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

Phase 1

Completed

• Conditions: Neoplasms
• Interventions: Drug: Vemurafenib

• Registration Number: NCT01767623
• Lead Sponsor: Hoffmann-La Roche

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 available

Study Timeline

• Study First Submitted: 2013-01-11
• Study First Submitted QC: 2013-01-11
• Study First Posted: 2013-01-14
• Study Start: 2013-08-20
• Primary Completion: 2017-04-20
• Study Completion: 2017-04-20
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-12
• Last Update Posted: 2018-02-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 8

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2: Participants with Severe Liver Dysfunction	Vemurafenib	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.
Cohort 1: Participants with Normal Liver Function	Vemurafenib	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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
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
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
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
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
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
Percentage of Participants with Adverse Events (AEs)	Baseline up to approximately 3 years

Trial Locations

Locations (8)

California Cancer Associates for Research & Excellence, Inc.; 🇺🇸 Encinitas, California, United States

Velindre Cancer Centre; 🇬🇧 Cardiff, United Kingdom

Peninsula and South Eastern Haematology and Oncology Grou; 🇦🇺 Frankston, Victoria, Australia

District General Hospital of Athens Laiko; 1st Internal Medicine Clinic; 🇬🇷 Athens, Greece

Rambam Health Care Campus; 🇮🇱 Haifa, Israel

Tel Aviv Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

SBIH " Clinical Oncological Dispensary # 1"; Chemotherapy department #1 and #2; 🇷🇺 Krasnodar, Russian Federation

Ege University Medicine Develoment and Pharmacokinetics Research Center; Pulmonary Diseases; 🇹🇷 Izmir, Turkey