Clinical trial NCT02441465: Bioavailability Study of Vemurafenib in Participants With BRAF^V600 Mutation-Positive Malignancies
Official title: A Phase 1, Open-Label, Absolute Bioavailability Study of Vemurafenib in Patients With BRAF^V600 Mutation-Positive Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma, Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-05-12
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to characterize the pharmacokinetics (PK) of a single intravenous (IV) infusion of 14C-labeled vemurafenib administered shortly after an oral dose of vemurafenib and following multiple oral doses of vemurafenib twice daily (BID) at steady state as well as to estimate the absolute bioavailability of multiple oral doses of vemurafenib BID at steady state in participants with BRAF\^V600 mutation-positive malignancies. The study has two periods: Period A and Period B. During Period A, participants will receive vemurafenib BID orally from Day 1 to Day 20 and during Period B, participants will receive single IV infusion of 14C-labeled vemurafenib along with vemurafenib BID oral dose.


Eligibility criteria: Inclusion Criteria:

* Participants with either unresectable or metastatic melanoma positive for the BRAF\^V600 mutation or other malignant tumor type that harbors a V600-activating mutation of BRAF, and for whom vemurafenib is an accepted standard of care or where there is no other generally accepted standard of care
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
* Life expectancy greater than or equal to (\>/=) 12 weeks
* Full recovery from the effects of any major surgery or significant traumatic injury within 14 days from the first dose of study drug
* Adequate hematologic and end organ function as defined by laboratory results obtained within 2 weeks prior to administration of study drug on Day 1
* Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use two effective methods of contraception during the study and at least 6 months after completion of the study drug
* Negative serum pregnancy test results within 7 days prior to Day 1 in women of childbearing potential
* Absence of any psychological, familial, or sociological condition, or geographical constraints that could potentially hamper compliance with the study protocol and follow-up schedule

Exclusion Criteria:

* Prior anti-cancer therapy before the administration of study drug on Day 1
* Invasive malignancy other than BRAF mutant melanoma or other qualifying malignant tumor with BRAF\^V600 mutation within the past 5 years
* History of clinically significant cardiac or pulmonary dysfunction
* Active central nervous system lesions
* Current, severe, uncontrolled systemic disease
* Inability or unwillingness to swallow tablets
* History of malabsorption, stomach or intestinal surgery/resection, or other condition that would potentially alter absorption and/or excretion of orally administered drugs
* History of clinically significant liver disease
* Active autoimmune disease
* Uncontrolled ascites requiring weekly large-volume paracentesis for 3 consecutive weeks prior to enrollment
* Pregnancy, lactation, or breastfeeding
* Need to take a concomitant medication, dietary supplement, or food that is prohibited during the study
* Known allergy or sensitivity to components of the vemurafenib formulation
* Active, uncontrolled or chronic infection requiring chronic suppressive antibiotics
* Use of any prescription medications/products, that are known to be strong cytochrome P450 (CYP)3A4 inhibitors or inducers within 2 weeks prior to Day 1
* Participation in any other investigational drug study in which receipt of an investigational study drug occurred within 30 days prior to Day 1 or within 5 times the elimination half-life of the respective drug (whichever is shorter)
* Participation in a trial involving administration of 14 C-radiolabeled compound(s) within 6 months prior to Day 1
* Poor peripheral venous access
* Any other acute or chronic condition that, in the opinion of the investigator, could limit the participant's ability to complete and/or participate in this clinical study

Primary outcomes:
measure: Area Under the Concentration-Time Curve (AUC) of 14C-Labeled Vemurafenib From Time 0 to Last Measurable Concentration Timepoint (AUC0-last)
timeFrame: Day 21: Predose (Hour 0); end of infusion (infusion duration: 15 minutes); 5, 15 and 30 minutes post-infusion; 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168 hours post-infusion of 14C-labeled vemurafenib
measure: AUC of 14C-Labeled Vemurafenib From Time 0 to Infinity (AUC0-inf)
timeFrame: Day 21: Predose (Hour 0); end of infusion (infusion duration: 15 minutes); 5, 15 and 30 minutes post-infusion; 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168 hours post-infusion of 14C-labeled vemurafenib
measure: AUC of Unlabeled Vemurafenib During the Dosing Interval (AUCtau)
timeFrame: Predose (0 hour) on Days 18, 19, 20; Day 21: pre-dose (0 hour), 15 minutes after oral dose (at the end of IV infusion), at 30 and 45 minutes, and 1.15, 2.25, 3.25, 4.25, 6.25, 8.25, and 12 hours following oral administration of unlabeled vemurafenib
measure: Maximum Observed Plasma Concentration (Cmax) of 14C-Labeled Vemurafenib
timeFrame: Day 21: Predose (Hour 0); end of infusion (infusion duration: 15 minutes); 5, 15 and 30 minutes post-infusion; 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168 hours post-infusion of 14C-labeled vemurafenib
measure: Terminal Half-Life (t1/2) of 14C-Labeled Vemurafenib
timeFrame: Day 21: Predose (Hour 0); end of infusion (infusion duration: 15 minutes); 5, 15 and 30 minutes post-infusion; 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168 hours post-infusion of 14C-labeled vemurafenib
measure: Clearance (CL) of 14C-Labeled Vemurafenib
timeFrame: Day 21: Predose (Hour 0); end of infusion (infusion duration: 15 minutes); 5, 15 and 30 minutes post-infusion; 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168 hours post-infusion of 14C-labeled vemurafenib
measure: Volume of Distribution (V) of 14C-Labeled Vemurafenib
timeFrame: Day 21: Predose (Hour 0); end of infusion (infusion duration: 15 minutes); 5, 15 and 30 minutes post-infusion; 1, 2, 3, 4, 6, 8, 12 hours post-infusion of 14C-labeled vemurafenib
measure: Absolute Bioavailability (%F) of Vemurafenib
timeFrame: Day 21 (detailed timeframe is provided in description field)
measure: Renal Clearance (CLr) of 14C-Labeled Vemurafenib
timeFrame: Day 21 (urine samples): Predose (-8 to 0 hour), 0-4, 4-12, 12-24, 24-48, 48-72, 72-96 hours post-infusion (infusion duration: 15 minutes) of 14C-labeled vemurafenib
measure: Total Amount of 14C-Labeled Vemurafenib (Parent Drug) Excreted Into Urine
timeFrame: Day 21 (urine samples): Predose (-8 to 0 hour), 0-4, 4-12, 12-24, 24-48, 48-72, 72-96 hours post-infusion (infusion duration: 15 minutes) of 14C-labeled vemurafenib
Secondary outcomes:
measure: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From Day 1 up to 6 months after last dose (up to approximately 7 months)
measure: Cmax of Unlabeled Vemurafenib
timeFrame: Predose (0 hour) on Days 18, 19, 20; Day 21: pre-dose (0 hour), 15 minutes after oral dose (at the end of IV infusion), at 30 and 45 minutes, and 1.15, 2.25, 3.25, 4.25, 6.25, 8.25, and 12 hours following oral administration of unlabeled vemurafenib
measure: Time to Maximum Concentration (Tmax) of Unlabeled Vemurafenib
timeFrame: Predose (0 hour) on Days 18, 19, 20; Day 21: pre-dose (0 hour), 15 minutes after oral dose (at the end of IV infusion), at 30 and 45 minutes, and 1.15, 2.25, 3.25, 4.25, 6.25, 8.25, and 12 hours following oral administration of unlabeled vemurafenib
measure: Percentage of 14C-Labeled Vemurafenib Dose Recovered as Total Radioactivity in Urine
timeFrame: Day 21 (urine samples): Predose (-8 to 0 hour), 0-4, 4-12, 12-24, 24-48, 48-72, 72-96 hours post-infusion (infusion duration: 15 minutes) of 14C-labeled vemurafenib
measure: Percentage of 14C-Labeled Vemurafenib Dose Recovered as Total Radioactivity in Feces
timeFrame: Day 21 (feces samples): Predose (-48 to 0 hour), 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-196 hours post-infusion (infusion duration: 15 minutes) of 14C-labeled vemurafenib
measure: 14C-Labeled Vemurafenib Concentration Over Time Intervals in Urine
timeFrame: Day 21 (urine samples): Predose (-8 to 0 hour), 0-4, 4-12, 12-24, 24-48, 48-72, 72-96 hours post-infusion (infusion duration: 15 minutes) of 14C-labeled vemurafenib
measure: 14C-Labeled Vemurafenib Concentration Over Time Intervals in Feces
timeFrame: Day 21 (feces samples): Predose (-48 to 0 hour), 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-196 hours post-infusion (infusion duration: 15 minutes) of 14C-labeled vemurafenib
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: