Neoplasms, BrainPhase 1/2NCT01677741
A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects
A Phase 1/2 study testing Dabrafenib in people with Neoplasms, Brain, run by Novartis Pharmaceuticals at 26 sites in 10 countries.
Trial summary
This was a 2-part, Phase I/IIa, multi-center, open label, study in pediatric and adolescent patients with advanced BRAF V600 mutation-positive solid tumors. Part 1 was a dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). Read more about this study
- Who is it for?
- Ages 12 months to 17 years
- Conditions the study is for
- Neoplasms, Brain
- What is being tested?
- Dabrafenib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 85 participants
- Where
- 26 sitesin 10 countries
- Study dates
- 23 May 2013to 4 Dec 2020
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 months to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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).
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- 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).
Who cannot join
- 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.
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- 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.
Trial locations and contacts
26 sites in 10 countries.
26 sites in 10 countries
United States8 sites
Novartis Investigative Site
Baltimore, Maryland, 21287
Novartis Investigative Site
Boston, Massachusetts, 02215
Novartis Investigative Site
Cincinnati, Ohio, 45229
Novartis Investigative Site
Memphis, Tennessee, 38105-3678
Novartis Investigative Site
New York, New York, 10065
Novartis Investigative Site
Orange, California, 92868
Novartis Investigative Site
Phoenix, Arizona, 85016-7710
Novartis Investigative Site
Seattle, Washington, 98105
France5 sites
Novartis Investigative Site
Marseille, 13385
Novartis Investigative Site
Paris, 75248
Novartis Investigative Site
Paris, 75571
Novartis Investigative Site
Toulouse, 31059
Novartis Investigative Site
Villejuif, 94805
Germany3 sites
Novartis Investigative Site
Berlin, 13353
Novartis Investigative Site
Heidelberg, Baden-Wurttemberg, 69120
Novartis Investigative Site
Regensburg, Bavaria, 93053
Israel2 sites
Novartis Investigative Site
Jerusalem, 91120
Novartis Investigative Site
Ramat Gan, 52621
Spain2 sites
Novartis Investigative Site
Esplugues de Llobregat. Barcelona, 08950
Novartis Investigative Site
Madrid, 28009
United Kingdom2 sites
Novartis Investigative Site
London, WC1N 3JH
Novartis Investigative Site
Sutton, Surrey, SM2 5PT
About this study
Official 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
This was a 2-part, Phase I/IIa, multi-center, open label, study in pediatric and adolescent patients with advanced BRAF V600 mutation-positive solid tumors. Part 1 was a dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). Part 2 was an expansion study to further evaluate the safety, tolerability, and clinical activity of dabrafenib in 4 tumor-specific pediatric populations. Patients participated in only either part 1 or part 2 of the study.
Read the detailed description
Part 1 was a dose escalation study in subjects with any BRAF V600 mutation-positive solid tumor, designed to optimize efficiency of enrollment, minimize the number of subjects being treated at potentially sub-efficacious dose levels, and incorporating the evolving pharmacokinetic, safety and efficacy data from the adult development program. Dose escalation part of the study was to determine the maximum tolerated dose (MTD) and recommend the dose for phase 2 studies (RP2D). An MTD has not been identified for dabrafenib in the adult population. This does not preclude the identification of an MTD in the pediatric population. Modified RSD was employed to determine the MTD. Part 1 used dual criteria of dose limiting toxicity (DLT) and observed dabrafenib exposures to make decisions to advance to the next dose level. Target exposure criteria based on adults treated at the approved adult dose of 300 mg (150 mg given BID) were observed in this study before meeting criteria for stopping dose escalation due to observations of DLTs, and served as the criteria for determining the RP2D for dabrafenib in pediatric subjects. Thus, MTD has not been established in pediatric population, similar to the previous dose finding efforts in adult subjects.
Part 2 was a tumor specific expansion study to further evaluate the safety/tolerability profile and to discover possible clinical efficacy of dabrafenib in 4 tumor-specific pediatric populations known to have BRAFV600 activation: high grade glioma (HGG), low grade glioma (LGG), Langerhans cell histiocytosis (LCH), miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other). The exposures for subjects dosed on the basis of weight were also evaluated by age categories.
- Conditions
- Neoplasms, Brain
- Being tested
- Dabrafenib
- Keywords
- Children and Adolescents, BRAF, dabrafenib, dose escalation, BRF116013, V600-mutation positive, BRF
- Medical subject headings
- Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DabrafenibDrug
Also called DRB436
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.
| Study group | Role | What they receive |
|---|---|---|
| Part 1: Dabrafenib treatment | Experimental | 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. Receives: Drug: Dabrafenib |
| Part 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutations | Experimental | 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. Receives: Drug: Dabrafenib |
| Part 2: Cohort 2 High-Grade Gliomas with BRAF V600 mutations | Experimental | 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. Receives: Drug: Dabrafenib |
| Part 2: Cohort 3 LCH with BRAF V600 mutations | Experimental | 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. Receives: Drug: Dabrafenib |
| Part 2: Cohort 4 Melanoma and PTC with BRAF V600 mutations | Experimental | 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. Receives: Drug: Dabrafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)
The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Measured: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
Maximum Concentration (Cmax) of Dabrafenib
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib was listed and summarized using descriptive statistics.
Measured: Week 1 Day 1, Week 3 Day 15
Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-τ)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC(0-τ) and AUC(0-inf) of dabrafenib were to be listed and summarized using descriptive statistics.
Measured: Week 1 Day 1
Secondary outcomes (14)
Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Pre-dose (trough) concentration (C tau) was to be listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Measured: Week 3 Day 15
The AUC(0-t) of Dabrafenib Metabolites
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]) dabrafenib metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) were to be listed and summarized using descriptive statistics.
Measured: Week 1 Day 1, Week 3 Day 15
The AUC(0-tau) of Dabrafenib and Its Metabolites
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) were to be listed and summarized using descriptive statistics.
Measured: Week 1 Day 1, Week 3 Day 15
Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. CL/F of dabrafenib was to be listed and summarized using descriptive statistics.
Measured: Week 1 Day 1, Week 3 Day 15
Maximum Concentration (Cmax) of Dabrafenib Metabolites
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) were listed and summarized using descriptive statistics.
Measured: Week 1 Day 1, Week 3 Day 15
Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Measured: Week 1 Day 1, Week 3 Day 15
Elimination Half Life (T½) of Dabrafenib and Its Metabolites
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. T1/2 of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]) was listed and summarized using descriptive statistics.
Measured: Week 3 Day 15
Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)
The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Event and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Measured: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects
Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.
Measured: Up to 6 months
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects
Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.
Measured: Up to 6 months
Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on total apparent clearance (CL/F) of dabrafenib estimated with the PopPK model is summarized in this record.
Measured: 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.
Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on volume of distribution (V/F) of dabrafenib estimated with the PopPK model is summarized in this record.
Measured: 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.
Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on absorption rate (ka) of dabrafenib estimated with a PopPK model is summarized in this record.
Measured: 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.
Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on coefficients for significant covariates of dabrafenib estimated with a PopPK model is summarized in this record.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Sep 2012 (estimated)
- Study start23 May 2013
- Primary completion4 Dec 2020
- Study completion4 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Neoplasms, BrainStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 85 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01677741
- Sponsor's protocol ID
- 116013
- Other IDs
- 2012-001499-12, CDRB436A2102
- Status last verified
- Oct 2021
- First submitted
- 30 Aug 2012
- Last updated
- 24 Nov 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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
Publications
Whitlock JA, Geoerger B, Dunkel IJ, Roughton M, Choi J, Osterloh L, Russo M, Hargrave D. Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv. 2023 Aug 8;7(15):3806-3815. doi: 10.1182/bloodadvances.2022008414.
PubMed 36884302Hargrave DR, Bouffet E, Tabori U, Broniscer A, Cohen KJ, Hansford JR, Geoerger B, Hingorani P, Dunkel IJ, Russo MW, Tseng L, Dasgupta K, Gasal E, Whitlock JA, Kieran MW. Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study. Clin Cancer Res. 2019 Dec 15;25(24):7303-7311. doi: 10.1158/1078-0432.CCR-19-2177.
PubMed 31811016Kieran MW, Geoerger B, Dunkel IJ, Broniscer A, Hargrave D, Hingorani P, Aerts I, Bertozzi AI, Cohen KJ, Hummel TR, Shen V, Bouffet E, Pratilas CA, Pearson ADJ, Tseng L, Nebot N, Green S, Russo MW, Whitlock JA. A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors. Clin Cancer Res. 2019 Dec 15;25(24):7294-7302. doi: 10.1158/1078-0432.CCR-17-3572. Epub 2019 Sep 10.
PubMed 31506385Wang J, Yao Z, Jonsson P, Allen AN, Qin ACR, Uddin S, Dunkel IJ, Petriccione M, Manova K, Haque S, Rosenblum MK, Pisapia DJ, Rosen N, Taylor BS, Pratilas CA. A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAFV600E-Mutant Brain Tumor. Cancer Discov. 2018 Sep;8(9):1130-1141. doi: 10.1158/2159-8290.CD-17-1263. Epub 2018 Jun 7.
PubMed 29880583
Study at a glance
From the registry record, last updated by the sponsor on 24 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT01677741
- Acronym / sponsor ID
- 116013
- Conditions
- Neoplasms, Brain
- Keywords
- Children and Adolescents, BRAF, dabrafenib, dose escalation, BRF116013, V600-mutation positive, BRF
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 85 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 23 May 2013 (actual)
- Primary completion
- 4 Dec 2020 (actual)
- Study completion
- 4 Dec 2020 (actual)
- First posted
- 3 Sep 2012 (estimated)
- Results
- Posted 24 Nov 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This was a 2-part, Phase I/IIa, multi-center, open label, study in pediatric and adolescent patients with advanced BRAF V600 mutation-positive solid tumors. Part 1 was a dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). Part 2 was an expansion study to further evaluate the safety, tolerability, and clinical activity of dabrafenib in 4 tumor-specific pediatric populations. Patients participated in only either part 1 or part 2 of the study.
Detailed description
Part 1 was a dose escalation study in subjects with any BRAF V600 mutation-positive solid tumor, designed to optimize efficiency of enrollment, minimize the number of subjects being treated at potentially sub-efficacious dose levels, and incorporating the evolving pharmacokinetic, safety and efficacy data from the adult development program. Dose escalation part of the study was to determine the maximum tolerated dose (MTD) and recommend the dose for phase 2 studies (RP2D). An MTD has not been identified for dabrafenib in the adult population. This does not preclude the identification of an MTD in the pediatric population. Modified RSD was employed to determine the MTD. Part 1 used dual criteria of dose limiting toxicity (DLT) and observed dabrafenib exposures to make decisions to advance to the next dose level. Target exposure criteria based on adults treated at the approved adult dose of 300 mg (150 mg given BID) were observed in this study before meeting criteria for stopping dose escalation due to observations of DLTs, and served as the criteria for determining the RP2D for dabrafenib in pediatric subjects. Thus, MTD has not been established in pediatric population, similar to the previous dose finding efforts in adult subjects.
Part 2 was a tumor specific expansion study to further evaluate the safety/tolerability profile and to discover possible clinical efficacy of dabrafenib in 4 tumor-specific pediatric populations known to have BRAFV600 activation: high grade glioma (HGG), low grade glioma (LGG), Langerhans cell histiocytosis (LCH), miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other). The exposures for subjects dosed on the basis of weight were also evaluated by age categories.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Part 1: Dabrafenib treatment | Experimental | Drug: DabrafenibThree 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. |
| Part 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutations | Experimental | Drug: DabrafenibSubjects 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. |
| Part 2: Cohort 2 High-Grade Gliomas with BRAF V600 mutations | Experimental | Drug: DabrafenibSubjects 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. |
| Part 2: Cohort 3 LCH with BRAF V600 mutations | Experimental | Drug: DabrafenibSubjects 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. |
| Part 2: Cohort 4 Melanoma and PTC with BRAF V600 mutations | Experimental | Drug: DabrafenibSubjects 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. |
Who may qualify
- Ages
- 12 months to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (12 listed)
- 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).
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DabrafenibAlso: DRB436Dabrafenib 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. | Drug | Part 1: Dabrafenib treatment, Part 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutations, Part 2: Cohort 2 High-Grade Gliomas with BRAF V600 mutations, Part 2: Cohort 3 LCH with BRAF V600 mutations, Part 2: Cohort 4 Melanoma and PTC with BRAF V600 mutations |
Primary outcome
Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)
Time frame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Maximum Concentration (Cmax) of Dabrafenib
Time frame: Week 1 Day 1, Week 3 Day 15
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib was listed and summarized using descriptive statistics.
Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-τ)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib
Time frame: Week 1 Day 1
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC(0-τ) and AUC(0-inf) of dabrafenib were to be listed and summarized using descriptive statistics.
14 secondary outcomes
Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites
Time frame: Week 3 Day 15
The AUC(0-t) of Dabrafenib Metabolites
Time frame: Week 1 Day 1, Week 3 Day 15
The AUC(0-tau) of Dabrafenib and Its Metabolites
Time frame: Week 1 Day 1, Week 3 Day 15
Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib
Time frame: Week 1 Day 1, Week 3 Day 15
Maximum Concentration (Cmax) of Dabrafenib Metabolites
Time frame: Week 1 Day 1, Week 3 Day 15
Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites
Time frame: Week 1 Day 1, Week 3 Day 15
Elimination Half Life (T½) of Dabrafenib and Its Metabolites
Time frame: Week 3 Day 15
Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)
Time frame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects
Time frame: Up to 6 months
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects
Time frame: Up to 6 months
Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model
Time frame: 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.
Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model
Time frame: 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.
Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model
Time frame: 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.
Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Nov 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36884302Whitlock JA, Geoerger B, Dunkel IJ, Roughton M, Choi J, Osterloh L, Russo M, Hargrave D. Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv. 2023 Aug 8;7(15):3806-3815. doi: 10.1182/bloodadvances.2022008414.
- Derived from this study: PubMed 31811016Hargrave DR, Bouffet E, Tabori U, Broniscer A, Cohen KJ, Hansford JR, Geoerger B, Hingorani P, Dunkel IJ, Russo MW, Tseng L, Dasgupta K, Gasal E, Whitlock JA, Kieran MW. Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study. Clin Cancer Res. 2019 Dec 15;25(24):7303-7311. doi: 10.1158/1078-0432.CCR-19-2177.
- Derived from this study: PubMed 31506385Kieran MW, Geoerger B, Dunkel IJ, Broniscer A, Hargrave D, Hingorani P, Aerts I, Bertozzi AI, Cohen KJ, Hummel TR, Shen V, Bouffet E, Pratilas CA, Pearson ADJ, Tseng L, Nebot N, Green S, Russo MW, Whitlock JA. A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors. Clin Cancer Res. 2019 Dec 15;25(24):7294-7302. doi: 10.1158/1078-0432.CCR-17-3572. Epub 2019 Sep 10.
- Derived from this study: PubMed 29880583Wang J, Yao Z, Jonsson P, Allen AN, Qin ACR, Uddin S, Dunkel IJ, Petriccione M, Manova K, Haque S, Rosenblum MK, Pisapia DJ, Rosen N, Taylor BS, Pratilas CA. A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAFV600E-Mutant Brain Tumor. Cancer Discov. 2018 Sep;8(9):1130-1141. doi: 10.1158/2159-8290.CD-17-1263. Epub 2018 Jun 7.
- Individual participant dataSharing planned: 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
26 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Dabrafenib in people with Neoplasms, Brain, run by Novartis Pharmaceuticals at 26 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 26 sites in United States, France, Germany, Israel, Spain and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation) (time frame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01677741, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Nov 2021.