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An Open Label Study to Examine the Effects of a High-Fat Meal and Particle Size on the Pharmacokinetics of Orally Administered GSK2118436 in Subjects With BRAF Mutation Positive Tumor

Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Cancer

Intervention: Regimen A (Drug); Regimen B (Drug); Regimen C (Drug); Regimen D (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

Summary

The study is designed to evaluate the effects of a high fat meal on the pharmacokinetics of 150 mg of GSK2118436, as well as the effects of particle size on the relative bioavailability of GSK2118436.

Clinical Details

Official title: An Open-Label Study to Examine the Effects of a High-Fat Meal and Particle Size on the Pharmacokinetics of Orally Administered GSK2118436 in Subjects With BRAF Mutation-Positive Tumor

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Prevention

Primary outcome:

Area under the plasma-concentration time curve (AUC) of GSK2118436

Maximum plasma concentration (Cmax) of GSK2118436

Time to Cmax (Tmax) of GSK2118436

Secondary outcome:

Terminal half-life (t1/2) of GSK2118436

AUC, Cmax, Tmax and t1/2 of GSK2118436 metabolites (GSK2285403, GSK2167542 and GSK2298683) and ratio of metabolite to parent drug GSK2118436

Number of subjects with adverse events as a measure of safety and tolerability

Detailed description: GSK2118436 is an orally administered, potent and selective small molecule BRAF inhibitor that is currently being developed for the treatment of BRAF mutation-positive tumors. This study is designed to evaluate the effects of particle size on the relative bioavailability of GSK2118436 (Cohort 1) and to evaluate the effects of a high-fat meal on the pharmacokinetics of GSK2118436 (Cohort 2). Subjects will randomly receive two of four possible regimens over two periods. Subjects enrolled in Cohort 1 will receive a single 150 mg dose of GSK2118436 as micronized particles fasted (gelatin capsule formulation) and a single 150 mg dose of GSK2118436 as non-micronized particles fasted (larger particle size). Subjects enrolled in Cohort 2 will receive a single 150 mg dose of GSK2118436 (HydroxyPropyl Methyl Cellulose (HPMC) capsule formulation) fasted and with a high-fat breakfast. GSK2118436 will be administered as the mesylate salt (equivalent to 150 mg free base). Safety and tolerability will also be evaluated. The study will be conducted at a sufficient number of centers to complete approximately 28 adult subjects (14 subjects per cohort) with BRAF mutation-positive tumors. Following completion of this study, subjects may continue dosing with GSK2118436 in the roll-over study, Protocol BRF114144.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Male or female at least 18 years of age at the time of signing the informed consent

form;

- Capable of giving written informed consent, which includes compliance with the

requirements and restrictions listed in the consent form;

- Body weight >/= to 45 kg and a Body Mass Index (BMI) >/= to 19 kg/m2 and less than

or equal to 35 kg/m2 (inclusive);

- Able to swallow and retain oral medication;

- BRAF mutation-positive tumor as determined via relevant genetic testing;

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at the time of

transition to this study. NOTE: Subjects with an ECOG performance status of - Women of child-bearing potential and men with reproductive potential must be willing

to practice acceptable methods of birth control. Additionally, women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment;

- Must have adequate organ function as defined by the following values:

- Absolute neutrophil count (ANC) >/= to 1. 2 x 10^9/L

- Hemoglobin >/= to 9 g/dL

- Platelets >/= to 100 x 10^9/L

- Serum bilirubin

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <5 x ULN if liver metastases are present (with approval of GSK medical monitor)

- Serum creatinine /= 60 mL/min

- Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin

time (PTT) < /= to 1. 3 x ULN

- Left ventricular ejection fraction (LVEF) >/= to institutional lower limit of normal

by Echocardiogram Exclusion Criteria:

- Currently receiving cancer therapy (e. g., chemotherapy with delayed toxicity,

extensive radiation therapy, immunotherapy, biologic therapy) within the last three weeks; chemotherapy regimens without delayed toxicity within the last two weeks; or use of an investigational anti-cancer drug within 28 days preceding the first dose of GSK2118436;

- Current use of a prohibited medication or requires any of these medications during

the study;

- Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from seven

days prior to the first dose of study medication;

- Current use of therapeutic warfarin (note: low molecular weight heparin and

prophylactic low-dose warfarin are permitted);

- History of sensitivity to heparin or heparin-induced thrombocytopenia;

- Any major surgery within the last four weeks;

- Unresolved toxicity greater than National Cancer Institute Common Terminology

Criteria for Adverse Events, version 4. 0 (NCI CTCAE v4. 0) [NCI, 2009] Grade 2 from previous anti-cancer therapy except alopecia;

- Presence of active gastrointestinal disease or other condition (e. g., small bowel or

large bowel resection) that will interfere significantly with the absorption of drugs. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the GSK medical monitor for permission to enroll the subject;

- A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or

Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of HBV clearance may be enrolled with permission of the GSK medical monitor);

- Presence of invasive malignancy other than one of the malignancies covered under

Inclusion Criterion #5; patients with a history of malignancy that have been definitively treated can be enrolled with approval of the GSK medical monitor;

- Subjects with brain metastases are excluded if their brain metastases are either:

Symptomatic Treated (surgery, radiation therapy) but not clinically and radiographically stable one month after local therapy, or Asymptomatic and untreated but > 1 cm in the longest dimension Patients with small (≤ 1 cm in the longest dimension), asymptomatic brain metastases that do not need immediate local therapy can be enrolled with the approval of the GSK medical monitor. Subjects on a stable dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least two weeks can be enrolled with approval of the GSK medical monitor. Subjects must also be off of enzyme-inducing anticonvulsants for more than four weeks;

- Presence of rheumatoid arthritis;

- History of alcohol or drug abuse within six months prior to screening;

- Corrected QT (QTc) interval >/= to 480 msecs;

- 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; abnormal cardiac valve morphology documented by echocardiogram (subjects with minimal abnormalities [ie, mild regurgitation/stenosis] can be entered on study with approval from the GSK medical monitor); or history of known cardiac arrhythmias (except sinus arrhythmias) within the past 24 weeks;

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs

chemically related to the study drugs, or excipients (note: to date there are no known drugs chemically related to GSK2118436 which are approved by the Food and Drug Administration);

- Uncontrolled medical conditions (e. g., diabetes mellitus, hypertension),

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;

- Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency;

- The subject has participated in a clinical trial and has received an investigational

product within the following time period prior to the first dosing day in the current study: 30 days, five half-lives or twice the duration of the biological effect of the investigational product (whichever is longer);

- Where participation in the study would result in donation of blood or blood products

in excess of 500 mL within a 56 day period;

- Pregnant females as determined by positive human chorionic gonadotrophin (hCG) test

at screening or prior to dosing;

- Lactating females who are actively breast feeding;

- Subject is mentally or legally incapacitated;

Locations and Contacts

GSK Investigational Site, Scottsdale, Arizona 85259, United States

GSK Investigational Site, Detroit, Michigan 48201, United States

GSK Investigational Site, Nashville, Tennessee 37203, United States

GSK Investigational Site, Salt Lake City, Utah 84112, United States

Additional Information

Starting date: October 2010
Last updated: May 29, 2014

Page last updated: August 23, 2015

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