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NCI 9343 (MC1211), A Phase 1 and Pharmacokinetic Study of Dabrafenib (GSK2118436B) in Patients with BRAFV600X Mutations and Renal or Hepatic Dysfunction.
Protocol Number:
Phase I
Michael Carducci
Primary Objective To determine the safety and tolerability of dabrafenib in patients with BRAFV600X mutations and renal or hepatic dysfunction. Secondary objextives include tumor response assessment and dosing recommendations for patients with hepatic or renal dysfunction. Additionally to assess pharmacokinetic and pharmacogenetic profile of dabrafenib. Patients entering this study will be stratified into 6 groups or cohorts according to their hepatic or renal function. Group N Hepatic: Normal function (Bilirubin less than / equal to ULN; AST less than / equal to ULN) Renal: Normal function (CrCl greater than / equal to 90 mL/min*) Group R3 Hepatic: Normal function (Bilirubin less than / equal to ULN; AST less than / equal to ULN) Renal: Severe dysfunction (CrCl greater than / equal to 15 and less than 30 mL/min*) Group R4 Hepatic: Normal function (Bilirubin less than / equal to ULN; AST less than / equal to ULN) Renal: Renal failure (hemodialysis) Group H1 Hepatic: Mild dysfunction (Bilirubin less than / equal to ULN; AST greater than ULN) Renal: Acceptable function (CrCl greater than / equal to 60 mL/min*) Group H2 Hepatic: Moderate dysfunction (Bilirubin greater than ULN and less than / equal to 3x ULN AST greater than ULN) Renal: Acceptable function (CrCl greater than / equal to 60 mL/min*) Group H3 Hepatic: Severe dysfunction (Bilirubin greater than 3x ULN and up to investigators discretion; AST greater than ULN) Renal: Acceptable function (CrCl greater than / equal to 60 mL/min*)
Eligible patients will be willing to provide tissue as required per protocol for central BRAF-V600 mutation testing Patients will be able to understand and willing to sign written informed consent. Age greater than 18 years with life expectancy of greater than 3 months. Patients must have BRAF-V600 mutated. Colorectal cancers with BRAF mutations ARE NOT allowed. Adequate marrow function as defined as : Absolute neutrophil count (ANC) greater than / equal to 1.5x109/L Hemoglobin greater than / equal to 9 g/dL Platelets greater than / equal to 75x109/L Hepatic and renal function as per cohort assignment. Patients will be able to swallow oral meds, have a good performance status and had no chemo for 4-6 weeks (depending on chemotherapy). No pregnant women. Women of child-bearing potential and men must agree to use adequate contraception. Willingness to provide to provide blood and tissue samples as required per protocol No active biliary obstruction permitted. Patients with recent stent placement should be 10 days out from procedure. Left ventricular ejection fraction (determined by echocardiogram) cannot be less than 50%. No patients with active hepatitis or HIV + patients on antiretroviral therapy. No other active malignancy. Certain medications made be disallowed or require change to be on trial due to interaction with trial meds. (specifically CYP3a or CYP2c8 medications) Some warfarin patient may be allowed with sponsor approval. No unresolved toxicity or side effect from prior treatment greater than grade 2 as assessed by clinical team according to the NCI CTCAE version 4. Other uncontrolled intercurrent illnesses may not be allowed, including but not limited to: ongoing/active infection, diabetes mellitus, hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with brain mets are allowed if previously treated and pt is stable for greater than 3 months. No history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system (see Appendix F); or history of known cardiac arrhythmias unless it has been stably controlled. Other conditions may not be allowed if the investigator feels they would pose unacceptable risk
Dabrafenib will be taken orally twice per day during a 28 day cycle. Exception: On Cycle 1, Day 1, patients will be instructed to take a single dose of dabrafenib. In general visits are weekly. Day 1 and day 15 are 8 hour days in clinic due to the requirement of a full day of research blood work collection throughout the day in addition to a 24 hour collection on day 2 and day 16. Scans for disease assessment will be every 2 months. Treatment will continue until progression of disease is noted or unacceptable toxicity occurs.
Last Update
08/02/2014 04:02 AM

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