Clinical trial NCT01677741: A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Neoplasms, Brain
Keywords: Children and Adolescents
BRAF
dabrafenib
dose escalation
BRF116013
V600-mutation positive
BRF
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-09-03
Enrollment: 85
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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). 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.

Eligibility criteria: 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).

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.

Primary outcomes:
measure: Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)
timeFrame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
measure: Maximum Concentration (Cmax) of Dabrafenib
timeFrame: Week 1 Day 1, Week 3 Day 15
measure: Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-τ)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib
timeFrame: Week 1 Day 1
Secondary outcomes:
measure: Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites
timeFrame: Week 3 Day 15
measure: The AUC(0-t) of Dabrafenib Metabolites
timeFrame: Week 1 Day 1, Week 3 Day 15
measure: The AUC(0-tau) of Dabrafenib and Its Metabolites
timeFrame: Week 1 Day 1, Week 3 Day 15
measure: Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib
timeFrame: Week 1 Day 1, Week 3 Day 15
measure: Maximum Concentration (Cmax) of Dabrafenib Metabolites
timeFrame: Week 1 Day 1, Week 3 Day 15
measure: Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites
timeFrame: Week 1 Day 1, Week 3 Day 15
measure: Elimination Half Life (T½) of Dabrafenib and Its Metabolites
timeFrame: Week 3 Day 15
measure: Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)
timeFrame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
measure: Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects
timeFrame: Up to 6 months
measure: Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects
timeFrame: Up to 6 months
measure: Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model
timeFrame: 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.
measure: Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model
timeFrame: 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.
measure: Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model
timeFrame: 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.
measure: Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model
timeFrame: 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.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Orange
country: United States
facility: Novartis Investigative Site
state: California
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Memphis
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Marseille Cedex 5
country: France
facility: Novartis Investigative Site
city: Paris cedex 05
country: France
facility: Novartis Investigative Site
city: Paris cedex 12
country: France
facility: Novartis Investigative Site
city: Toulouse cedex 9
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Ramat-Gan
country: Israel
facility: Novartis Investigative Site
city: Milan
country: Italy
facility: Novartis Investigative Site
city: Esplugues De Llobregat. Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Hargrave 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.
citation: Kieran 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.
citation: Wang 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.