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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02124772




Registration number
NCT02124772
Ethics application status
Date submitted
24/04/2014
Date registered
28/04/2014
Date last updated
9/06/2020

Titles & IDs
Public title
Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations
Scientific title
An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Children and Adolescents With Cancers Harboring V600 Mutations
Secondary ID [1] 0 0
2013-003596-35
Secondary ID [2] 0 0
116540
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types
Neurological 0 0 0 0
Other neurological disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Trametinib
Treatment: Drugs - Dabrafenib

Experimental: Part A - Trametinib Dose-Escalation: Trametinib is administered orally once daily (OD) under fasting conditions. The starting dose of trametinib (0.0125 milligram per kilogram per dose [mg/kg/dose]) is 50% of the recommended fixed dose in adults (2 mg OD). The second dose level (0.025 mg/kg) is equivalent to the recommended dose in adults (2 mg PO daily). The third dose level (0.040 mg/kg) is equivalent to the maximum tolerated dose [MTD] in adults (3 mg PO daily).

Experimental: Part B - Tumor-Specific Expansion: Trametinib is administered orally once daily under fasting conditions in 4 disease-specific cohorts of subjects Trametinib will be continued until disease progression.

Experimental: Part C - The trametinib dose administered in Part C will be the trametinib monotherapy RP2D from Part A. The monotherapy RP2D of dabrafenib in children will be established on a separate trial (BRF116013). The specifics for Part C will be determined following completion of enrollment into Part A.

Experimental: Part D - The trametinib and dabrafenib doses administered in Part D will be the combination trametinib and dabrafenib RP2D from Part C.


Treatment: Drugs: Trametinib
Trametinib is available in tablet (0.125mg, 0.5mg, 2mg dose) as well as in powder form for Oral Solution (0.05mg/mL dose). It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.

Treatment: Drugs: Dabrafenib
Dabrafenib is available in capsules (50mg and 75mg) as well as in powder form for Oral Suspension (10 mg/mL dose) and taken twice a day. It is recommended that subjects drink approximately 1 ounce (30 mL) of water for every 10 pounds of body weight following dosing.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Safety Assessment of trametinib as assessed by Adverse Events (AEs)
Timepoint [1] 0 0
From screening up to 63 months
Primary outcome [2] 0 0
Safety Assessment of trametinib as assessed by electrocardiogram (ECG) - Single 12-lead ECGs will be obtained to assess safety
Timepoint [2] 0 0
From screening up to 63 months
Primary outcome [3] 0 0
Safety Assessment of trametinib as assessed by echocardiogram (ECHO) - ECHOs will be performed to assess cardiac ejection fraction and cardiac valve morphology
Timepoint [3] 0 0
From screening up to 63 months
Primary outcome [4] 0 0
Safety Assessment of trametinib as assessed by changes in laboratory values - Laboratory assessments will include Hematology, Clinical Chemistry, Routine Urinalysis and Other screening tests
Timepoint [4] 0 0
From screening up to 63 months
Primary outcome [5] 0 0
Safety Assessment of trametinib assessed by changes in vital signs - Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
Timepoint [5] 0 0
From screening up to 63 months
Primary outcome [6] 0 0
To determine the dose of trametinib that achieves similar exposures (Ctau) to the recommended adult dose - Steady state Ctau of trametinib
Timepoint [6] 0 0
Days 15 and 22
Secondary outcome [1] 0 0
PK Assessment of trametinib - PK parameters including Ctau (trough concentration), area under the concentration-time curve over a period of time (AUC [0-t]), area under the concentration-time curve over the dosing interval (AUC [0-tau]), apparent clearance following oral dosing (CL/F), maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax) (tmax) and half-life (t1/2) of trametinib will be assessed
Timepoint [1] 0 0
Day 15 and Day 22
Secondary outcome [2] 0 0
Safety and tolerability assessments for trametinib for AEs
Timepoint [2] 0 0
From screening up to 63 months
Secondary outcome [3] 0 0
Safety and tolerability assessments for trametinib for ECG - 12-lead ECGs will be performed to assess safety and tolerability
Timepoint [3] 0 0
From screening up to 63 months
Secondary outcome [4] 0 0
Safety and tolerability assessments for trametinib for changes in laboratory values - Laboratory parameter including chemistry and hematology
Timepoint [4] 0 0
From screening up to 63 months
Secondary outcome [5] 0 0
Safety and tolerability assessments for trametinib for vital signs - Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
Timepoint [5] 0 0
From screening up to 63 months
Secondary outcome [6] 0 0
Tumor response for trametinib - Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)
Timepoint [6] 0 0
From screening up to 63 months
Secondary outcome [7] 0 0
Effect of age and weight on the PK of trametinib - PK parameter will include CL/F, volume of distribution (V/F), absorption rate (ka), and coefficients for significant covariates
Timepoint [7] 0 0
Day 15 and Day 22
Secondary outcome [8] 0 0
PK assessment of trametinib and dabrafenib when administered in combination - PK parameters include Ctau, AUC (0-t), AUC (0-tau), CL/F, Cmax, tmax, and Cavg
Timepoint [8] 0 0
Day 1, Day 15 and Day 22 of Part C and Part D
Secondary outcome [9] 0 0
Palatability of trametinib and/or dabrafenib in pediatric subjects assessed by palatability questionnaire - To be completed after the first dose of study drug and no later than Day 8 (+/-3 days). Subjects will complete a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste).
Timepoint [9] 0 0
Day 8
Secondary outcome [10] 0 0
Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Adverse Events (AEs)
Timepoint [10] 0 0
From screening up to 63 months
Secondary outcome [11] 0 0
Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by ECGs. - 12-lead ECGs will be performed to assess safety and tolerability
Timepoint [11] 0 0
From screening up to 63 months
Secondary outcome [12] 0 0
Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Echo.
Timepoint [12] 0 0
From screening up to 63 months
Secondary outcome [13] 0 0
Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in laboratory values - Laboratory parameter including chemistry, hematology and urinalysis.
Timepoint [13] 0 0
From screening up to 63 months
Secondary outcome [14] 0 0
Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in vital sign values - Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
Timepoint [14] 0 0
From screening up to 63 months
Secondary outcome [15] 0 0
Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by AEs
Timepoint [15] 0 0
From screening up to 63 months
Secondary outcome [16] 0 0
Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by ECGs - 12-lead ECGs will be performed to assess safety and tolerability
Timepoint [16] 0 0
From screening up to 63 months
Secondary outcome [17] 0 0
Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by Echo
Timepoint [17] 0 0
From screening up to 63 months
Secondary outcome [18] 0 0
Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in lab values - Laboratory parameter including chemistry, hematology and urinalysis.
Timepoint [18] 0 0
From screening up to 63 months
Secondary outcome [19] 0 0
Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in vital sings - Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate.
Timepoint [19] 0 0
From screening up to 63 months
Secondary outcome [20] 0 0
Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by steady state Ctau of trametinib and by steady state AUC (0-12) of dabrafenib
Timepoint [20] 0 0
Day 15 and Day 22 of Part C and Part D
Secondary outcome [21] 0 0
Tumor response for trametinib in combination with dabrafenib - Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)
Timepoint [21] 0 0
From screening up to 63 months

Eligibility
Key inclusion criteria
- General Eligibility Criteria (All Parts)

- Written informed consent - a signed informed consent and/or assent (as age
appropriate) for study participation including PK sampling will be obtained according
to institutional guidelines.

- Male or female between one month and <18 years of age (inclusive) at the time of
signing the informed consent form (Part C and Part D between 12 months and <18 years
of age, inclusive).

- Must have a disease that is relapsed/refractory to all potentially curative standard
treatment regimens or must have a current disease for which there is no known curative
therapy, or therapy proven to prolong survival with an acceptable quality of life.

- Prior therapy: The subject's disease (i.e. cancer, neurofibromatosis type 1 [NF-1]
with plexiform neurofibroma [PN], or Langerhans cell histocytosis [LCH]) must have
relapsed after or failed to respond to frontline curative therapy or there must not be
other potentially curative treatment options available. Curative therapy may include
surgery, radiation therapy, chemotherapy, or any combination of these modalities. All
subjects must have recovered to grade <=1 from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to enrollment. Prior therapy
includes; myelosuppressive chemotherapy, differentiating agents/ biologic response
modifiers (small molecules, antibodies, viral therapies) (anti-cancer agent),
non-myelosuppressive anticancer agents, investigational agent, radiation therapy, stem
cell transplantation or infusion, number of prior treatment regimens, colony
stimulating factors, corticosteroids.

- Performance score of >=50% according to the Karnofsky/Lansky performance status scale.

- Females of child-bearing potential must be willing to practice acceptable methods of
birth control. Additionally, females of childbearing potential must have a negative
serum pregnancy test within 7 days prior to start of study drugs, throughout treatment
period and for 4 months after last dose of study drugs.

- Must have adequate organ function as defined by the following values: renal function -
24 hr creatinine clearance (revised Schwartz formula), or radioisotope glomerular
filtration rate (GFR) >=60 milliliter (mL) per minute per 1.73 meter square
(mL/min/1.73m^2); or a serum creatinine <=upper limit of normal (ULN) for age and
gender; liver functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN
for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes of enrollment
and toxicity monitoring the ULN for ALT will be 45 unit per liter (U/L); cardiac
function - corrected QT (QTcB) interval <480 milliseconds (msec), left ventricular
ejection fraction (LVEF) >=lower limit of normal (LLN) by ECHO.

- Able to swallow and retain enterally (per oral [PO] or nasogastric or gastric tube)
administered medication and does not have any clinically significant gastrointestinal
abnormalities that may alter absorption such as malabsorption syndrome or major
resection of the stomach or bowels.

- Adequate Blood Pressure Control defined as: Blood pressure <= the 95th percentile for
age, height, and gender.

- French subjects: In France, a subject will be eligible for inclusion in this study
only if either affiliated to or a beneficiary of a social security category.

- Specific Eligibility Criteria, Part A

- Subjects must meet general eligibility criteria.

- For the initial dose escalation to identify the maximum tolerable or PK target dose,
age between 2 years and <18 years (inclusive) at the time of signing the informed
consent form. Children < 2 years of age will be enrolled once the age specific
expansion cohorts are open.

- Histologically confirmed solid tumors, which may include but are not limited to
rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors,
osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, primary
brain tumors, NF-1 associated PF and LCH. In subjects with brain stem gliomas the
requirement for histological confirmation can be waived if a biopsy was not performed.
For plexiform neurofibromas, histologic confirmation of tumor is not necessary in the
presence of consistent clinical and radiological findings, but should be considered if
malignant degeneration of a PN is clinically suspected.

- Measurable or evaluable tumors. Subjects with neuroblastoma that is only detectable by
Meta-iodobenzylguanidine (MIBG) scan are eligible. Subjects with neuroblastoma that is
only detected by bone marrow aspirate/biopsy or elevated homovanillic acid /
vanillylmandelic acid (HVA/VMA) are not eligible.

- Adequate bone marrow function defined as absolute neutrophil count (ANC)
>=1000/microliter, hemoglobin >=8.0 gram per deciliter (g/dL) (may receive red blood
cell transfusions), platelets >=75,000/ microliter (transfusion independent, defined
as not receiving platelet transfusions within a 7 day period prior to enrollment).

- Specific Eligibility Criteria, Part B

- Subjects must meet general eligibility criteria. The specific eligibility criteria
listed here will apply to subjects enrolling to different cohorts of Part B.

- Tumor tissue (archived or fresh) is required and must be available to be shipped to
GSK or site specific laboratory.

- Solid tumor cohort (B1) specific criteria

- B1: Refractory or relapsed neuroblastoma

- B2: Recurrent or unresectable low grade gliomas with BRAF tandem duplication with
fusion

- B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that
are unresectable and medically significant.

- B4: BRAF V600 mutant tumors.

- Specific Eligibility Criteria, Part C - Subjects must meet general eligibility
criteria.

- Tumors that have been documented by CLIA or equivalent certified laboratory test to
harbor BRAF V600 mutation at diagnosis or relapse

- Measurable or evaluable disease

- Adequate bone marrow function

- Specific Eligibility Criteria, Part D - Subjects must meet general eligibility
criteria

- Measurable or evaluable disease

- Recurrent or refractory BRAFV600 mutant LGG or LCH tumors

- Adequate bone marrow function
Minimum age
1 Month
Maximum age
17 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Lactating or pregnant female.

- History of another malignancy including resected non-melanomatous skin cancer.

- Subjects with NF-1 associated optic pathway tumors are excluded if they are actively
receiving therapy for the optic pathway tumor or do not meet criteria for PN or
malignant solid tumor.

- Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya).

- Subjects with NF-1 actively receiving therapy for the optic pathway tumor.

- Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis
(only applicable to Part B).

- Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures.

- Any prohibited medication(s), currently used or expected to be required.

- Any medications for treatment of left ventricular systolic dysfunction.

- Part B, Part C and Part D only: Previous treatment with dabrafenib or any BRAF
inhibitor, trametinib or another MEK inhibitor, or and Extracellular signal-regulated
kinase inhibitor (exception: prior treatment with sorafenib is permitted). Patients
who have received prior dabrafenib or another BRAF inhibitor may enrol into Part B4.
Patients who have had prior dabrafenib or BRAF inhibitor therapy may enroll in Part C
or Part D if they have had prior benefit to dabrafenib or BRAF inhibitor monotherapy,
as determined by the investigator.

- Administration of an investigational study treatment within 30 days preceding the
first dose of study treatment(s) in this study.

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study treatment or excipients that contraindicate their
participation.

- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, or liver metastases).

- History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the
prior 3 months.

- History of heparin-induced thrombocytopenia.

- History of interstitial lung disease or pneumonitis.

- History of or current evidence of retinal vein occlusion (RVO).

- For subjects with solid tumors that are not primary central nervous system (CNS)
tumors or NF-1 associated plexiform neurofibromas subjects with symptomatic or
untreated leptomeningeal or brain metastases or spinal cord compression are excluded.
NOTE: Subjects previously treated for these conditions that have had stable CNS
disease (verified with consecutive imaging studies) for >3 months, are asymptomatic
and are not currently taking corticosteroids, or are on stable dose or decreasing of
corticosteroids for at least 7 days prior to enrolment are permitted.

- A history of known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.
Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.

- Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous
anti-cancer therapy, except alopecia.

- Presence of active gastrointestinal (GI) disease or other condition that will
interfere significantly with the absorption of drugs.

- A history or evidence of cardiovascular risk including: a QT interval corrected for
heart rate using the Bazett's formula (QTcB) >=480 msec; a history or evidence of
current clinically significant uncontrolled arrhythmias (clarification: Subjects with
atrial fibrillation controlled for >30 days prior to dosing are eligible); a history
of acute coronary syndromes (including myocardial infarction or unstable angina),
coronary angioplasty, or stenting within 6 months prior to randomization; a history or
evidence of current >=Class II congestive heart failure as defined by the New York
Heart Association (NYHA) guidelines; subjects with intra-cardiac defibrillators;
abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects
with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on
study). Subjects with moderate valvular thickening should not be entered on study.
Subjects with prosthetic valves can be considered eligible provided they meet the
criteria as stated above; Treatment refractory hypertension defined as a blood
pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg (or
above 95th age-specific percentile listed in protocol), which cannot be controlled by
anti-hypertensive therapy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Novartis Investigative Site - Westmead
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Maryland
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Ohio
Country [9] 0 0
United States of America
State/province [9] 0 0
Pennsylvania
Country [10] 0 0
United States of America
State/province [10] 0 0
Tennessee
Country [11] 0 0
Canada
State/province [11] 0 0
Ontario
Country [12] 0 0
France
State/province [12] 0 0
Paris Cedex 05
Country [13] 0 0
France
State/province [13] 0 0
Villejuif Cedex
Country [14] 0 0
United Kingdom
State/province [14] 0 0
Surrey
Country [15] 0 0
United Kingdom
State/province [15] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is 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 is a repeat dose,
dose escalation monotherapy study that will identify the recommended phase II dose (RP2D) on
the continuous dosing schedule using a 3 + 3 dose- escalation procedure. Part B will evaluate
the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects.
Each cohort will enroll at least 10 response-evaluable subjects (evaluable for response is
defined as a subject with a pre-dose and at least 1 post-dose disease assessment or clinical
assessment of progression of disease). Part C is will be 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. Part C will enroll up to 24 subjects. Part D will
evaluate the preliminary activity of trametinib in combination with dabrafenib in 2
disease-specific cohorts of subjects diagnosed with LGG and LCH. LGG cohort will enroll
approximately 20 response-evaluable subjects and the LCH cohort will enroll approximately 10
response-evaluable subjects. The overall goal of this trial is 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.
Trial website
https://clinicaltrials.gov/show/NCT02124772
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications