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

Study Description

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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
Neoplasms	Drug: Vemurafenib	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
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 :	August 20, 2013
Actual Primary Completion Date :	April 20, 2017
Actual Study Completion Date :	April 20, 2017

Arms and Interventions

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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

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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 [ 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 ]
2. 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 ]

Secondary Outcome Measures :

1. Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline up to approximately 3 years ]
2. 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 ]
3. 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 ]
4. 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 ]
5. 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 ]
6. 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 ]
7. 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 ]
8. 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 ]
9. 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 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

Study Director:	Clinical Trials	Hoffmann-La Roche

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT01767623 History of Changes
Other Study ID Numbers:	GO28053; 2012-003820-18 ( EudraCT Number )
First Posted:	January 14, 2013
Last Update Posted:	February 13, 2018
Last Verified:	February 2018

Additional relevant MeSH terms:

Vemurafenib; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action