Bioavailability Study of Vemurafenib in Participants With BRAF^V600 Mutation-Positive Malignancies

• ClinicalTrials.gov Identifier: NCT02441465
• Recruitment Status: Completed
• First Posted: May 12, 2015
• Last Update Posted: November 14, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Malignant Melanoma, Cancer	Drug: Vemurafenib; Drug: 14C-Labeled Vemurafenib	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Phase 1, Open-Label, Absolute Bioavailability Study of Vemurafenib in Patients With BRAF^V600 Mutation-Positive Malignancies
• Actual Study Start Date: August 13, 2015
• Actual Primary Completion Date: August 18, 2016
• Actual Study Completion Date: January 9, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Vemurafenib; Participants will receive oral vemurafenib BID from Day 1 to Day 28 and a single IV infusion of 14C-labeled vemurafenib on Day 21.	Drug: Vemurafenib; Oral vemurafenib will be administered at a dose of 960 milligrams BID from Day 1 to Day 28.; Other Name: Zelboraf®, RO5185426; Drug: 14C-Labeled Vemurafenib; IV infusion of 18.5 kilobecquerel (kBq) of 14C-labeled vemurafenib (3 milliliters [mL], which corresponds to a dose of 20 micrograms [mcg] of vemurafenib) on Day 21 (immediately after the morning oral dose of vemurafenib).

Outcome Measures

Primary Outcome Measures :

1. Area Under the Concentration-Time Curve (AUC) of 14C-Labeled Vemurafenib From Time 0 to Last Measurable Concentration Timepoint (AUC0-last) [ Time Frame: 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 ]
2. AUC of 14C-Labeled Vemurafenib From Time 0 to Infinity (AUC0-inf) [ Time Frame: 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 ]
3. AUC of Unlabeled Vemurafenib During the Dosing Interval (AUCtau) [ Time Frame: 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 ]
4. Maximum Observed Plasma Concentration (Cmax) of 14C-Labeled Vemurafenib [ Time Frame: 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 ]
5. Terminal Half-Life (t1/2) of 14C-Labeled Vemurafenib [ Time Frame: 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 ]
6. Clearance (CL) of 14C-Labeled Vemurafenib [ Time Frame: 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 ]
7. Volume of Distribution (V) of 14C-Labeled Vemurafenib [ Time Frame: 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 ]
8. Absolute Bioavailability (%F) of Vemurafenib [ Time Frame: Day 21 (detailed timeframe is provided in description field) ]

   %F is the ratio of dose normalized AUCtau following vemurafenib oral dose to dose normalized AUC0-inf following IV dose.

   Time Frame: Vemurafenib oral dose (Day 21: Predose [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); Vemurafenib IV dose (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).

9. Renal Clearance (CLr) of 14C-Labeled Vemurafenib [ Time Frame: 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 ]
10. Total Amount of 14C-Labeled Vemurafenib (Parent Drug) Excreted Into Urine [ Time Frame: 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 Outcome Measures :

1. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From Day 1 up to 6 months after last dose (up to approximately 7 months) ]
2. Cmax of Unlabeled Vemurafenib [ Time Frame: 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 ]
3. Time to Maximum Concentration (Tmax) of Unlabeled Vemurafenib [ Time Frame: 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 ]
4. Percentage of 14C-Labeled Vemurafenib Dose Recovered as Total Radioactivity in Urine [ Time Frame: 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 ]
5. Percentage of 14C-Labeled Vemurafenib Dose Recovered as Total Radioactivity in Feces [ Time Frame: 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 ]
6. 14C-Labeled Vemurafenib Concentration Over Time Intervals in Urine [ Time Frame: 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 ]
7. 14C-Labeled Vemurafenib Concentration Over Time Intervals in Feces [ Time Frame: 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Hungary

Magyar Honvedseg Egeszsegugyi Kozpont

Budapest, Hungary, H-1134

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02441465
• Other Study ID Numbers: GO28395; 2013-004144-34 ( EudraCT Number )
• First Posted: May 12, 2015
• Last Update Posted: November 14, 2017
• Last Verified: November 2017

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Vemurafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action