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

NCT01231568 | Completed Phase 1

• 1 other identifier: 113468
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 4

Brief 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.

Conditions

Cancer

Keywords

food effect; high fat meal; GSK2118436; pharmacokinetic; particle size; BRAF inhibitor; BRAF positive tumor

Outcome Measures

Primary Outcomes (3)

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

  0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose

• Maximum plasma concentration (Cmax) of GSK2118436

  0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose

• Time to Cmax (Tmax) of GSK2118436

  0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose

Secondary Outcomes (3)

• Terminal half-life (t1/2) of GSK2118436

  0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose

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

  0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose

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

  From date of first dose until transition to rollover protocol BRF114144 (approximately 12 days) or study follow up visit if subject does not transition to BRF114144 (approx 22 days)

Study Arms (4)

Cohort 1 Treatment Sequence 1

EXPERIMENTAL

Subjects will receive two 75 mg micronized gelatin capsules, dosed fasted (Regimen A) in Period 1 and two 75 mg non-micronized gelatin capsules, dosed fasted (Regimen B) in Period 2. Dosing will occur in the morning of Day 1 in each period, and dosing between periods will be separated by at least one week.

Drug: Regimen A; Drug: Regimen B

Cohort 1 Treatment Sequence 2

EXPERIMENTAL

Subjects will receive two 75 mg non-micronized gelatin capsules, dosed fasted (Regimen B) in Period 1 and two 75 mg micronized gelatin capsules, dosed fasted (Regimen A) in Period 2. Dosing will occur in the morning of Day 1 in each period, and dosing between periods will be separated by at least one week.

Drug: Regimen A; Drug: Regimen B

Cohort 2 Treatment Sequence 1

EXPERIMENTAL

Subjects will receive two 75 mg micronized HPMC capsules, dosed fasted (Regimen C) in Period 1 and two 75 mg micronized HPMC capsules, dosed with a high-fat meal (Regimen D) in Period 2. Dosing will occur in the morning of Day 1 in each period, and dosing between periods will be separated by at least one week.

Drug: Regimen C; Drug: Regimen D

Cohort 2 Treatment Sequence 2

EXPERIMENTAL

Subjects will receive two 75 mg micronized HPMC capsules, dosed with a high-fat meal (Regimen D) in Period 1 and two 75 mg micronized HPMC capsules, dosed fasted (Regimen C) in Period 2. Dosing will occur in the morning of Day 1 in each period, and dosing between periods will be separated by at least one week.

Drug: Regimen C; Drug: Regimen D

Interventions

Regimen A DRUG

Two gelatin capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, micronized particles, equivalent to 150 mg free base), dosed fasted

Cohort 1 Treatment Sequence 1; Cohort 1 Treatment Sequence 2

Regimen B DRUG

Two gelatin capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, larger, non-micronized particles, equivalent to 150 mg free base), dosed fasted

Cohort 1 Treatment Sequence 1; Cohort 1 Treatment Sequence 2

Regimen C DRUG

Two Hydroxy Propyl Methyl Cellulose (HPMC) capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, micronized particles, equivalent to 150 mg free base), dosed fasted

Cohort 2 Treatment Sequence 1; Cohort 2 Treatment Sequence 2

Regimen D DRUG

Two HPMC capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, micronized particles, equivalent to 150 mg free base), dosed with a high-fat meal

Cohort 2 Treatment Sequence 1; Cohort 2 Treatment Sequence 2

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 \>/= 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 \</= to 2 may be eligible with the approval of the GlaxoSmithKline (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 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 \</= to 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \</= to 2.5 x ULN; \<5 x ULN if liver metastases are present (with approval of GSK medical monitor)
• Serum creatinine \</= to ULN or calculated creatinine clearance \>/= 60 mL/min
• Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) \< /= to 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) 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);
• 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;

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (4)

GSK Investigational Site

Scottsdale, Arizona, 85259, United States

Location

GSK Investigational Site

Detroit, Michigan, 48201, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37203, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Ouellet D, Grossmann KF, Limentani G, Nebot N, Lan K, Knowles L, Gordon MS, Sharma S, Infante JR, Lorusso PM, Pande G, Krachey EC, Blackman SC, Carson SW. Effects of particle size, food, and capsule shell composition on the oral bioavailability of dabrafenib, a BRAF inhibitor, in patients with BRAF mutation-positive tumors. J Pharm Sci. 2013 Sep;102(9):3100-9. doi: 10.1002/jps.23519. Epub 2013 Apr 22.

  PMID: 23608920 DERIVED

Related Links

• Results for study 113468 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms

Interventions

OOS-A regimen; Regimen B

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: October 21, 2010
• First Posted: November 1, 2010
• Study Start: October 21, 2010
• Primary Completion: May 13, 2011
• Study Completion: May 13, 2011
• Last Updated: November 14, 2017

Record last verified: 2017-11

Locations

US (4)