Trial Outcomes & Findings for A Study of the Effect of Food on the Pharmacokinetics of Single Dose RO5185426 And the Safety And Efficacy of Continuous Administration in Patients With BRAF V600E Mutation-Positive Metastatic Melanoma (NCT NCT01264380)

Last Updated: 2016-11-02

Results Overview

Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

16 participants

Primary outcome timeframe

Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 hours (h) post-dose (pd) on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Results posted on

2016-11-02

Participant Flow

Participant milestones

Participant milestones
Measure	Vemurafenib (RO5185426): Fasted Then Fed Single oral dose of vemurafenib tablet at 960 milligrams (mg) on Day 1 was administered to participants in fasted condition (Period A \[Day 1 to Day 10\]) followed by single oral dose of vemurafenib tablet at 960 mg on Day 1 in fed condition (Period B \[Day 11 to Day 20\]). A washout period of 10 days was maintained between Period A and B.	Vemurafenib (RO5185426): Fed Then Fasted Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition (Period A \[Day 1 to Day 10\]) followed by single oral dose of vemurafenib tablet at 960 mg on Day 1 in fasted condition Period B \[Day 11 to Day 20\]). A washout period of 10 days was maintained between Period A and B.	Vemurafenib (RO5185426) Participants received vemurafenib tablet at 960 mg orally twice daily in 21-day cycles starting from Day 21 until disease progression, unacceptable toxicity, or consent withdrawal (Period C).
Period A STARTED	8	8	0
Period A COMPLETED	8	8	0
Period A NOT COMPLETED	0	0	0
Period B STARTED	8	8	0
Period B COMPLETED	8	8	0
Period B NOT COMPLETED	0	0	0
Period C STARTED	0	0	16
Period C COMPLETED	0	0	2
Period C NOT COMPLETED	0	0	14

Reasons for withdrawal

Reasons for withdrawal
Measure	Vemurafenib (RO5185426): Fasted Then Fed Single oral dose of vemurafenib tablet at 960 milligrams (mg) on Day 1 was administered to participants in fasted condition (Period A \[Day 1 to Day 10\]) followed by single oral dose of vemurafenib tablet at 960 mg on Day 1 in fed condition (Period B \[Day 11 to Day 20\]). A washout period of 10 days was maintained between Period A and B.	Vemurafenib (RO5185426): Fed Then Fasted Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition (Period A \[Day 1 to Day 10\]) followed by single oral dose of vemurafenib tablet at 960 mg on Day 1 in fasted condition Period B \[Day 11 to Day 20\]). A washout period of 10 days was maintained between Period A and B.	Vemurafenib (RO5185426) Participants received vemurafenib tablet at 960 mg orally twice daily in 21-day cycles starting from Day 21 until disease progression, unacceptable toxicity, or consent withdrawal (Period C).
Period C Disease Progression	0	0	4
Period C Death	0	0	2
Period C Follow-up for survival status	0	0	6
Period C Withdrawal by Subject	0	0	1
Period C Adverse Event	0	0	1

Baseline Characteristics

A Study of the Effect of Food on the Pharmacokinetics of Single Dose RO5185426 And the Safety And Efficacy of Continuous Administration in Patients With BRAF V600E Mutation-Positive Metastatic Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=16 Participants Included all participants who received single oral dose of vemurafenib tablet at 960 mg in fasted condition first and fed condition first in Period A and Period B and twice daily dose of vemurafenib tablet at 960 mg in Period C.
Age, Continuous	60.6 years STANDARD_DEVIATION 10.31 • n=5 Participants
Gender Female	6 Participants n=5 Participants
Gender Male	10 Participants n=5 Participants

PRIMARY outcome

Timeframe: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 hours (h) post-dose (pd) on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Population: PK analysis population included participants who received both single doses of vemurafenib in Periods A and B without protocol violation and provided adequate PK assessments to calculate important PK parameters. Here "number of participants analyzed"=participants who were evaluable for this outcome measure.

Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=15 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States	115 microgramshour per milliliter (µgh/mL) Standard Deviation 110	351 microgramshour per milliliter (µgh/mL) Standard Deviation 189

PRIMARY outcome

Timeframe: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Population: PK analysis population. Here "number of participants analyzed"=participants who were evaluable for this outcome measure.

PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=15 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=14 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Sample With Last Measurable Concentration (AUC[0-last]) in the Fasted and Fed States	94.3 µg*h/mL Standard Deviation 81.8	320 µg*h/mL Standard Deviation 158

PRIMARY outcome

Population: PK analysis population.

PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States	3.48 µg/mL Standard Deviation 2.02	7.38 µg/mL Standard Deviation 1.98

PRIMARY outcome

Timeframe: Pre-dose on Periods A and B

Population: PK analysis population.

Single dose Pre-dose concentration is referred as Cmin here. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States	NA µg/mL Standard Deviation NA Since the study was a single-dose study, Cmin was not reached.	NA µg/mL Standard Deviation NA Since the study was a single-dose study, Cmin was not reached.

PRIMARY outcome

Population: PK analysis population.

PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States	4 hour Interval 2.0 to 12.58	7.51 hour Interval 5.0 to 16.0

PRIMARY outcome

Population: PK analysis population. Here "number of participants analyzed"=participants who were evaluable for this outcome measure.

T1/2 is the time required for the concentration of the drug to reach half of its original value. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=16 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=15 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States	24.6 hour Standard Deviation 17.2	26.0 hour Standard Deviation 17.1

PRIMARY outcome

Population: PK analysis population. Here "number of participants analyzed"=participants who were evaluable for this outcome measure.

Apparent first-order terminal elimination rate constant (kel), was calculated as the negative slope of the linear regression of the terminal phase in plasma vemurafenib concentration-time profile using specific appropriate time points. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=15 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=14 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States	0.04 1/h Standard Deviation 0.03	0.04 1/h Standard Deviation 0.02

SECONDARY outcome

Timeframe: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until disease progression or death (Up to Week 124)

Population: Intent-to-treat (ITT) population included participants with measurable disease who received at least 1 dose of vemurafenib. Here "number of participants analyzed"=participants who were evaluable for this outcome measure.

BOR was defined as the best objective response assessed by investigator during the treatment period according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. BOR was the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. It is defined as the number of participants whose best objective response was complete response (CR) or partial response (PR) divided by the total number of efficacy evaluable participants. CR: disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) were non-pathological in size (less than \[\<\] 10 millimeter \[mm\] short axis). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Outcome measures
Measure	Vemurafenib (RO5185426): Fasted n=14 Participants Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed Single oral dose of vemurafenib tablet at 960 mg on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).
Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR)	64.3 percentage of participants Interval 35.1 to 87.2	—

SECONDARY outcome

Timeframe: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until death (Up to Week 124)

Population: Data for OS was not collected as there was a change in planned analysis, not to collect the data.

OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.

Outcome measures

Outcome data not reported

Adverse Events

Vemurafenib (RO5185426): Fasted

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Vemurafenib (RO5185426): Fed

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Vemurafenib (RO5185426)

Serious events: 9 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Vemurafenib (RO5185426): Fasted n=16 participants at risk Single oral dose of vemurafenib tablet at 960 milligram (mg) on Day 1 was administered to participants in fasted condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426): Fed n=16 participants at risk Single oral dose of vemurafenib tablet at 960 milligram (mg) on Day 1 was administered to participants in fed condition, in any intervention periods (Period A or B).	Vemurafenib (RO5185426) n=16 participants at risk Participants received vemurafenib tablet at 960 mg orally twice daily in 21-day cycles starting from Day 21 until disease progression, unacceptable toxicity, or consent withdrawal (Period C).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	31.2% 5/16 • Baseline up to 28 days after last dose (Week 114)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Keratoacanthoma	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	12.5% 2/16 • Baseline up to 28 days after last dose (Week 114)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	6.2% 1/16 • Baseline up to 28 days after last dose (Week 114)
Cardiac disorders Coronary artery disease	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	6.2% 1/16 • Baseline up to 28 days after last dose (Week 114)
Gastrointestinal disorders Mesenteric vein thrombosis	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	6.2% 1/16 • Baseline up to 28 days after last dose (Week 114)
Infections and infestations Cellulitis	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	6.2% 1/16 • Baseline up to 28 days after last dose (Week 114)
Investigations Transaminases increased	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	6.2% 1/16 • Baseline up to 28 days after last dose (Week 114)
Nervous system disorders Haemorrhage intracranial	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	0.00% 0/16 • Baseline up to 28 days after last dose (Week 114)	6.2% 1/16 • Baseline up to 28 days after last dose (Week 114)

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER