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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

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ClinicalTrials.gov Identifier: NCT01767623
Recruitment Status : Completed
First Posted : January 14, 2013
Last Update Posted : February 13, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE January 11, 2013
First Posted Date  ICMJE January 14, 2013
Last Update Posted Date February 13, 2018
Actual Study Start Date  ICMJE August 20, 2013
Actual Primary Completion Date April 20, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2017)
  • Dose-Normalized Area Under the Concentration-Time Curve (AUC) of Vemurafenib During the Dose Interval (12 hours) (AUCtau) on Day 20 [ Time Frame: 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 ]
  • Dose-Normalized Maximum Observed Concentration (Cmax) of Vemurafenib on Day 20 [ Time Frame: 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 11, 2013)
  • Dose-normalized area under the concentration-time curve (AUC) during the dose interval on Day 20 (steady state) [ Time Frame: Pre-dose and up to 168 hours after the morning dose Day 20 ]
  • Dose-normalized maximum concentration (Cmax) on Day 20 (steady state) [ Time Frame: Pre-dose and up to 168 hours after the morning dose on Day 20 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2017)
  • Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline up to approximately 3 years ]
  • Dose-Normalized AUCtau of of Vemurafenib on Day 1 [ Time Frame: Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on Day 1 ]
  • Dose-Normalized AUC from Time 0 to Last Measurable Concentration Time Point (AUC0-last) of Vemurafenib on Day 20 [ Time Frame: 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 ]
  • Dose-Normalized AUC from Time 0 to Infinity (AUC0-∞) of Vemurafenib on Day 20 [ Time Frame: 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 ]
  • Dose-Normalized Cmax of Vemurafenib on Day 1 [ Time Frame: Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on Day 1 ]
  • Time to Maximum Concentration (tmax) of Vemurafenib on Day 1 and Day 20 [ Time Frame: 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 ]
  • Half-life (t1/2) of Vemurafenib in Plasma on Day 20 [ Time Frame: 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 ]
  • Dose Normalized Apparent Clearance (CL/F) of Vemurafenib on Day 20 [ Time Frame: 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 ]
  • Trough Plasma Concentration (Cmin or Ctrough) of Vemurafenib [ Time Frame: 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2013)
  • Safety: Incidence of adverse events [ Time Frame: approximately 1.5 years ]
  • Dose-normalized AUC on Day 1 [ Time Frame: Day 1 ]
  • Dose-normalized AUC on Day 20 [ Time Frame: Day 20 ]
  • Dose-normalized Cmax on Day 1 [ Time Frame: Day 1 ]
  • Time to maximum concentration (tmax) on Day 1 and 20 [ Time Frame: Days 1 and 20 ]
  • Half-life (t1/2) in plasma on Day 20 [ Time Frame: Day 20 ]
  • Dose-normalized clearance (CL/F) on Day 20 [ Time Frame: Day 20 ]
  • Trough plasma concentration (Cmin or Ctrough) [ Time Frame: up to Day 20 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of The Impact of Severe Hepatic Impairment on the Pharmacokinetics and Safety of Vemurafenib in BRAF V600 Mutation-Positive Cancer Participants
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE Drug: Vemurafenib
Vemurafenib orally BID 960 or 720 mg.
Other Names:
  • RO5185426
  • Zelboraf®
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Vemurafenib
  • 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.
    Intervention: Drug: Vemurafenib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 5, 2017)
8
Original Estimated Enrollment  ICMJE
 (submitted: January 11, 2013)
16
Actual Study Completion Date  ICMJE April 20, 2017
Actual Primary Completion Date April 20, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Greece,   Israel,   Russian Federation,   Turkey,   United Kingdom,   United States
Removed Location Countries Argentina,   Peru
 
Administrative Information
NCT Number  ICMJE NCT01767623
Other Study ID Numbers  ICMJE GO28053
2012-003820-18 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP