A Pharmacokinetics (PK) Study of the Effects Rabeprazole and Rifampin on Dabrafenib in Subjects With BRAF V600 Mutation Positive Tumors

NCT01954043 | Completed Phase 1 FDA Drug

• 1 other identifier: 200072
• Study Type: interventional
• Target: 23
• Locations: 3 countries
• Sites: 6

Brief Summary

The study is being conducted to evaluate the effect of rifampin (a strong CYP3A4 inducer) and rabeprazole (a pH elevating agent) on the PK of dabrafenib (a CYP3A4/CYP2C8 substrate). The study will be conducted in subjects with BRAF V600 mutation-positive tumors. Data collected from this study will be used to inform recommendations regarding use of concomitant medications with dabrafenib and future clinical pharmacologic evaluation of dabrafenib.

Conditions

Cancer

Keywords

melanoma; dabrafenib; BRAF V600; rabeprazole; rifampin

Outcome Measures

Primary Outcomes (3)

• PK assessment (Cmax) of Dabrafenib with and without Rabeprazole or Rifampin

  Blood samples will be collected to assess PK parameters including: maximum observed concentration (Cmax)

  Day 15, 19 and Day 29

• PK assessment (tmax) of Dabrafenib with and without Rabeprazole or Rifampin

  Blood samples will be collected to assess PK parameters including: time to Cmax (tmax)

  Day 15, 19 and Day 29

• PK assessment (AUC[0-tau]) of Dabrafenib with and without Rabeprazole or Rifampin

  Blood samples will be collected to assess PK parameters including: area under the concentration-time curve over the dosing interval (AUC\[0-tau\])

  Day 15, 19 and Day 29

Secondary Outcomes (11)

• PK assessment of Dabrafenib co administered with rabeprazole or rifampin

  Day 15, 19 and Day 29

• PK assessment (AUC[0-tau]) of hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib

  Day 15, 19 and Day 29

• PK assessment (Cmax and Ctau,) of hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib

  Day 15, 19 and Day 29

• PK assessment (tmax) of hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib

  Day 15, 19 and Day 29

• Ratio of metabolite to Dabrafenib

  Day 15, 19 and Day 29

Study Arms (1)

Arm A

EXPERIMENTAL

Subjects will administer Dabrafenib from Day 1 to Day 15, Dabrafenib and Rabeprazole from Day 16 to Day 19, Dabrafenib and Rifampin from Day 20 to Day 29. The serial PK samples will be collected for 12 hours following dosing on Day 15 (Dabrafenib alone), Day 19 (Dabrafenib and Rabeprazole), and Day 29 (Dabrafenib and Rifampin).

Drug: Dabrafenib 150 mg twice a day (BID); Drug: Rabeprazole 40 mg once daily (OD); Drug: Rifampin 600 mg OD

Interventions

Dabrafenib 150 mg twice a day (BID) DRUG

Dabrafenib dosed at 150mg twice a day from Day 1 to the morning of Day 29

Arm A

Rabeprazole 40 mg once daily (OD) DRUG

Rabeprazole dosed at 40mg each morning on Days 16 to 19

Arm A

Rifampin 600 mg OD DRUG

Rifampin dosed at 600mg each morning on Days 20 to 29

Arm A

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.
• Provided signed written informed consent.
• Capable of compliance with the requirements and restrictions listed in the consent form.
• Body weight \>=45 kilogram (kg) and a body mass index (BMI) \>=19 Kilogram per meter squared (kg/m\^2) and \<40 kg/m\^2 (inclusive).
• Able to swallow and retain oral medication.
• BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory or equivalent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate baseline organ function defined in study protocol.
• Women of child-bearing 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.

You may not qualify if:

• History of another malignancy with exceptions below, or any malignancy with confirmed activating RAS mutation. Exception: (a) Subjects who have been successfully treated and are disease-free for 5 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score \<=6, and PSA \<10 nanogram per milliliter \[ng/mL\]) requiring no or only anti-hormonal therapy, are eligible.
• Cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) or investigational anti-cancer drugs within the last 3 weeks, or chemotherapy without delayed toxicity within the last 2 weeks, preceding the first dose of dabrafenib.
• Unresolved toxicity greater than Grade 2 from previous anti-cancer therapy except alopecia.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
• Current use of therapeutic warfarin.
• Any prohibited medication(s) or herbal preparation as described in study protocol or requires any of these medications during the study.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to dabrafenib, rabeprazole and rifampin, or excipients that contraindicates their participation.
• Pregnant or nursing females.
• A history or evidence of cardiovascular risk including any of the following: a QT interval corrected for heart rate using the Bazett's formula (QTcB) \>=480 milliseconds (msec); a history or evidence of current clinically significant uncontrolled arrhythmias; a history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; a history or evidence of current \>=Class II congestive heart failure (CHF) as defined by the New York Heart Association (NYHA) guidelines; Abnormal cardiac valve morphology (\>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
• Presence of active gastrointestinal (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, or Hepatitis C Virus infection.
• Subjects with brain metastases are excluded if their brain metastases are: Symptomatic, Treated (surgery, radiation therapy) but not clinically and radiographically stable one month after local therapy, or asymptomatic and untreated but \>1 centimeter (cm) in the longest dimension. 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 \>1 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (6)

GSK Investigational Site

Goodyear, Arizona, 85338, United States

Location

GSK Investigational Site

Dallas, Texas, 75201, United States

Location

GSK Investigational Site

Tacoma, Washington, 98405, United States

Location

GSK Investigational Site

Heidelberg, Victoria, 3084, Australia

Location

GSK Investigational Site

Melbourne, Victoria, 3004, Australia

Location

GSK Investigational Site

London, W1G 6AD, United Kingdom

Location

Related Links

• Results for study 200072 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms; Melanoma

Interventions

dabrafenib; Rabeprazole; Rifampin

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

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: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2013
• First Posted: October 1, 2013
• Study Start: December 20, 2013
• Primary Completion: February 29, 2016
• Study Completion: February 29, 2016
• Last Updated: November 14, 2017

Record last verified: 2017-11

Locations

US (3); AU (2); GB (1)