A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects

NCT01677741 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 1160132012-001499-12CDRB436A2102
• Study Type: interventional
• Target: 85
• Locations: 10 countries
• Sites: 26

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.

Conditions

Neoplasms, Brain

Keywords

Children and Adolescents; BRAF; dabrafenib; dose escalation; BRF116013; V600-mutation positive; BRF

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  Week 1 Day 1

Secondary Outcomes (14)

• Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites

  Week 3 Day 15

• The AUC(0-t) of Dabrafenib Metabolites

  Week 1 Day 1, Week 3 Day 15

• The AUC(0-tau) of Dabrafenib and Its Metabolites

  Week 1 Day 1, Week 3 Day 15

• Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib

  Week 1 Day 1, Week 3 Day 15

• Maximum Concentration (Cmax) of Dabrafenib Metabolites

  Week 1 Day 1, Week 3 Day 15

Study Arms (5)

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.

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.

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.

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.

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.

Drug: Dabrafenib

Interventions

Dabrafenib DRUG

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.

Also known as: DRB436

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

Eligibility Criteria

• Age: 12 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (26)

Novartis Investigative Site

Phoenix, Arizona, 85016-7710, United States

Location

Novartis Investigative Site

Orange, California, 92868, United States

Location

Novartis Investigative Site

Baltimore, Maryland, 21287, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02215, United States

Location

Novartis Investigative Site

New York, New York, 10065, United States

Location

Novartis Investigative Site

Cincinnati, Ohio, 45229, United States

Location

Novartis Investigative Site

Memphis, Tennessee, 38105-3678, United States

Location

Novartis Investigative Site

Seattle, Washington, 98105, United States

Location

Novartis Investigative Site

Parkville, Victoria, 3052, Australia

Location

Novartis Investigative Site

Toronto, Ontario, M5G 1X8, Canada

Location

Novartis Investigative Site

Copenhagen, DK-2100, Denmark

Location

Novartis Investigative Site

Marseille, 13385, France

Location

Novartis Investigative Site

Paris, 75248, France

Location

Novartis Investigative Site

Paris, 75571, France

Location

Novartis Investigative Site

Toulouse, 31059, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Novartis Investigative Site

Regensburg, Bavaria, 93053, Germany

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Jerusalem, 91120, Israel

Location

Novartis Investigative Site

Ramat Gan, 52621, Israel

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Novartis Investigative Site

Milan, 20133, Italy

Location

Novartis Investigative Site

Esplugues de Llobregat. Barcelona, 08950, Spain

Location

Novartis Investigative Site

Madrid, 28009, Spain

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Novartis Investigative Site

London, WC1N 3JH, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 36884302 DERIVED

• 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.

  PMID: 31811016 DERIVED

• 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.

  PMID: 31506385 DERIVED

• 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.

  PMID: 29880583 DERIVED

MeSH Terms

Conditions

Brain Neoplasms

Interventions

dabrafenib

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2012
• First Posted: September 3, 2012
• Study Start: May 23, 2013
• Primary Completion: December 4, 2020
• Study Completion: December 4, 2020
• Last Updated: November 24, 2021
• Results First Posted: November 24, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share

Locations

FR (5); US (8); DE (3); ES (2); AU (1); GB (2); DK (1); IL (2); CA (1); IT (1)