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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT02124772
Ethics application status
Date submitted
24/04/2014
Date registered
28/04/2014
Date last updated
14/07/2021

Titles & IDs
Public title
Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations
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 - TMT 0.0125 mg/kg/day - Participants treated with trametinib 0.0125 mg/kg/day

Experimental: Part A - TMT 0.025 mg/kg/day - Participants treated with trametinib 0.025 mg/kg/day

Experimental: Part A - TMT 0.032 mg/kg/day - Participants under 6 years of age treated with trametinib 0.032 mg/kg/day

Experimental: Part A - TMT 0.04 mg/kg/day - Participants treated with trametinib 0.04 mg/kg/day

Experimental: Part B - Neuroblastoma - Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Experimental: Part B - LGG fusion - Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Experimental: Part B - NF-1 with PN - Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day

Experimental: Part B - BRAF V600 mutant solid tumor - Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day

Experimental: Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D - Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for \<12 years old subjects and 2.25 mg/kg/day for =12 years old subjects)

Experimental: Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D - Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for =12 years old subjects)

Experimental: Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D - Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)

Experimental: Part D - LGG - Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for = 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for =12 years old subjects)

Experimental: Part D - LCH - Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for = 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for =12 years old subjects)


Treatment: Drugs: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Treatment: Drugs: Dabrafenib
Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy
Timepoint [1] 0 0
From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months
Primary outcome [2] 0 0
Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy)
Timepoint [2] 0 0
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.
Secondary outcome [1] 0 0
Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib
Timepoint [1] 0 0
pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
Secondary outcome [2] 0 0
Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
Timepoint [2] 0 0
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.
Secondary outcome [3] 0 0
Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
Timepoint [3] 0 0
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.
Secondary outcome [4] 0 0
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
Timepoint [4] 0 0
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.
Secondary outcome [5] 0 0
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
Timepoint [5] 0 0
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.
Secondary outcome [6] 0 0
Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib
Timepoint [6] 0 0
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.
Secondary outcome [7] 0 0
Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib
Timepoint [7] 0 0
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.
Secondary outcome [8] 0 0
Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib
Timepoint [8] 0 0
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
Secondary outcome [9] 0 0
Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
Timepoint [9] 0 0
From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
Secondary outcome [10] 0 0
Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
Timepoint [10] 0 0
From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
Secondary outcome [11] 0 0
Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
Timepoint [11] 0 0
From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months
Secondary outcome [12] 0 0
Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model
Timepoint [12] 0 0
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.
Secondary outcome [13] 0 0
Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model
Timepoint [13] 0 0
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.
Secondary outcome [14] 0 0
Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model
Timepoint [14] 0 0
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.
Secondary outcome [15] 0 0
Significant Covariates Estimated With a PopPK Model
Timepoint [15] 0 0
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.
Secondary outcome [16] 0 0
Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib
Timepoint [16] 0 0
pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.
Secondary outcome [17] 0 0
Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib
Timepoint [17] 0 0
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.
Secondary outcome [18] 0 0
Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib
Timepoint [18] 0 0
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.
Secondary outcome [19] 0 0
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
Timepoint [19] 0 0
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.
Secondary outcome [20] 0 0
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
Timepoint [20] 0 0
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.
Secondary outcome [21] 0 0
Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib
Timepoint [21] 0 0
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.
Secondary outcome [22] 0 0
Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib
Timepoint [22] 0 0
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.
Secondary outcome [23] 0 0
Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire
Timepoint [23] 0 0
After the first dose of trametinib oral solution and no later than Day 8 (±3 days)
Secondary outcome [24] 0 0
Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire
Timepoint [24] 0 0
After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days)

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
Sex
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
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
15/01/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
29/12/2020
Sample size
Target
Accrual to date
Final
139
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 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.
Trial website
https://clinicaltrials.gov/study/NCT02124772
Trial related presentations / publications
Bouffet E, Geoerger B, Moertel C, Whitlock JA, Aerts I, Hargrave D, Osterloh L, Tan E, Choi J, Russo M, Fox E. Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. J Clin Oncol. 2023 Jan 20;41(3):664-674. doi: 10.1200/JCO.22.01000. Epub 2022 Nov 14.
Shahid S, Kushner BH, Modak S, Basu EM, Rubin EM, Gundem G, Papaemmanuil E, Roberts SS. Association of BRAF V600E mutations with vasoactive intestinal peptide syndrome in MYCN-amplified neuroblastoma. Pediatr Blood Cancer. 2021 Oct;68(10):e29265. doi: 10.1002/pbc.29265. Epub 2021 Jul 31.
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

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02124772