10 ng/mL | Geometric Coefficient of Variation 159.6 |
| Part A - TMT 0.04 mg/kg/Day | Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 38.2 ng/mL | Geometric Coefficient of Variation 130.9 |
| Part B - Neuroblastoma | Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 11.8 ng/mL | Geometric Coefficient of Variation 869.4 |
| Part B - LGG Fusion | Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 5.36 ng/mL | Geometric Coefficient of Variation 429.6 |
| Part B - NF-1 With PN | Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 42.7 ng/mL | Geometric Coefficient of Variation 137.4 |
Secondary
Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib
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.
Time frame: pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
Population: All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 4.37 ng/mL | Geometric Coefficient of Variation 30.6 |
| Part A - TMT 0.025 mg/kg/Day | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 11.1 ng/mL | Geometric Coefficient of Variation 44 |
| Part A - TMT 0.032 mg/kg/Day | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 10.2 ng/mL | Geometric Coefficient of Variation 19.4 |
| Part A - TMT 0.04 mg/kg/Day | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 15.6 ng/mL | Geometric Coefficient of Variation 30.1 |
| Part B - Neuroblastoma | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 10.7 ng/mL | Geometric Coefficient of Variation 43.3 |
| Part B - LGG Fusion | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 9.45 ng/mL | Geometric Coefficient of Variation 53.6 |
| Part B - NF-1 With PN | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 9.25 ng/mL | Geometric Coefficient of Variation 29 |
| Part B - BRAF V600 Mutant Solid Tumor | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 11.3 ng/mL | Geometric Coefficient of Variation 50.3 |
| Part B - All Tumor Types TMT 0.025 mg/kg/Day | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 10.1 ng/mL | Geometric Coefficient of Variation 43.6 |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 8.31 ng/mL | — |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 10.2 ng/mL | — |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 3.86 ng/mL | Geometric Coefficient of Variation 34.9 |
| Part D - LGG | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 8.60 ng/mL | Geometric Coefficient of Variation 42.2 |
| Part D - LCH | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 3.74 ng/mL | Geometric Coefficient of Variation 66.3 |
| Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 3.05 ng/mL | Geometric Coefficient of Variation 50.7 |
| Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D | Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib | 8.68 ng/mL | Geometric Coefficient of Variation 38.6 |