A Pharmacokinetics Study of the Effects of GSK2118436 on Warfarin, the Effects of Ketoconazole and Gemfibrozil on GSK2118436, and the Effects of Repeat Doses of GSK2118436 in Subjects With BRAF Mutant Solid Tumors

NCT01340846 | Completed Phase 1

• 1 other identifier: 113771
• Study Type: interventional
• Target: 48
• Locations: 3 countries
• Sites: 11

Brief Summary

GSK2118436 is an orally administered, potent and selective small molecule BRAF inhibitor that is being developed for the treatment of BRAF mutation-positive tumors. This is a 4-part study (in 4 separate cohorts of subjects) designed to examine the interaction potential of GSK2118436, either as a perpetrator (i.e., effect of GSK2118436 on warfarin; Part A) or victim (i.e., effect of other drugs on GSK2118436; Part B: ketoconazole and Part C: gemfibrozil), as well as to evaluate the single and repeat dose pharmacokinetic parameters of GSK2118436 (Part D). A sufficient number of subjects will be screened to obtain approximately 12 evaluable subjects each for Part A, Part B, Part C and Part D. Following completion of this study, subjects may continue dosing with GSK2118436 in the roll-over study, Protocol BRF114144.

Conditions

Cancer

Keywords

gemfibrozil; BRAF; Drug Interactions; GSK2118436; warfarin; ketoconazole; BRAF inhibitor; oncology; BRAF positive tumor

Outcome Measures

Primary Outcomes (12)

• Maximum plasma concentration (Cmax) of S-warfarin with and without GSK2118436

  Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)

• Area under the concentration time curve (AUC) of S-warfarin with and without GSK2118436

  Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)

• Maximum plasma concentration (Cmax) of GSK2118436 with and without an inhibitor

  Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)

• Area under the concentration time curve (AUC) of GSK2118436 with and without an inhibitor

  Up to12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)

• Cmax of GSK2118436 and metabolites after single and multiple 75mg HPMC dose

  Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18

• AUC of GSK2118436 and metabolites after single and multiple 75mg HPMC dose

  Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18

• Time to Cmax (Tmax) of GSK2118436 and metabolites after single and multiple 75mg HPMC dose

  Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18

• Half-life of GSK2118436 and metabolites after single 75mg HPMC dose

  Up to 24 hours after dosing on Day 1

• Cmax of GSK2118436 and metabolites after single and multiple 150mg HPMC dose

  Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18

• AUC of GSK2118436 and metabolites after single and multiple 150mg HPMC dose

  Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18

• Tmax of GSK2118436 and metabolites after single and multiple 150mg HPMC dose

  Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18

• Half-life of GSK2118436 and metabolites after single 150mg HPMC dose

  Up to 24 hours after dosing on Day 1

Secondary Outcomes (15)

• Cmax of R-warfarin with and without GSK2118436

  Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)

• Time to Cmax (Tmax) of R-warfarin

  Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)

• Trough concentration of GSK2118436

  Up to168 hours after dosing on Day 22

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

  From date of first dose to transition to Rollover protocol BRF114144 (22 - 29 days) or study follow up visit if subject does not transition to BRF114144 (approximately 29 - 39 days)

• Tmax for GSK2118436 with and without an inhibitor

  Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)

Study Arms (4)

Part A

EXPERIMENTAL

Warfarin dosed at 15mg

Drug: Warfarin; Drug: GSK2118436 150mg

Part B

EXPERIMENTAL

Ketoconazole dosed at 400mg

Drug: Ketoconazole; Drug: GSK2118436 75mg

Part C

EXPERIMENTAL

Gemfibrozil dosed at 600mg

Drug: Gemfibrozil; Drug: GSK2118436 75mg

Part D

EXPERIMENTAL

GSK2118436 dosed alone

Drug: GSK2118436 150mg

Interventions

Warfarin DRUG

Warfarin dosed at 15mg on Day 1 and Day 22

Part A

Ketoconazole DRUG

Ketoconazole dosed at 400mg daily on Days 19 through 22

Part B

Gemfibrozil DRUG

Gemfibrozil dosed at 600mg twice daily on Days 19 through 22

Part C

GSK2118436 150mg DRUG

GSK2118436 dosed at 150mg twice daily

Part A; Part D

GSK2118436 75mg DRUG

GSK2118436 dosed at 75mg twice daily

Part B; Part C

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 V600 mutation-positive tumor as determined in a CLIA-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing);
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; NOTE: Subjects with a performance status of 2 can be enrolled if the patient's confinement to bed and inability to carry out work activities is due solely to cancer-related pain, as assessed by the Investigator;
• 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 medication;
• Must have adequate organ function as defined by the following values:
• Absolute neutrophil count (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) AST and 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 PT/INR and partial thromboplastin time (PTT) \>/= 1.3 x ULN Left ventricular ejection fraction \>/= institutional lower limit of normal by ECHO
• CYP2C9 genotype of \*1/\*1 (wildtype), \*1/\*2 or \*1/\*3 (Part A only)

You may not qualify if:

• 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 2 weeks;
• 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: 28 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is warranted by the data);
• Current use of a prohibited medication or herbal preparation 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;
• 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 GI 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;
• 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);
• Presence of invasive malignancy, other than the primary diagnosis;
• Parts B and C: Subjects with brain metastases are excluded if their brain metastases are either:
• Corrected QT (QTcB) 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;
• 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 FDA);

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (11)

GSK Investigational Site

Scottsdale, Arizona, 85259, United States

Location

GSK Investigational Site

Sarasota, Florida, 34232, United States

Location

GSK Investigational Site

Detroit, Michigan, 48201, United States

Location

GSK Investigational Site

Columbus, Ohio, 43210, United States

Location

GSK Investigational Site

Oklahoma City, Oklahoma, 73104, United States

Location

GSK Investigational Site

Greenville, South Carolina, 29605, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37203, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84112, United States

Location

GSK Investigational Site

Nedlands, Western Australia, 6009, Australia

Location

GSK Investigational Site

Headington, OX3 7LJ, United Kingdom

Location

GSK Investigational Site

London, W1G 6AD, United Kingdom

Location

Related Links

• Results for study 113771 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms

Interventions

Warfarin; Ketoconazole; Gemfibrozil; dabrafenib

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Piperazines; Fibric Acids; Isobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Pentanoic Acids; Valerates; Phenyl Ethers; Ethers; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2011
• First Posted: April 25, 2011
• Study Start: September 3, 2012
• Primary Completion: November 14, 2012
• Study Completion: November 14, 2012
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

US (8); AU (1); GB (2)