A Study of RO5185426 in Previously Treated Melanoma Patients With Brain Metastases

Study Overview
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Brief Summary
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This open-label study will assess the safety and efficacy of RO5185426 in previously treated metastatic melanoma patients with brain metastases. Patients will receive RO5185426 at a dose of 960 mg twice daily orally until disease progression or unacceptable toxicity occurs.

Official Title
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An Open-label, Pilot Study of RO5185426 in Previously Treated Metastatic Melanoma Patients With Brain Metastases

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: RO5185426


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Metastatic melanoma (Stage IV, American Joint Committee on Cancer) with BRAF mutation (cobas 4800 BRAF V600 Mutation Test) Brain metastases for which surgical resection is not a treatment option Patients must have failed at least one previous treatment for brain metastases Requiring corticosteroids for symptom control Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Exclusion Criteria: Increasing corticosteroid dose during the 7 days prior to study entry Previous malignancy within the past 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix Concurrent administration of any anticancer therapies other than those administered in the study Clinically significant cardiovascular disease or event within the 6 months prior to first dose of study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br> | Drug: RO5185426<br>* 960 mg b.i.d. orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) | AE:any unfavorable and unintended sign, symptom, or disease associated with use of study drug, regardless of relation to study drug. Pre-existing conditions that worsened and laboratory or clinical tests that resulted in change in treatment or discontinuation from study drug were reported as AEs. Serious AE: resulted in death, life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect or was medically significant. Grade-1:discomfort but no disruption of normal daily activity. Grade-2:discomfort sufficient to reduce or affect daily activity,no intervention indicated.Grade-3:inability to perform normal daily activity,intervention indicated.Grade-4:immediate threat to life or leading to permanent mental or physical condition that prevented performing normal daily activities.Grade 5: death. Any AE included participants with serious and non-serious AE. | From baseline up to last dose (0.1 to 11.3 months) plus 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) by Disease Site | Objective response was assessed by the investigator according to Response Evaluation Criteria in Solid Tumours (RECIST) (Version 1.1). CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Best overall response was calculated separately for brain, other sites (extracranial) and whole body. Percentage of participants with 95 percent (%) Clopper-Pearson confidence interval (CI) are reported. | Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months) | 
| Duration of Response by Disease Site | Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease (PD) or death, only for those participants whose best overall response was CR or PR. CR and PR were assessed by investigator according to RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 millimeter (mm), progression of existing non-target lesions, or presence of new lesions. Duration of response was calculated by Kaplan-Meier estimates separately for brain, other sites (extracranial) and whole body. | Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease or death (up to 16 months) | 
| Time to Response by Disease Site | Time to response was defined as the interval between the date of first treatment and the date of first documentation of CR or PR (whichever occurred first). CR and PR were assessed by investigator according to RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Time of response was calculated by Kaplan-Meier estimates separately for brain, other sites (extracranial) and whole body. | Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months) | 
| Duration of Stable Disease (SD) by Disease Site | Duration of SD was defined as the time between the first documented date of SD and date of PD or death from any cause. SD was defined (according to RECIST version 1.1) as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Duration of SD was calculated by Kaplan-Meier estimates separately for brain, other sites (extracranial) and whole body. | Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months) | 
| Time to New Lesion by Disease Site | Time to new lesions was defined as the interval between the date of first treatment and the date of first documentation of new lesions. Time to new lesion was calculated by Kaplan-Meier estimates separately for brain, other sites (extracranial) and whole body. | Baseline, Week 4, Week 8 and thereafter every eighth week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months) | 
| Percentage of Participants With Disease Progression or Death by Disease Site | Disease progression (according to RECIST version 1.1) was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Percentage of participants with disease progression by brain, other sites (extracranial) and whole body are reported. | Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months) | 
| Progression Free Survival (PFS) | PFS was defined as the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Disease progression (according to RECIST version 1.1) was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates separately for brain, other sites (extracranial) and whole body. | Baseline, Week 4, Week 8 and thereafter every eighth week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months) | 
| Percentage of Participants Who Died | Percentage of participants who died due to any reason are reported. | Baseline up to end of the study and every 3 months during follow-up (up to 16 months) | 
| Overall Survival (OS) | OS was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. Participants who discontinued the study treatment for any reason other than withdrawal of consent were continued to be followed for survival. The end of study occurred when all participants had been followed for a period of 6 months, had died, withdrawn consent or were lost to follow-up, whichever occurred first. OS was calculated by Kaplan-Meier estimates. | From start of treatment up to end of the study and every 3 months during follow up (up to 16 months) | 
| Percentage of Participants With Improvement in Total Daily Dose of Corticosteroids | An improvement in corticosteroid dose was defined as a dose reduction of at least 33% of baseline dose for at least 28 days or stopping use completely. Percentage of participants and 95% Clopper-Pearson CI are reported. | Baseline, every week during the first 8 weeks and every second week thereafter up to last dose (0.1 to 11.3 months) plus 28 days | 
| Percentage of Participants With Improvement in Total Daily Dose of Narcotic Pain Analgesic | An improvement in narcotic pain analgesics was defined as a dose reduction of at least 33% of baseline dose for at least 28 days or stopping use completely. | Baseline, every week during the first 8 weeks and every second week thereafter up to last dose (0.1 to 11.3 months) plus 28 days | 
| Percentage of Participants With Improvement in Visual Analog Scale (VAS) Assessment of Pain | VAS is a measure of pain intensity. The participant was asked to mark on a 100 mm line where their pain level was on the day they completed the scale. The beginning of the line represented no pain and the end of the line represented maximum pain. Total score ranged from 0 - 100. Reported values are decrease in VAS of greater than (>) 20 mm or >30 mm from baseline. | Baseline; Day 1 of Cycles 2-8 (28-day cycle) and at the end of study visit (up to 16 months) | 
| Percentage of Participants With Improvement in Physician's Assessment of Global Performance Status | Physician's Assessment of Global Performance Status was assessed on 7 point scale (1- Very much better, 2-Much better, 3-A little better, 4-No change, 5-A little worse, 6-Much worse, 7- Very much worse). An improvement was classed as a difference from baseline of at least -1 point. Percentage of participants with 95% Clopper-Pearson CI were reported for participants with improvement in Physician's Assessment of Global Performance Status at any visit. | Baseline, Day 1 of every 28-day cycle, at end of study and at the 28-day follow-up visit (up to 16 months) |