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

Completed · Phase 1/Phase 2

Conditions studied: Neoplasms, Brain

In brief

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.

Key facts

Study ID

NCT01677741

Run by

Novartis Pharmaceuticals

People needed

85

Starts

2013-05-23

Expected to finish

2020-12-04

Last updated by the study team

2021-11-24

Who can join

Age: 1 and older, up to 17. Sex: any. Healthy volunteers: not accepted.

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.
• 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.

Where it is running

• Novartis Investigative Site — Phoenix, Arizona, United States
• Novartis Investigative Site — Orange, California, United States
• Novartis Investigative Site — Baltimore, Maryland, United States
• Novartis Investigative Site — Boston, Massachusetts, United States
• Novartis Investigative Site — New York, New York, United States
• Novartis Investigative Site — Cincinnati, Ohio, United States
• Novartis Investigative Site — Memphis, Tennessee, United States
• Novartis Investigative Site — Seattle, Washington, United States
• Novartis Investigative Site — Parkville, Victoria, Australia
• Novartis Investigative Site — Toronto, Ontario, Canada
• Novartis Investigative Site — Copenhagen, Denmark
• Novartis Investigative Site — Marseille, France
• Novartis Investigative Site — Paris, France
• Novartis Investigative Site — Paris, France
• Novartis Investigative Site — Toulouse, France
• Novartis Investigative Site — Villejuif, France
• Novartis Investigative Site — Heidelberg, Baden-Wurttemberg, Germany
• Novartis Investigative Site — Regensburg, Bavaria, Germany
• Novartis Investigative Site — Berlin, Germany
• Novartis Investigative Site — Jerusalem, Israel
• Novartis Investigative Site — Ramat Gan, Israel
• Novartis Investigative Site — Milan, Italy
• Novartis Investigative Site — Esplugues de Llobregat. Barcelona, Spain
• Novartis Investigative Site — Madrid, Spain
• Novartis Investigative Site — Sutton, Surrey, United Kingdom

Full record on ClinicalTrials.gov

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