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

Phase 1

Completed

• Conditions: Malignant Melanoma
• Interventions: Drug: RO5185426

• Registration Number: NCT01264380
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. Patients will be randomized to receive in a crossover design single oral doses of RO5185426 with or without food, with a 10-day washout period between doses. Following the crossover periods, patients will receive RO5185426 orally twice daily on a continuous basis until disease progression or unacceptable toxicity occurs.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2010-12-20
• Study First Submitted QC: 2010-12-20
• Study First Posted: 2010-12-21
• Study Start: 2011-01
• Primary Completion: 2013-05
• Study Completion: 2013-05
• Results First Submitted: 2015-07-29
• Results First Submitted QC: 2015-11-16
• Results First Posted: 2015-12-17
• Status Verified: 2016-11
• Last Update Submitted: 2016-11-01
• Last Update Posted: 2016-11-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

• Adult patients, >/= 18 years of age
• Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer)
• Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test
• Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Evaluable disease (measurable for disease progression according to RECIST criteria)
• Adequate hematological, renal and liver function

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Exclusion Criteria

• Active CNS lesions
• History of or known spinal cord compression or carcinomatous meningitis
• Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study
• Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix
• Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor
• Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
1	RO5185426	-
2	RO5185426	-
C	RO5185426	-

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States	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	Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.
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	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	PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States	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	PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States	Pre-dose on Periods A and B	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.
Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States	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	PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States	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	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.
Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States	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	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	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)	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.
Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR)	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)	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.