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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01677741




Registration number
NCT01677741
Ethics application status
Date submitted
30/08/2012
Date registered
3/09/2012

Titles & IDs
Public title
A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects
Scientific title
Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects With Advanced BRAF V600-Mutation Positive Solid Tumors
Secondary ID [1] 0 0
2012-001499-12
Secondary ID [2] 0 0
116013
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms, Brain 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

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

Experimental: Part 1: Dabrafenib treatment - Three subjects will receive a single dose of 3 mg/kg dabrafenib on Day 1 and repeat dose will begin from Day 2, evenly divided in two daily doses. Once all 3 subjects have been fully evaluated for the first 28 days (including Day 15 PK) and no DLTs are observed, a next subject will be enrolled at the next higher dose levels (i.e., dose escalation to 3.75 mg/kg \[+1\] and may be further to 4.5 mg/kg \[+2\] and so on). If all 3 subjects have not been fully evaluated for the first 28 days or 1 DLT occurred, the fourth subject will be enrolled at the same dose level. If 2 or more DLTs are observed, the next subject will be enrolled at the next lower dose level (i.e., de-escalated to 2.25 mg/kg \[-1\] and may be further to 1.5 mg/kg \[-2\]). Similarly, the process is repeated for the fifth and sixth subjects in a cohort. All subjects will receive treatment till end of study.

Experimental: Part 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutations - Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Experimental: Part 2: Cohort 2 High-Grade Gliomas with BRAF V600 mutations - Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Experimental: Part 2: Cohort 3 LCH with BRAF V600 mutations - Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Experimental: Part 2: Cohort 4 Melanoma and PTC with BRAF V600 mutations - Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.


Treatment: Drugs: Dabrafenib
Dabrafenib is available as 50 mg or 75 mg capsules and as oral suspension (10 mg/mL for subjects unable to swallow capsules). Dabrafenib (either formulation) will be administered orally as a single dose on Day 1 and twice daily from Day 2, based on weight at the appropriate study dose level.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)
Timepoint [1] 0 0
From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
Primary outcome [2] 0 0
Maximum Concentration (Cmax) of Dabrafenib
Timepoint [2] 0 0
Week 1 Day 1, Week 3 Day 15
Primary outcome [3] 0 0
Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-t)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib
Timepoint [3] 0 0
Week 1 Day 1
Secondary outcome [1] 0 0
Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites
Timepoint [1] 0 0
Week 3 Day 15
Secondary outcome [2] 0 0
The AUC(0-t) of Dabrafenib Metabolites
Timepoint [2] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [3] 0 0
The AUC(0-tau) of Dabrafenib and Its Metabolites
Timepoint [3] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [4] 0 0
Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib
Timepoint [4] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [5] 0 0
Maximum Concentration (Cmax) of Dabrafenib Metabolites
Timepoint [5] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [6] 0 0
Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites
Timepoint [6] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [7] 0 0
Elimination Half Life (T½) of Dabrafenib and Its Metabolites
Timepoint [7] 0 0
Week 3 Day 15
Secondary outcome [8] 0 0
Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)
Timepoint [8] 0 0
From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
Secondary outcome [9] 0 0
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects
Timepoint [9] 0 0
Up to 6 months
Secondary outcome [10] 0 0
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects
Timepoint [10] 0 0
Up to 6 months
Secondary outcome [11] 0 0
Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model
Timepoint [11] 0 0
Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Secondary outcome [12] 0 0
Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model
Timepoint [12] 0 0
Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Secondary outcome [13] 0 0
Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model
Timepoint [13] 0 0
Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Secondary outcome [14] 0 0
Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model
Timepoint [14] 0 0
Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Eligibility
Key inclusion criteria
* Written informed consent - a signed informed consent and/or assent (as age appropriate) will be obtained according to institutional guidelines.
* Male or female >=12 months and <18 years of age at the time of signing the informed consent form.
* Recurrent disease, refractory disease, or progressive disease after having received at least one standard therapy for their disease. Note: Subjects with metastatic (and surgically unresectable) melanoma can be enrolled for first-line treatment; Melanoma subjects with CNS involvement may be enrolled.
* At least one evaluable lesion.
* BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing; centralized testing can confirm V600E and V600K mutations only).
* Performance score of >=50% according to the Karnofsky/Lansky performance status scale (subjects with a performance status of <=50% can be enrolled if the subject's confinement to bed and inability to carry out activities is due solely to cancer-related pain, as assessed by the investigator).
* Females of child-bearing potential (with negative serum pregnancy test within 7 days prior to the first dose of study medication) must be willing to practice acceptable methods of birth control .
* Sexually active males, who do not agree to abstinence, must be willing to use a condom during intercourse while taking the study drug, and for 16 weeks after stopping treatment and should not father a child in this period.
* Must have adequate organ function as defined by the following values: Adequate bone marrow function defined as-absolute neutrophil count (ANC) >=1000/ microliter (µL), hemoglobin >=8.0 grams (g)/ deciliter (dL) (may receive red blood cell transfusions), platelets >=75,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment).
* Adequate renal and metabolic function defined as: calculated glomerular filtration rate (eGFR) (Schwartz formula), or radioisotope GFR >=90 milliliters/minutes (mL/min)/1.73 meter square (m^2); or a serum creatinine within the institutional reference range upper limit of normal (for age/gender, if available).
* Adequate liver function defined as: bilirubin (sum of conjugated + unconjugated) <=1.5 x upper limit of normal (ULN) for age, aspartate aminotransaminase (AST) and alanine transaminase (ALT) <=2.5 x ULN; AST/ALT may be <5 x ULN at baseline if disease under treatment involves the liver (requires radiographic confirmation of liver involvement).
* Adequate cardiac function defined as: left ventricular ejection fraction (LVEF) of either >=50% by ECHO or greater than institutional lower limit of normal (LLN) by echocardiogram (ECHO) (while not receiving medications for cardiac function), corrected QT using Bazett's (QTcB) interval <450 milliseconds (msecs).
Minimum age
12 Months
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Part 2 ONLY: Previous treatment with dabrafenib, another RAF inhibitor, or a mitogen-activated protein kinase (MEK) inhibitor (exception: prior treatment with sorafenib is permitted).
* Malignancy OTHER than the BRAF mutant malignancy under study.
* Had chemotherapy or radiotherapy within 3 weeks (or 6 weeks for nitrosoureas or mitomycin C) prior to administration of the first dose of study treatment.
* The subject has received an investigational product within the following time period prior to the first dosing day in the current study: 28 days or 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is warranted by the data).
* History of another malignancy. Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission are eligible.
* Current use of a prohibited medication or herbal preparation or requires any of these medications during the study.
* Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 Grade 2 or higher from previous anti-cancer therapy, including major surgery except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of dabrafenib (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy).
* Has leukaemia.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib and its excipients.
* Autologous or allogeneic stem cell transplant within 3 months prior to enrolment [NOTE: subjects with evidence of active graph versus host disease are excluded].
* History of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongation.
* Subjects with abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (NOTE: subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study).
* Subjects with moderate valvular thickening.
* Known, uncontrolled cardiac arrhythmias (except sinus arrhythmia) within the past 24 weeks
* Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
* Presence of active GI disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.
* Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of Hepatitis B Virus clearance may be enrolled).
* Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing.
* Lactating females who are actively breast feeding.

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
23/05/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/12/2020
Sample size
Target
Accrual to date
Final
85
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Parkville
Recruitment postcode(s) [1] 0 0
3052 - Parkville
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
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Tennessee
Country [8] 0 0
United States of America
State/province [8] 0 0
Washington
Country [9] 0 0
Canada
State/province [9] 0 0
Ontario
Country [10] 0 0
Denmark
State/province [10] 0 0
Copenhagen
Country [11] 0 0
France
State/province [11] 0 0
Marseille Cedex 5
Country [12] 0 0
France
State/province [12] 0 0
Paris cedex 05
Country [13] 0 0
France
State/province [13] 0 0
Paris cedex 12
Country [14] 0 0
France
State/province [14] 0 0
Toulouse cedex 9
Country [15] 0 0
France
State/province [15] 0 0
Villejuif Cedex
Country [16] 0 0
Germany
State/province [16] 0 0
Baden-Wuerttemberg
Country [17] 0 0
Germany
State/province [17] 0 0
Bayern
Country [18] 0 0
Germany
State/province [18] 0 0
Berlin
Country [19] 0 0
Israel
State/province [19] 0 0
Jerusalem
Country [20] 0 0
Israel
State/province [20] 0 0
Ramat-Gan
Country [21] 0 0
Italy
State/province [21] 0 0
Milan
Country [22] 0 0
Spain
State/province [22] 0 0
Esplugues De Llobregat. Barcelona
Country [23] 0 0
Spain
State/province [23] 0 0
Madrid
Country [24] 0 0
United Kingdom
State/province [24] 0 0
Surrey
Country [25] 0 0
United Kingdom
State/province [25] 0 0
London

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

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
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

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT01677741