Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Pediatric Subjects Aged 1 Month to less than 18 Years with Advanced BRAF V600-Mutation Positive Solid Tumors
This research is being done to test the safety of the investigational drug dabrafenib at different doses in children aged between 1 month and 18 years of age who have certain kinds of cancerous tumors (BRAF V600 Mutation Positive Solid Tumors). This study will look at how people react to dabrafenib and how the body processes dabrafenib at different doses. We will give participants different amounts of dabrafenib at different times. The effects of the drug, both good and bad, will be studied. The study has two parts. Each participant will only take part in one part of the study. In Part 1, dabrafenib will be given at different doses. In Part 2, the dose will be set depending on the results of Part 1.
Ages Eligible for Study: 1 Month to 17 Years Genders Eligible for Study: Both Accepts Healthy Volunteers: No CriteriaInclusion Criteria:ï¿½Written informed consent - a signed informed consent and/or assent (as age appropriate) will be obtained according to institutional guidelinesï¿½Male or female between one month and less than 18 years of age (inclusive) at the time of signing the informed consent formï¿½Recurrent disease or progressive disease after having received at least one standard therapy for their diseaseï¿½At least one evaluable lesionï¿½BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory or equivalentï¿½Performance score of greater than equal to 50% according to the Karnofsky/Lansky performance status scale (subjects with a performance status of less than equal to 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)ï¿½Females of child-bearing potential (with negative serum pregnancy test within 7 days prior to the first dose of study medication) and males with reproductive potential must be willing to practice acceptable methods of birth control.ï¿½Must have adequate organ function as defined by the following values: Adequate bone marrow function defined as-absolute neutrophil count (ANC) greater than equal to 1000/ microliter (ÂµL), hemoglobin greater than equal to 8.0 grams (g)/ deciliter (dL) (may receive red blood cell transfusions), platelets greater than equal to 75,000/ÂµL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment; adequate renal and metabolic function defined as: calculated creatinine clearance (Cockcroft-Gault), calculated glomerular filtration rate (GFR) (revised Schwartz formula), or radioisotope GFR greater than equal to 60 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) less than equal to 1.5 x upper limit of normal (ULN) for age, aspartate aminotransaminase (AST) and alanine transaminase (ALT) less than equal to 2.5 x ULN; AST/ALT may be less than 5 x ULN at baseline if liver metastases are present (requires radiographic confirmation of liver metastases) and adequate cardiac function defined as: left ventricular ejection fraction (LVEF) of either greater than equal to 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 less than 450 milliseconds (msecs).Exclusion Criteria:ï¿½Part 2 ONLY: Previous treatment with dabrafenib, another RAF inhibitor, or a mitogen-activated protein kinase (MEK) inhibitor (exception: prior treatment with sorafenib is permitted)ï¿½Malignancy OTHER than the BRAF mutant malignancy under studyï¿½Had chemotherapy or radiotherapy within 3 weeks (or 6 weeks for nitrosoureas or mitomycin C) prior to administration of the first dose of study treatmentï¿½The 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)ï¿½History of another malignancyï¿½Exception: (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, or (e) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score less than equal to 6, and prostate specific antigen [PSA] less than 10 nanograms (ng)/mL) requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligibleï¿½Current use of a prohibited medication or herbal preparation or requires any of these medications during the studyï¿½Unresolved 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 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)ï¿½Has leukaemiaï¿½History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib and its excipients.ï¿½Autologous or allogeneic stem cell transplant within 3 months prior to enrolmentï¿½History of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongationï¿½Subjects with abnormal cardiac valve morphology ( greater than equal to grade 2) documented by echocardiogram, moderate valvular thickening.ï¿½Subjects with known glucose-6-phosphate dehydrogenase (G6PD) deficiencyï¿½Known, uncontrolled cardiac arrhythmias (except sinus arrhythmia) within the past 24 weeksï¿½Uncontrolled 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 protocolï¿½Presence of active GI disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.ï¿½A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of Hepatitis B Virus clearance may be enrolled)ï¿½Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing and lactating females who are actively breast feeding.
Approximately 6 to 18 subjects will participate in Part 1 and will receive a starting dose of 3 mg/kg and dose will deescalate or escalate between 1.5 milligram (mg)/kilogram (kg) and 4.5 mg/kg. Up to 6 subjects will be enrolled at one dose level dependent upon the number of subjects at the current dose level, the number of subjects who have experienced a dose limiting toxicity (DLT) at the current dose level, and the number of subjects enrolled but with data pending at the current dose level. Escalation may proceed until either a maximum tolerated dose (MTD) is established, or until the dose in which the median pharmacokinetic parameters consistent with exposure in adults are achieved. Cohorts may be added in order to evaluate additional dose levels.Part 2 consists of four disease-specific cohorts of subjects with tumors known to have BRAF V600 activation (pediatric low-grade gliomas, pediatric high-grade gliomas, Langerhans cell histiocytosis [LCH], and other tumors such as melanoma and papillary thyroid carcinoma [PTC]). Each cohort will enroll at least 10 subjects with a pre-dose and at least 1 post-dose disease assessment.In both the parts of the study, on Day 1, a single first dose will be administered, and repeat dosing will begin on Day 2. PK sampling will be performed on Day 1 and Day 15 for subjects greater than equal to 25 kg in weight. For subjects less than 25 kg in weight, blood samples for PK analysis will be collected after repeated administration on Day 15 only.Safety and tolerability will be assessed throughout the study. Treatment with dabrafenib will be continued until disease progression or until no clinical benefit or development of an unacceptable toxicity, or until they withdraw consent or begin a new therapy. At the end of treatment, a final study visit will occur.
12/07/2013 04:02 AM