Clinical trial NCT01767623: A Study of The Impact of Severe Hepatic Impairment on the Pharmacokinetics and Safety of Vemurafenib in BRAF V600 Mutation-Positive Cancer Participants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-01-14
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Dose-Normalized Area Under the Concentration-Time Curve (AUC) of Vemurafenib During the Dose Interval (12 hours) (AUCtau) on Day 20
timeFrame: 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
measure: Dose-Normalized Maximum Observed Concentration (Cmax) of Vemurafenib on Day 20
timeFrame: 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:
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Baseline up to approximately 3 years
measure: Dose-Normalized AUCtau of of Vemurafenib on Day 1
timeFrame: Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on Day 1
measure: Dose-Normalized AUC from Time 0 to Last Measurable Concentration Time Point (AUC0-last) of Vemurafenib on Day 20
timeFrame: 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
measure: Dose-Normalized AUC from Time 0 to Infinity (AUC0-∞) of Vemurafenib on Day 20
timeFrame: 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
measure: Dose-Normalized Cmax of Vemurafenib on Day 1
timeFrame: Pre-dose (0 hour); 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose on Day 1
measure: Time to Maximum Concentration (tmax) of Vemurafenib on Day 1 and Day 20
timeFrame: 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
measure: Half-life (t1/2) of Vemurafenib in Plasma on Day 20
timeFrame: 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
measure: Dose Normalized Apparent Clearance (CL/F) of Vemurafenib on Day 20
timeFrame: 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
measure: Trough Plasma Concentration (Cmin or Ctrough) of Vemurafenib
timeFrame: 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
Other outcomes:
Locations:
city: Encinitas
country: United States
facility: California Cancer Associates for Research & Excellence, Inc.
state: California
city: Frankston
country: Australia
facility: Peninsula and South Eastern Haematology and Oncology Grou
state: Victoria
city: Athens
country: Greece
facility: District General Hospital of Athens Laiko; 1st Internal Medicine Clinic
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Krasnodar
country: Russian Federation
facility: SBIH " Clinical Oncological Dispensary # 1"; Chemotherapy department #1 and #2
city: Izmir
country: Turkey
facility: Ege University Medicine Develoment and Pharmacokinetics Research Center; Pulmonary Diseases
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: