Clinical Trials /

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

NCT01767623

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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: 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

Clinical Trial IDs

  • ORG STUDY ID: GO28053
  • SECONDARY ID: 2012-003820-18
  • NCT ID: NCT01767623

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
VemurafenibRO5185426, Zelboraf®Cohort 1: Participants with Normal Liver Function

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: Participants with Normal Liver FunctionActive ComparatorParticipants 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.
  • Vemurafenib
Cohort 2: Participants with Severe Liver DysfunctionExperimentalParticipants 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.
  • Vemurafenib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of Participants with Adverse Events (AEs)
Time Frame:Baseline up to approximately 3 years
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Hoffmann-La Roche

Last Updated

February 13, 2018