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

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

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.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Vemurafenib

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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
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

Outcome Measure	Time Frame
Percentage of Participants with Adverse Events (AEs)	Baseline up to approximately 3 years
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 20, 2013
• Primary Completion (ACTUAL): April 20, 2017
• Study Completion (ACTUAL): April 20, 2017

Study Registration Dates

• First Submitted: January 11, 2013
• First Submitted That Met QC Criteria: January 11, 2013
• First Posted (ESTIMATE): January 14, 2013

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2018
• Last Update Submitted That Met QC Criteria: February 12, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Vemurafenib
• Other Study ID Numbers: GO28053; 2012-003820-18 (EUDRACT_NUMBER)