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A Study of The Impact of Severe Hepatic Impairment on the Pharmacokinetics and Safety of Vemurafenib in BRAF V600 Mutation-Positive Cancer Participants

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01767623
Collaborator
(none)
8
Enrollment
8
Locations
2
Arms
44
Actual Duration (Months)
1
Patient Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This open-label, Phase I study will evaluate the impact of severe hepatic impairment on the pharmacokinetics and safety of vemurafenib in participants with BRAF V600 mutation positive cancer. Participants will receive vemurafenib 960 milligrams (mg) (normal hepatic function) or 720 mg (severe hepatic impairment) orally twice daily (BID) on Days 1 to 20 (morning dose) and from Day 27 onward until disease progression or unacceptable toxicity occurs.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
8 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open Label, Phase I Study to Evaluate the Impact of Severe Hepatic Impairment on the Pharmacokinetics and Safety of Vemurafenib in BRAF V600 Mutation Positive Cancer Patients
Actual Study Start Date :
Aug 20, 2013
Actual Primary Completion Date :
Apr 20, 2017
Actual Study Completion Date :
Apr 20, 2017

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Cohort 1: Participants with Normal Liver Function

Participants with normal liver function (according to National Cancer Institute [NCI] liver dysfunction criteria) will receive vemurafenib 960 mg BID from Day 1 until the morning dose on Day 20 and then from Day 27 onward until disease progression, safety-related treatment termination, withdrawal of consent, death, or a decision by the Sponsor to terminate the study, whichever occurs first.

Drug: Vemurafenib
Vemurafenib orally BID 960 or 720 mg.
Other Names:
  • RO5185426
  • Zelboraf®

    		•
    Experimental: Cohort 2: Participants with Severe Liver Dysfunction

    Participants with severe liver dysfunction (according to NCI liver dysfunction criteria) will receive vemurafenib 720 mg BID from Day 1 until the morning dose on Day 20 and then from Day 27 onward until disease progression, safety-related treatment termination, withdrawal of consent, death, or a decision by the Sponsor to terminate the study, whichever occurs first.

    Drug: Vemurafenib
    Vemurafenib orally BID 960 or 720 mg.
    Other Names:
  • RO5185426
  • Zelboraf®

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Dose-Normalized Area Under the Concentration-Time Curve (AUC) of Vemurafenib During the Dose Interval (12 hours) (AUCtau) on Day 20 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose on Day 20]

    2. Dose-Normalized Maximum Observed Concentration (Cmax) of Vemurafenib on Day 20 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose on Day 20]

    Secondary Outcome Measures

    1. Percentage of Participants with Adverse Events (AEs) [Baseline up to approximately 3 years]

    2. Dose-Normalized AUCtau of of Vemurafenib on Day 1 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on Day 1]

    3. Dose-Normalized AUC from Time 0 to Last Measurable Concentration Time Point (AUC0-last) of Vemurafenib on Day 20 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose on Day 20]

    4. Dose-Normalized AUC from Time 0 to Infinity (AUC0-∞) of Vemurafenib on Day 20 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose on Day 20]

    5. Dose-Normalized Cmax of Vemurafenib on Day 1 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on Day 1]

    6. Time to Maximum Concentration (tmax) of Vemurafenib on Day 1 and Day 20 [Day 1: Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose; Day 20: Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose]

    7. Half-life (t1/2) of Vemurafenib in Plasma on Day 20 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose on Day 20]

    8. Dose Normalized Apparent Clearance (CL/F) of Vemurafenib on Day 20 [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose on Day 20]

    9. Trough Plasma Concentration (Cmin or Ctrough) of Vemurafenib [Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on Day 1; Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after the morning dose on Day 20; Before the morning dose on Days 9 and 15]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Histologically confirmed BRAF V600 mutation-positive advanced solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective

    • Normal or impaired hepatic function (hepatic function will be classified according to the NCI Organ Dysfunction Working Group criteria)

    • For participants with hepatic impairment: Stable hepatic function for at least 2 weeks (greater than [>] 14 days) before Day 1

    • Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (</=) 2

    • Participants with a history of recent brain metastases must have completed any radiation therapy at least 4 weeks before Day 1, be without intervening signs of brain lesion progression and not require steroids before starting the protocol (Day 1). Participants with gliomas or known brain metastases who require anticonvulsants must be seizure free for 1 month prior to enrollment

    • Life expectancy greater than or eual to (>/=) 8 weeks

    • Adequate hematologic and renal function

    • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of less than (<) 1 percent per year during the treatment period and for at least 6 months after the last dose of study drug

    Exclusion Criteria:

    • Allergy or hypersensitivity to components of the vemurafenib formulation

    • Requirement for immediate or urgent treatment with twice a day vemurafenib and for whom the intermittent schedule of vemurafenib employed during Days 1-26 of this trial is not clinically acceptable

    • Chemotherapy, biologic therapy, immunotherapy, or radiotherapy within 4 weeks prior to entering the study, or those who have not recovered from AEs because of agents administered more than 4 weeks earlier

    • Gliomas or known brain metastases that require corticosteroids

    • History of clinically significant cardiac or pulmonary dysfunction

    • Human Immunodeficiency Virus (HIV)-positive participant requiring antiviral treatment including protease inhibitors

    • Active infection or chronic infection requiring chronic suppressive antibiotics

    • Pregnancy or breastfeeding at Day 1

    • History of malabsorption or other clinically significant metabolic dysfunction

    • Active autoimmune disease

    • Current, recent (within 28 days prior to Day 1), or planned use of any investigational product outside this study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 California Cancer Associates for Research & Excellence, Inc. Encinitas California United States 92008
    2 Peninsula and South Eastern Haematology and Oncology Grou Frankston Victoria Australia 3199
    3 District General Hospital of Athens Laiko; 1st Internal Medicine Clinic Athens Greece 11527
    4 Rambam Health Care Campus Haifa Israel 31096
    5 Tel Aviv Sourasky Medical Center Tel Aviv Israel 64239
    6 SBIH " Clinical Oncological Dispensary # 1"; Chemotherapy department #1 and #2 Krasnodar Russian Federation 350040
    7 Ege University Medicine Develoment and Pharmacokinetics Research Center; Pulmonary Diseases Izmir Turkey 35040
    8 Velindre Cancer Centre Cardiff United Kingdom CF14 2TL

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01767623
    Other Study ID Numbers:
    • GO28053
    • 2012-003820-18
    First Posted:
    Jan 14, 2013
    Last Update Posted:
    Feb 13, 2018
    Last Verified:
    Feb 1, 2018
    Additional relevant MeSH terms:
    Vemurafenib

    Study Results

    No Results Posted as of Feb 13, 2018