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

Neoplasms Clinical Trial

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 Details — Status: Completed

Administrative data

• NCT number: NCT01767623
• Other study ID #: GO28053
• Secondary ID: 2012-003820-18
• Status: Completed
• Phase: Phase 1
• First received: January 11, 2013
• Last updated: February 12, 2018
• Start date: August 20, 2013
• Est. completion date: April 20, 2017

Study information

• Verified date: February 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: April 20, 2017
• Est. primary completion date: April 20, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms

Intervention

Drug:
• Vemurafenib
Vemurafenib orally BID 960 or 720 mg.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Greece,  Israel,  Russian Federation,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Percentage of Participants with Adverse Events (AEs)		Baseline up to approximately 3 years
Secondary	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
Secondary	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
Secondary	Dose-Normalized AUC from Time 0 to Infinity (AUC0-8) 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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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