Determination of the Absolute Bioavailability of GSK2118436 Following a Single Oral Dose Co-Administered With an Intravenous Radiolabelled Microtracer of GSK2118436 in Subjects With BRAF Mutant Solid Tumors

NCT01340833 | Completed Phase 1

• 1 other identifier: 113479
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

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 is an open-label, non-randomized study designed to determine the absolute bioavailability of an oral dose of 150 mg of GSK2118436 co-administered with an intravenous 50 microgram dose of \[14C\]GSK2118436 in subjects with BRAF mutant solid tumors. Pharmacokinetic samples will be obtained up to 72 hours post-dose. Safety assessments will be performed throughout the study. After completing all assessments, eligible subjects may transition to BRF114144, an open-label, rollover study of GSK2118436 to continue treatment.

Conditions

Cancer

Keywords

GSK2118436; BRAF inhibitor; BRAF-mutation positive tumor; Oncology; absolute bioavailability; microtracer

Outcome Measures

Primary Outcomes (1)

• The percent of absolute bioavailability (F) of GSK2118436 following single-dose oral HPMC capsule and a concomitant IV microdose

  Up to 72 hours

Secondary Outcomes (8)

• Maximum plasma concentration (Cmax) of plasma GSK2118436 and [14C]GSK2118436

  Up to 72 hours

• Time to Cmax (Tmax) of plasma GSK2118436 and [14C]GSK2118436

  Up to 72 hours

• Area under the plasma-concentration time curve (AUC) of plasma GSK2118436 and [14C]GSK2118436

  Up to 72 hours

• Terminal half-life (t1/2) of plasma GSK2118436 and [14C]GSK2118436

  Up to 72 hours

• Oral clearance (CL/F) of GSK2118436

  Up to 72 hours

Study Arms (1)

Study Medication

EXPERIMENTAL

GSK2118436

Drug: GSK2118436

Interventions

GSK2118436 DRUG

Two capsules each containing 75 mg GSK2118436, followed by a single IV dose of 50 ug (no more than 7.4 kBq or 200 nCi) \[14C\]GSK2118436, starting 1.75 hours after the oral dose

Study Medication

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \>/= 45 kg and a body mass index \>/= 19 kg/m2 and \</= 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
• Women of child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control. Additionally, women of childbearing 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:
• ANC \>/=1.2 x 109/L Hemoglobin \>/=9 g/dL Platelets \>/=100 x 109/L Serum bilirubin \</=1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \</= 2.5 x ULN; \<5 x ULN if liver metastases are present Serum creatinine \</= ULN or calculated creatinine clearance \>/= 60 mL/min Prothrombin time / INR and partial thromboplastin time \</=1.3 x ULN Left ventricular ejection fraction \>/= institutional lower limit of normal by ECHO

You may not qualify if:

• Currently receiving cancer therapy (e.g., chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks; or use of an investigational anti-cancer drug within 28 days preceding the first dose of GSK2118436; use of any other investigational product within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is warranted by data);
• Has participated in a 14C human research study in the 12 months prior to administration of study medication;
• 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 7 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 4 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 enrol the subject;
• A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with documented laboratory evidence of HBV clearance may be enrolled);
• Subjects with brain metastases are excluded if their brain metastases are either:
• Symptomatic Treated (surgery, radiation therapy), but not clinically and radiographically stable for a period of at least one month prior to study entry, or Asymptomatic and untreated but \> 1 cm in the longest dimension Exception: Subjects with small (≤ 1 cm in the longest dimension), asymptomatic brain metastases that do not need immediate local therapy can be enrolled. Subjects on a stable dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks;
• Corrected QT (QTc) interval \>/= 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 ECHO \[subjects with minimal abnormalities (i.e., mild regurgitation/stenosis) can be entered on study - if clarification is needed as to whether an ECHO abnormality is minimal, please contact the GSK medical monitor); or history of known cardiac arrhythmias (except sinus arrythmias) within the past 24 weeks;

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Tacoma, Washington, 98418, United States

Location

Related Publications (1)

• Denton CL, Minthorn E, Carson SW, Young GC, Richards-Peterson LE, Botbyl J, Han C, Morrison RA, Blackman SC, Ouellet D. Concomitant oral and intravenous pharmacokinetics of dabrafenib, a BRAF inhibitor, in patients with BRAF V600 mutation-positive solid tumors. J Clin Pharmacol. 2013 Sep;53(9):955-61. doi: 10.1002/jcph.127. Epub 2013 Jul 12.

  PMID: 23846776 BACKGROUND

Related Links

• Results for study 113479 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms

Interventions

dabrafenib

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2011
• First Posted: April 25, 2011
• Study Start: June 8, 2011
• Primary Completion: September 12, 2011
• Study Completion: September 12, 2011
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

US (1)