An Absorption, Distribution, Metabolism and Excretion (ADME) Study of Single Oral Dose [14C] GSK2118436 in Subjects With BRAF Mutant Solid Tumors

NCT01262963 | Completed Phase 1

• 1 other identifier: 113463
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

The study is a Phase 1, open-label study designed to characterize the absorption, distribution, metabolism and excretion of GSK2118436 following administration of a single oral 14C labeled dose of GSK2118436 as a suspension in subjects with BRAF mutation positive tumors.

Conditions

Cancer

Keywords

GSK2118436; BRAF inhibitor; BRAF positive tumor; ADME; Oncology

Outcome Measures

Primary Outcomes (2)

• • Excretion of radioactivity in urine following oral administration of [14C]GSK2118436

  Pre-dose, and post-dose for a minimum of 96 hours, and a maximum of 240 hours after dosing.

• • Excretion of radioactivity in feces following oral administration of [14C]GSK2118436

  Pre-dose, and post-dose for a minimum of 96 hours, and a maximum of 240 hours after dosing.

Secondary Outcomes (15)

• • Quantity of GSK2118436 metabolites in plasma

  Pre-dose, and up to 48 hours post dose.

• • Potential covalent binding of drug-related material to plasma proteins

  Pre-dose, and up to 48 hours post dose.

• • Blood total radioactivity

  Pre-dose, and post-dose for a minimum of 96 hours, and a maximum of 240 hours after dosing.

• • Blood:plasma ratio of total drug-related material (radioactivity)

  Pre-dose, and post-dose for a minimum of 96 hours, and a maximum of 240 hours after dosing.

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

  Pre-dose, and up to 48 hours post dose.

Study Arms (1)

Study Medication

EXPERIMENTAL

GSK2118436 suspension

Drug: GSK2118436

Interventions

GSK2118436 DRUG

A single oral dose of 95 mg of GSK2118436 containing approximately 80 µCi of radioactivity

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 (BMI) \>/= 19 kg/m2 and \</= 35 kg/m2 (inclusive);
• Able to swallow and retain oral medication;
• BRAF mutation-positive tumor (V600 E/K mutation) as determined via relevant genetic testing;
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 \[Oken, 1982\]; NOTE: Subjects with an ECOG performance status of 2 may be eligible with the approval of the GSK Medical Monitor
• 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:
• Absolute neutrophil count (ANC) \>/=1.2 x 10\^9/L
• Hemoglobin \>/=9 g/dL
• Platelets \>/=100 x 10\^9/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 (with approval of GSK medical monitor)
• Serum creatinine \</= ULN or calculated creatinine clearance \>/= 60 mL/min
• Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) \</=1.3 x ULN

You may not qualify if:

• Currently receiving cancer therapy (e.g., chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) within the last three weeks; chemotherapy regimens without delayed toxicity within the last two weeks; or use of an investigational anti-cancer drug within four weeks 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;
• The radiation exposure from the previous three year period is over 10 millisieverts (mSv) for subjects who have been exposed to ionizing radiation above background as a result of their work with radiation as Category A (classified) workers or as a result of research studies they may have been involved in. Subjects will be excluded if exposure levels cannot be verified. Clinical (therapeutic or diagnostic) exposure will not be included;
• An occupation which requires monitoring for radiation exposure, nuclear medicine procedures or excessive x-rays within the past 12 months;
• Any major surgery within the last four weeks;
• Unresolved toxicity equal to or 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., gastrectomy, bariatric surgery, small bowel or large bowel resection) that may 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 HBV clearance may be enrolled with permission of the GSK medical monitor);
• 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;
• History of alcohol or drug abuse within six months prior to screening;

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Tacoma, Washington, 98418, United States

Location

Related Publications (1)

• Bershas DA, Ouellet D, Mamaril-Fishman DB, Nebot N, Carson SW, Blackman SC, Morrison RA, Adams JL, Jurusik KE, Knecht DM, Gorycki PD, Richards-Peterson LE. Metabolism and disposition of oral dabrafenib in cancer patients: proposed participation of aryl nitrogen in carbon-carbon bond cleavage via decarboxylation following enzymatic oxidation. Drug Metab Dispos. 2013 Dec;41(12):2215-24. doi: 10.1124/dmd.113.053785. Epub 2013 Oct 4.

  PMID: 24097902 BACKGROUND

Related Links

• Results for study 113463 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: December 2, 2010
• First Posted: December 20, 2010
• Study Start: January 26, 2011
• Primary Completion: April 8, 2011
• Study Completion: April 8, 2011
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

US (1)