Clinical Trials /

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

NCT01954043

Description:

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.

Related Conditions:
  • Cancer
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

A Pharmacokinetics (PK) Study of the Effects Rabeprazole and Rifampin on <span class="go-doc-concept go-doc-intervention">Dabrafenib</span> in Subjects With <span class="go-doc-concept go-doc-biomarker">BRAF</span> V600 <span class="go-doc-concept go-doc-keyword">Mutation</span> Positive Tumors

Title

  • Brief Title: A Pharmacokinetics (PK) Study of the Effects Rabeprazole and Rifampin on Dabrafenib in Subjects With BRAF V600 Mutation Positive Tumors
  • Official Title: An Open-label Study to Evaluate the Effects of a Potent CYP3A4 Inducer and the Effects of a pH Elevating Agent on the Repeat Dose Pharmacokinetics of Dabrafenib (GSK2118436) in Subjects With BRAF V600 Mutation Positive Tumors
  • Clinical Trial IDs

    NCT ID: NCT01954043

    ORG ID: 200072

    Trial Conditions

    Cancer

    Trial Interventions

    Drug Synonyms Arms
    Dabrafenib 150 mg twice a day (BID) Arm A
    Rabeprazole 40 mg once daily (OD) Arm A
    Rifampin 600 mg OD Arm A

    Trial Purpose

    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.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    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). Dabrafenib 150 mg twice a day (BID), Rabeprazole 40 mg once daily (OD), Rifampin 600 mg OD

    Eligibility Criteria

    Inclusion Criteria:

    - 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.

    Exclusion Criteria:

    - 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

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

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

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

    Secondary Outcome Measures

    PK assessment of Dabrafenib co administered with rabeprazole or rifampin

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

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

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

    Ratio of metabolite to Dabrafenib

    Safety and tolerability assessment to measure vital signs

    Safety and tolerability assessment for 12-lead ECG

    Safety and tolerability assessment for laboratory tests

    Safety and tolerability assessment of dabrafenib in combination with rabeprazole or rifampin

    Concentrations of Rabeprazole in the presence of Dabrafenib

    Concentrations of Rifampin in the presence of Dabrafenib

    Trial Keywords

    rifampin

    melanoma

    BRAF V600

    rabeprazole

    dabrafenib