A Phase 1/2 interventional study of Trametinib and Dabrafenib in Cancer, sponsored by Novartis Pharmaceuticals. Completed at 16 sites in 5 countries. Open to participants aged 1 Month to 17 Years. Per ClinicalTrials.gov, last updated 2021-07-14.
Sponsored by Novartis Pharmaceuticals (part of Novartis) · Phase 1/2, Interventional, and Treatment
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.
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.
63 studies on the registry are indexed under Neurofibroma, Plexiform; 19 are open to participants now.
This study's enrollment of 139 is above the median of 36 across 43 interventional studies indexed under Neurofibroma, Plexiform.
Browse Neurofibroma, Plexiform studies →Novartis Pharmaceuticals is the lead sponsor of 2,718 studies on the registry; 221 are open to participants now.
Of its 585 completed or terminated interventional studies of FDA-regulated products, 438 (75%) have results posted.
Compared within Neurofibroma, Plexiform, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Neoplasms. The counts are of registry records indexed under each term, refreshed daily. How we classify →
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Cancer that has spread to the leptomeninges, the thin layers covering the brain and spinal cord, and the fluid between them. It is not the same as brain metastases.
Criteria often treat it separately, and many studies leave it out even where treated brain metastases are allowed.
Cancer deposits in the brain from a cancer that started elsewhere in the body (CNS metastases include the spinal cord).
Studies differ: some leave out any brain metastases, some accept ones treated and stable for some weeks. Check what this study allows.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Relapsed and refractory
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Karnofsky performance status (KPS)
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Histologically or cytologically confirmed
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Leptomeningeal disease
Cancer that has spread to the leptomeninges, the thin layers covering the brain and spinal cord, and the fluid between them. It is not the same as brain metastases.
Criteria often treat it separately, and many studies leave it out even where treated brain metastases are allowed.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Brain metastases
Cancer deposits in the brain from a cancer that started elsewhere in the body (CNS metastases include the spinal cord).
Studies differ: some leave out any brain metastases, some accept ones treated and stable for some weeks. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CTCAE grade
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
NYHA class (heart failure)
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants treated with trametinib 0.0125 mg/kg/day
Drug: Trametinib
Participants treated with trametinib 0.025 mg/kg/day
Drug: Trametinib
Participants under 6 years of age treated with trametinib 0.032 mg/kg/day
Drug: Trametinib
Participants treated with trametinib 0.04 mg/kg/day
Drug: Trametinib
Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day
Drug: Trametinib
Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day
Drug: Trametinib
Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day
Drug: Trametinib
Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day
Drug: Trametinib
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)
Drug: Trametinib · Drug: Dabrafenib
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)
Drug: Trametinib · Drug: Dabrafenib
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)
Drug: Trametinib · Drug: Dabrafenib
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)
Drug: Trametinib · Drug: Dabrafenib
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)
Drug: Trametinib · Drug: Dabrafenib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).
Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).
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
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.
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.
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.
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.
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.
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.
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.
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.
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
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
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
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)
Participants took part in 16 investigative sites in 5 countries.
| Milestone | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 3 | 19 | 12 | 16 | 11 | 10 | 10 | 10 | 3 | 9 | 6 | 20 | 10 |
| Completed | 0 | 5 | 6 | 3 | 2 | 2 | 2 | 1 | 2 | 2 | 4 | 14 | 8 |
| Not completed | 3 | 14 | 6 | 13 | 9 | 8 | 8 | 9 | 1 | 7 | 2 | 6 | 2 |
| Withdrew: Lack of efficacy | 2 | 0 | 0 | 1 | 2 | 3 | 0 | 2 | 0 | 1 | 0 | 0 | 1 |
| Withdrew: Adverse event | 1 | 4 | 1 | 5 | 2 | 1 | 1 | 5 | 0 | 3 | 1 | 3 | 1 |
| Withdrew: Withdrawal consent | 0 | 1 | 1 | 1 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
| Withdrew: Investigator discretion | 0 | 2 | 2 | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
| Withdrew: Progressive disease | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Other | 0 | 7 | 2 | 5 | 4 | 3 | 4 | 1 | 1 | 1 | 1 | 1 | 0 |
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.
| Participants | 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 |
|---|---|---|---|---|---|---|---|---|
| AEs | 3 | 19 | 12 | 16 | 11 | 10 | 10 | 10 |
| Treatment-related AEs | 3 | 19 | 12 | 16 | 10 | 10 | 10 | 10 |
| SAEs | 1 | 8 | 3 | 11 | 6 | 6 | 6 | 5 |
| Treatment-related SAEs | 0 | 5 | 1 | 6 | 1 | 2 | 2 | 3 |
| Fatal SAEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| AEs leading to discontinuation | 1 | 4 | 1 | 6 | 4 | 1 | 1 | 5 |
| AEs requiring dose interruptions | 0 | 12 | 6 | 14 | 3 | 8 | 5 | 8 |
| AEs requiring dose reductions | 0 | 9 | 5 | 9 | 2 | 4 | 3 | 7 |
| AEs requiring dose reductions or interruptions | 0 | 13 | 7 | 14 | 3 | 8 | 6 | 9 |
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.
| ng/mL | 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 B - All Tumor Types TMT 0.025 mg/kg/Day |
|---|---|---|---|---|---|---|---|---|---|
| Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) | 5.76 ± 24.8 | 13.9 ± 27.1 | 15.2 ± 16.9 | 21.3 ± 20.7 | 15.1 ± 36.0 | 13.2 ± 40.4 | 13.5 ± 25.1 | 15.8 ± 42.8 | 14.3 ± 35.8 |
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.
| ng/mL | 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 B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 4.37 ± 30.6 | 11.1 ± 44.0 | 10.2 ± 19.4 | 15.6 ± 30.1 | 10.7 ± 43.3 | 9.45 ± 53.6 | 9.25 ± 29.0 | 11.3 ± 50.3 | 10.1 ± 43.6 | 8.31 | 10.2 | 3.86 ± 34.9 | 8.60 ± 42.2 | 3.74 ± 66.3 | 3.05 ± 50.7 | 8.68 ± 38.6 |
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.
| ng/mL | 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 B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 9.61 ± 32.9 | 21.1 ± 33.3 | 26.1 ± 16.8 | 32.6 ± 28.9 | 26.6 ± 39.6 | 22.1 ± 41.9 | 21.6 ± 26.1 | 27.5 ± 31.6 | 24.2 ± 35.6 | 26.0 | 24.5 | 23.7 ± 36.3 | 22.9 ± 29.2 | 15.6 ± 52.5 | 25.9 ± 35.8 | 20.0 ± 38.1 |
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.
| hours | 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 B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 1.00 (1.00 to 2.00) | 2.00 (1.00 to 4.00) | 1.00 (1.00 to 2.00) | 2.00 (1.00 to 24.0) | 1.00 (1.00 to 4.00) | 1.50 (1.00 to 2.00) | 1.00 (1.00 to 2.00) | 1.00 (1.00 to 2.00) | 1.00 (1.00 to 4.00) | 1.00 (1.00 to 1.00) | 1.00 (1.00 to 1.00) | 1.50 (1.00 to 2.00) | 2.00 (1.00 to 3.00) | 1.00 (1.00 to 4.00) | 1.00 (1.00 to 1.00) | 2.00 (1.00 to 4.00) |
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.
| hours*ng/mL | 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 B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 138 ± 24.8 | 341 ± 28.3 | 364 ± 16.9 | 413 ± 76.2 | 362 ± 36.0 | 316 ± 40.4 | 304 ± 36.9 | 379 ± 42.8 | 337 ± 38.6 | 290 | 331 | 122 ± 29.0 | 270 ± 35.8 | 118 ± 53.4 | 126 ± 30.7 | 255 ± 49.2 |
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.
| hours*ng/mL | 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 B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 138 ± 24.8 | 334 ± 27.1 | 364 ± 16.9 | 511 ± 20.7 | 362 ± 36.0 | 316 ± 40.4 | 323 ± 25.1 | 379 ± 42.8 | 343 ± 35.8 | 290 | 331 | 236 ± 28.4 | 308 ± 20.0 | 186 ± 23.7 | 228 ± 33.1 | 286 ± 28.4 |
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.
| mL/hour | 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 B - All Tumor Types TMT 0.025 mg/kg/Day | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 | 2750 ± 69.4 | 1530 ± 64.5 | 1240 ± 25.5 | 2040 ± 71.5 | 1710 ± 55.6 | 1910 ± 47.8 | 1590 ± 65.3 | 1820 ± 42.6 | 1750 ± 51.5 | 2590 | 3770 | 2010 ± 38.5 | 3540 ± 54.0 | 3060 ± 44.9 | 2180 ± 23.9 | 3810 ± 49.6 |
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.
| ng/mL | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D |
|---|---|---|---|---|---|---|---|
| Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib | 12.1 | 13.8 | 9.83 ± 28.4 | 12.8 ± 20.0 | 7.76 ± 23.7 | 9.50 ± 33.1 | 11.9 ± 28.4 |
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.
| Participants | 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 |
|---|---|---|---|---|---|
| AEs | 3 | 9 | 6 | 20 | 10 |
| Treatment-related AEs | 3 | 9 | 6 | 20 | 10 |
| SAEs | 1 | 5 | 2 | 8 | 6 |
| Treatment-related SAEs | 0 | 2 | 1 | 5 | 3 |
| Fatal SAEs | 0 | 0 | 0 | 0 | 0 |
| AEs leading to discontinuation | 0 | 3 | 1 | 5 | 1 |
| AEs requiring dose interruptions | 1 | 6 | 4 | 16 | 8 |
| AEs requiring dose reductions | 1 | 3 | 1 | 6 | 1 |
| AEs requiring dose reductions or interruptions | 1 | 7 | 4 | 16 | 8 |
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.
| Participants | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Complete response (CR) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 3 |
| Partial response (PR) | 0 | 1 | 1 | 0 | 1 | 3 | 0 | 5 | 2 | 3 | 2 | 9 | 3 |
| Stable disease (SD) | 1 | 2 | 3 | 4 | 1 | 7 | 8 | 4 | 1 | 5 | 1 | 8 | 3 |
| Progressive disease (PD) | 0 | 0 | 2 | 0 | 5 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Non-CR/Non-PD | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Missing | 2 | 16 | 6 | 10 | 3 | 0 | 2 | 0 | 0 | 0 | 1 | 0 | 1 |
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.
| percentage of participants | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 0 (0.0 to 70.8) | 5.3 (0.1 to 26.0) | 8.3 (0.2 to 38.5) | 0 (0.0 to 20.6) | 9.1 (0.2 to 41.3) | 30.0 (6.7 to 65.2) | 0 (0.0 to 30.8) | 50.0 (18.7 to 81.3) | 66.7 (9.4 to 99.2) | 33.3 (7.5 to 70.1) | 66.7 (22.3 to 95.7) | 55.0 (31.5 to 76.9) | 60.0 (26.2 to 87.8) |
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.
| percentage of participants | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment | 33.3 (0.8 to 90.6) | 15.8 (3.4 to 39.6) | 33.3 (9.9 to 65.1) | 25.0 (7.3 to 52.4) | 18.2 (2.3 to 51.8) | 100 (69.2 to 100) | 80.0 (44.4 to 97.5) | 90.0 (55.5 to 99.7) | 100 (29.2 to 100) | 88.9 (51.8 to 99.7) | 83.3 (35.9 to 99.6) | 95.0 (75.1 to 99.9) | 90.0 (55.5 to 99.7) |
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.
| liters/hour | Part A, B, C and D - All Participants With PK Data |
|---|---|
| Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model | 5.07 |
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.
| liters | Part A, B, C and D - All Participants With PK Data |
|---|---|
| Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model | 184 |
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.
| 1/hours | Part A, B, C and D - All Participants With PK Data |
|---|---|
| Ka1 | 0.134 |
| Ka2 | 1.55 |
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.
| no units | Part A, B, C and D - All Participants With PK Data |
|---|---|
| Effect of weight on CL/F | 0.788 |
| Effect of sex on CL/F | 1.24 |
| Effect of weight on Q/F | 0.679 |
| Effect of combination with dabrafenib on relative bioavailability F1 | 0.876 |
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.
| ng/mL | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D |
|---|---|---|---|---|---|---|---|
| Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib | 88.9 ± 99.6 | 28.6 ± 203.5 | 8.10 ± 159.6 | 38.2 ± 130.9 | 11.8 ± 869.4 | 5.36 ± 429.6 | 42.7 ± 137.4 |
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.
| ng/mL | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D |
|---|---|---|---|---|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib | 630 ± 235.2 | 1560 ± 35.3 | 1440 ± 43.3 | 1360 ± 55.6 | 1490 ± 88.1 | 1840 ± 35.2 | 1290 ± 68.7 |
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.
| hours | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D |
|---|---|---|---|---|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib | 2.00 (2.00 to 4.00) | 1.00 (1.00 to 2.00) | 2.00 (1.00 to 2.00) | 2.00 (1.00 to 3.00) | 1.00 (1.00 to 3.00) | 1.00 (1.00 to 3.00) | 2.00 (1.00 to 3.00) |
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.
| hours*ng/mL | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 Dabrafenib When Administered in Combination With Trametinib | 2560 ± 157.1 | 4160 ± 24.6 | 3910 ± 48.8 | 4030 ± 46.4 | 3800 ± 35.4 | 3990 ± 28.3 | 3950 ± 46.9 |
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.
| hours*ng/mL | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | 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 Dabrafenib When Administered in Combination With Trametinib | 2870 ± 116.6 | 4160 ± 24.6 | 4040 ± 47.9 | 4070 ± 46.7 | 3910 ± 37.4 | 4150 ± 30.2 | 3990 ± 47.3 |
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.
| mL/hour | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D |
|---|---|---|---|---|---|---|---|
| Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib | 22900 ± 191.2 | 20400 ± 45.4 | 10100 ± 67.0 | 25400 ± 70.5 | 12500 ± 63.0 | 10200 ± 41.6 | 25100 ± 69.3 |
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.
| ng/mL | 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 | Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D | Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D |
|---|---|---|---|---|---|---|---|
| Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib | 239 ± 116.6 | 347 ± 24.6 | 337 ± 47.9 | 339 ± 46.7 | 326 ± 37.4 | 346 ± 30.2 | 332 ± 47.3 |
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.
| Participants | TMT 0.0125 mg/kg/Day | TMT 0.025 mg/kg/Day | TMT 0.032 mg/kg/Day | TMT 0.04 mg/kg/Day |
|---|---|---|---|---|
| Was the medicine difficult to mix? — Yes | 0 | 1 | 1 | 0 |
| Was the medicine difficult to mix? — No | 2 | 26 | 19 | 4 |
| Was the medicine difficult to mix? — missing | 0 | 2 | 1 | 0 |
| Was the medicine difficult to measure? — Yes | 0 | 0 | 2 | 0 |
| Was the medicine difficult to measure? — No | 2 | 29 | 18 | 4 |
| Was the medicine difficult to measure? — missing | 0 | 0 | 1 | 0 |
| Was the medicine difficult to administer? — Yes | 0 | 5 | 5 | 1 |
| Was the medicine difficult to administer? — No | 2 | 24 | 15 | 3 |
| Was the medicine difficult to administer? — missing | 0 | 0 | 1 | 0 |
| Did the subject like the taste of the medicine? — Yes | 2 | 8 | 6 | 2 |
| Did the subject like the taste of the medicine? — No | 0 | 16 | 13 | 1 |
| Did the subject like the taste of the medicine? — missing | 0 | 5 | 2 | 1 |
| Did the subject have difficulty in taking the medicine? — Yes | 0 | 6 | 7 | 1 |
| Did the subject have difficulty in taking the medicine? — No | 2 | 19 | 13 | 3 |
| Did the subject have difficulty in taking the medicine? — missing | 0 | 4 | 1 | 0 |
| Did the subject resist taking the medicine? — Yes | 0 | 7 | 6 | 1 |
| Did the subject resist taking the medicine? — No | 2 | 18 | 14 | 3 |
| Did the subject resist taking the medicine? — missing | 0 | 4 | 1 | 0 |
| Was the medicine bitter? — Yes | 0 | 3 | 0 | 0 |
| Was the medicine bitter? — No | 0 | 2 | 1 | 0 |
| Was the medicine bitter? — missing | 2 | 24 | 20 | 4 |
| Was the medicine sweet? — Yes | 0 | 2 | 1 | 0 |
| Was the medicine sweet? — No | 0 | 3 | 0 | 0 |
| Was the medicine sweet? — missing | 2 | 24 | 20 | 4 |
| Was the medicine sour? — Yes | 0 | 2 | 0 | 0 |
| Was the medicine sour? — No | 0 | 3 | 1 | 0 |
| Was the medicine sour? — missing | 2 | 24 | 20 | 4 |
| Was the medicine gritty? — Yes | 0 | 1 | 0 | 0 |
| Was the medicine gritty? — No | 0 | 4 | 1 | 0 |
| Was the medicine gritty? — missing | 2 | 24 | 20 | 4 |
| Was the medicine difficult to swallow? — Yes | 0 | 1 | 0 | 0 |
| Was the medicine difficult to swallow? — No | 0 | 5 | 1 | 0 |
| Was the medicine difficult to swallow? — missing | 2 | 23 | 20 | 4 |
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.
| Participants | TMT 0.025 mg/kg/Day + 50% DRB RP2D | TMT 0.025 mg/kg/Day + 100% DRB RP2D | TMT 0.032 mg/kg/Day + 100% DRB RP2D |
|---|---|---|---|
| Was the medicine difficult to mix? — Yes | — | 0 | 1 |
| Was the medicine difficult to mix? — No | — | 4 | 5 |
| Was the medicine difficult to mix? — missing | — | 0 | 0 |
| Was the medicine difficult to measure? — Yes | — | 0 | 1 |
| Was the medicine difficult to measure? — No | — | 4 | 5 |
| Was the medicine difficult to measure? — missing | — | 0 | 0 |
| Was the medicine difficult to administer? — Yes | — | 0 | 1 |
| Was the medicine difficult to administer? — No | — | 4 | 5 |
| Was the medicine difficult to administer? — missing | — | 0 | 0 |
| Did the subject like the taste of the medicine? — Yes | — | 0 | 4 |
| Did the subject like the taste of the medicine? — No | — | 1 | 2 |
| Did the subject like the taste of the medicine? — missing | — | 3 | 0 |
| Did the subject have difficulty in taking the medicine? — Yes | — | 0 | 2 |
| Did the subject have difficulty in taking the medicine? — No | — | 1 | 4 |
| Did the subject have difficulty in taking the medicine? — missing | — | 3 | 0 |
| Did the subject resist taking the medicine? — Yes | — | 0 | 4 |
| Did the subject resist taking the medicine? — No | — | 1 | 2 |
| Did the subject resist taking the medicine? — missing | — | 3 | 0 |
| Was the medicine bitter? — Yes | — | 1 | 0 |
| Was the medicine bitter? — No | — | 2 | 0 |
| Was the medicine bitter? — missing | — | 1 | 6 |
| Was the medicine sweet? — Yes | — | 0 | 0 |
| Was the medicine sweet? — No | — | 3 | 0 |
| Was the medicine sweet? — missing | — | 1 | 6 |
| Was the medicine sour? — Yes | — | 2 | 0 |
| Was the medicine sour? — No | — | 1 | 0 |
| Was the medicine sour? — missing | — | 1 | 6 |
| Was the medicine gritty? — Yes | — | 1 | 0 |
| Was the medicine gritty? — No | — | 2 | 0 |
| Was the medicine gritty? — missing | — | 1 | 6 |
| Was the medicine difficult to swallow? — Yes | — | 0 | 0 |
| Was the medicine difficult to swallow? — No | — | 3 | 0 |
| Was the medicine difficult to swallow? — missing | — | 1 | 6 |
Collected over From the day of the first dose of any study drug up to 30 days after the last dose, up to maximum duration of 64 months.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part A - TMT 0.0125 mg/kg/Day | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Part A - TMT 0.025 mg/kg/Day | 0/19 (0%) | 8/19 (42.1%) | 19/19 (100%) |
| Part A - TMT 0.032 mg/kg/Day | 0/12 (0%) | 3/12 (25%) | 12/12 (100%) |
| Part A - TMT 0.04 mg/kg/Day | 0/16 (0%) | 11/16 (68.8%) | 16/16 (100%) |
| Part B - Neuroblastoma | 0/11 (0%) | 6/11 (54.5%) | 11/11 (100%) |
| Part B - LGG Fusion | 0/10 (0%) | 6/10 (60%) | 10/10 (100%) |
| Part B - NF-1 With PN | 0/10 (0%) | 6/10 (60%) | 10/10 (100%) |
| Part B - BRAF V600 Mutant Solid Tumor | 0/10 (0%) | 5/10 (50%) | 10/10 (100%) |
| Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D | 0/9 (0%) | 5/9 (55.6%) | 9/9 (100%) |
| Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D | 0/6 (0%) | 2/6 (33.3%) | 6/6 (100%) |
| Part D - LGG | 0/20 (0%) | 8/20 (40%) | 20/20 (100%) |
| Part D - LCH | 0/10 (0%) | 6/10 (60%) | 10/10 (100%) |
| Event | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PyrexiaGeneral disorders | 0/3 | 2/19 | 1/12 | 1/16 | 2/11 | 0/10 | 2/10 | 2/10 | 0/3 | 3/9 | 1/6 | 4/20 | 4/10 |
| TachycardiaCardiac disorders | 1/3 | 0/19 | 0/12 | 0/16 | 0/11 | 0/10 | 0/10 | 0/10 | 0/3 | 0/9 | 0/6 | 0/20 | 1/10 |
| Brain oedemaNervous system disorders | 0/3 | 0/19 | 0/12 | 0/16 | 0/11 | 0/10 | 0/10 | 0/10 | 1/3 | 0/9 | 0/6 | 0/20 | 0/10 |
| VomitingGastrointestinal disorders | 0/3 | 1/19 | 1/12 | 1/16 | 0/11 | 1/10 | 0/10 | 1/10 | 0/3 | 2/9 | 0/6 | 0/20 | 0/10 |
| Ejection fraction decreasedInvestigations | 0/3 | 0/19 | 0/12 | 0/16 | 0/11 | 0/10 | 0/10 | 0/10 | 0/3 | 2/9 | 0/6 | 1/20 | 0/10 |
| Device related infectionInfections and infestations | 0/3 | 0/19 | 0/12 | 1/16 | 0/11 | 1/10 | 0/10 | 2/10 | 0/3 | 0/9 | 0/6 | 0/20 | 0/10 |
| SeizureNervous system disorders | 0/3 | 0/19 | 0/12 | 3/16 | 0/11 | 0/10 | 0/10 | 1/10 | 0/3 | 0/9 | 0/6 | 1/20 | 0/10 |
| Upper respiratory tract infectionInfections and infestations | 0/3 | 1/19 | 0/12 | 0/16 | 0/11 | 0/10 | 1/10 | 1/10 | 0/3 | 0/9 | 1/6 | 0/20 | 1/10 |
| VaricellaInfections and infestations | 0/3 | 0/19 | 0/12 | 0/16 | 0/11 | 1/10 | 1/10 | 0/10 | 0/3 | 0/9 | 1/6 | 0/20 | 0/10 |
| DehydrationMetabolism and nutrition disorders | 0/3 | 0/19 | 0/12 | 0/16 | 0/11 | 0/10 | 0/10 | 0/10 | 0/3 | 1/9 | 1/6 | 0/20 | 0/10 |
| Event | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| RashSkin and subcutaneous tissue disorders | 1/3 | 9/19 | 5/12 | 8/16 | 4/11 | 5/10 | 6/10 | 2/10 | 3/3 | 6/9 | 2/6 | 3/20 | 2/10 |
| DiarrhoeaGastrointestinal disorders | 1/3 | 17/19 | 10/12 | 9/16 | 6/11 | 6/10 | 5/10 | 6/10 | 2/3 | 3/9 | 3/6 | 7/20 | 5/10 |
| ParonychiaInfections and infestations | 0/3 | 16/19 | 10/12 | 12/16 | 0/11 | 4/10 | 7/10 | 7/10 | 2/3 | 1/9 | 1/6 | 6/20 | 1/10 |
| Dry skinSkin and subcutaneous tissue disorders | 1/3 | 12/19 | 10/12 | 6/16 | 4/11 | 7/10 | 5/10 | 6/10 | 2/3 | 5/9 | 3/6 | 8/20 | 5/10 |
| PyrexiaGeneral disorders | 1/3 | 11/19 | 8/12 | 10/16 | 5/11 | 5/10 | 6/10 | 4/10 | 0/3 | 7/9 | 4/6 | 15/20 | 8/10 |
| VomitingGastrointestinal disorders | 1/3 | 13/19 | 9/12 | 6/16 | 3/11 | 3/10 | 3/10 | 6/10 | 1/3 | 4/9 | 4/6 | 9/20 | 7/10 |
| FatigueGeneral disorders | 1/3 | 10/19 | 9/12 | 4/16 | 1/11 | 1/10 | 0/10 | 6/10 | 2/3 | 4/9 | 1/6 | 9/20 | 4/10 |
| Decreased appetiteMetabolism and nutrition disorders | 2/3 | 11/19 | 4/12 | 5/16 | 1/11 | 3/10 | 2/10 | 3/10 | 0/3 | 1/9 | 0/6 | 4/20 | 0/10 |
| Dermatitis acneiformSkin and subcutaneous tissue disorders | 0/3 | 6/19 | 4/12 | 10/16 | 1/11 | 4/10 | 3/10 | 4/10 | 2/3 | 4/9 | 1/6 | 8/20 | 1/10 |
| Rash maculo-papularSkin and subcutaneous tissue disorders | 2/3 | 3/19 | 4/12 | 4/16 | 2/11 | 4/10 | 2/10 | 3/10 | 1/3 | 0/9 | 2/6 | 6/20 | 5/10 |
| Age, Customized(Participants) | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| < 2 years | 0 | 4 | 1 | 2 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 10 |
| 2 - <6 years | 1 | 5 | 11 | 0 | 3 | 4 | 4 | 5 | 0 | 2 | 5 | 2 | 6 | 48 |
| 6 - <12 years | 1 | 4 | 0 | 9 | 5 | 5 | 3 | 1 | 1 | 2 | 0 | 9 | 3 | 43 |
| ≥ 12 years | 1 | 6 | 0 | 5 | 2 | 1 | 2 | 4 | 2 | 5 | 0 | 9 | 1 | 38 |
| Sex: Female, Male(Participants) | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | 1 | 7 | 6 | 7 | 6 | 5 | 5 | 5 | 0 | 6 | 4 | 10 | 2 | 64 |
| Male | 2 | 12 | 6 | 9 | 5 | 5 | 5 | 5 | 3 | 3 | 2 | 10 | 8 | 75 |
| Race (NIH/OMB)(Participants) | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Asian | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 | 1 | 2 | 0 | 0 | 1 | 8 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 2 | 0 | 1 | 2 | 2 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 9 |
| White | 3 | 16 | 7 | 14 | 9 | 6 | 7 | 5 | 2 | 6 | 4 | 16 | 3 | 98 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Unknown or Not Reported | 0 | 0 | 5 | 0 | 0 | 2 | 1 | 3 | 0 | 0 | 2 | 4 | 4 | 21 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
This study is completed, as verified in Jun 2021. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Trametinib