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

NCT01767623 | Completed Phase 1

• 2 other identifiers: GO280532012-003820-18
• Study Type: interventional
• Target: 8
• Locations: 7 countries
• Sites: 8

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.

Conditions

Neoplasms

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (9)

• 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

Study Arms (2)

Cohort 1: Participants with Normal Liver Function

ACTIVE COMPARATOR

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

Cohort 2: Participants with Severe Liver Dysfunction

EXPERIMENTAL

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

Interventions

Vemurafenib DRUG

Vemurafenib orally BID 960 or 720 mg.

Also known as: RO5185426, Zelboraf®

Cohort 1: Participants with Normal Liver Function; Cohort 2: Participants with Severe Liver Dysfunction

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (8)

California Cancer Associates for Research & Excellence, Inc.

Encinitas, California, 92008, United States

Location

Peninsula and South Eastern Haematology and Oncology Grou

Frankston, Victoria, 3199, Australia

Location

District General Hospital of Athens Laiko; 1st Internal Medicine Clinic

Athens, 11527, Greece

Location

Rambam Health Care Campus

Haifa, 31096, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 64239, Israel

Location

SBIH " Clinical Oncological Dispensary # 1"; Chemotherapy department #1 and #2

Krasnodar, 350040, Russia

Location

Ege University Medicine Develoment and Pharmacokinetics Research Center; Pulmonary Diseases

Izmir, 35040, Turkey (Türkiye)

Location

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

Location

MeSH Terms

Conditions

Neoplasms

Interventions

Vemurafenib

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 11, 2013
• First Posted: January 14, 2013
• Study Start: August 20, 2013
• Primary Completion: April 20, 2017
• Study Completion: April 20, 2017
• Last Updated: February 13, 2018

Record last verified: 2018-02

Locations

GB (1); AU (1); US (1); GR (1); IL (2); TU (1); RU (1)