Clinical Trial Results:
An Open-Label, Multicenter Study to Assess the Safety of RO5185426 (Vemurafenib) in Patients with Metastatic Melanoma
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Summary
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EudraCT number |
2010-023526-21 |
Trial protocol |
ES AT SE NL SI GR DE GB CZ HU SK BE BG NO PT LV FI IT DK EE LT IE |
Global end of trial date |
24 Feb 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Aug 2017
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First version publication date |
06 Aug 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MO25515
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01307397 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Hoffmann-La Roche
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Sponsor organisation address |
Grenzacherstrasse, Basel, Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Mar 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Feb 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the safety and tolerability of vemurafenib in participants with metastatic melanoma (surgically incurable and unresectable Stage IIIC or Stage IV, American Joint Committee on Cancer [AJCC]), harboring the BRAF V600 mutation (identified by the cobas® 4800 BRAF V600 Mutation Test)
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Protection of trial subjects |
The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol. Approval from the Ethics Committee (EC)/Institutional Review Board (IRB) was obtained before study start. Roche also obtained approval from the relevant Competent Authority prior to starting the study. No modifications were made to the protocol after receipt of the EC/IRB approval.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Mar 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Albania: 12
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Country: Number of subjects enrolled |
Argentina: 19
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Country: Number of subjects enrolled |
Australia: 158
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Country: Number of subjects enrolled |
Austria: 59
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Country: Number of subjects enrolled |
Belgium: 66
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Country: Number of subjects enrolled |
Bosnia and Herzegovina: 27
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Country: Number of subjects enrolled |
Brazil: 53
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Country: Number of subjects enrolled |
Bulgaria: 42
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Country: Number of subjects enrolled |
Canada: 145
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Country: Number of subjects enrolled |
Colombia: 17
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Country: Number of subjects enrolled |
Croatia: 21
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Country: Number of subjects enrolled |
Czech Republic: 137
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Country: Number of subjects enrolled |
Denmark: 28
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Country: Number of subjects enrolled |
Ecuador: 1
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Country: Number of subjects enrolled |
Estonia: 8
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Country: Number of subjects enrolled |
Finland: 18
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Country: Number of subjects enrolled |
Germany: 389
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Country: Number of subjects enrolled |
Greece: 55
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Country: Number of subjects enrolled |
Hungary: 55
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Country: Number of subjects enrolled |
India: 3
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Country: Number of subjects enrolled |
Ireland: 12
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Country: Number of subjects enrolled |
Israel: 73
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Country: Number of subjects enrolled |
Italy: 383
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Country: Number of subjects enrolled |
Korea, Republic of: 41
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Country: Number of subjects enrolled |
Latvia: 12
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Country: Number of subjects enrolled |
Lithuania: 13
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Country: Number of subjects enrolled |
Macedonia, the former Yugoslav Republic of: 20
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Country: Number of subjects enrolled |
Mexico: 10
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Country: Number of subjects enrolled |
Netherlands: 234
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Country: Number of subjects enrolled |
Norway: 47
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Country: Number of subjects enrolled |
Peru: 5
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Country: Number of subjects enrolled |
Poland: 75
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Country: Number of subjects enrolled |
Portugal: 21
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Country: Number of subjects enrolled |
Romania: 29
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Country: Number of subjects enrolled |
Russian Federation: 60
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Country: Number of subjects enrolled |
Serbia: 28
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Country: Number of subjects enrolled |
Slovakia: 18
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Country: Number of subjects enrolled |
Slovenia: 21
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Country: Number of subjects enrolled |
South Africa: 34
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Country: Number of subjects enrolled |
Spain: 300
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Country: Number of subjects enrolled |
Sweden: 77
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Country: Number of subjects enrolled |
Switzerland: 36
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Country: Number of subjects enrolled |
Turkey: 111
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Country: Number of subjects enrolled |
United Kingdom: 246
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Worldwide total number of subjects |
3219
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EEA total number of subjects |
2366
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
3
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Adults (18-64 years) |
2371
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From 65 to 84 years |
825
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85 years and over |
20
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 7495 participants were screened; 3224 participants were enrolled and 3219 participants received at least 1 dose of vemurafenib. Further 38 participants were screened at a site in Austria and 29 of these participants were enrolled and treated; however, they were not included in analysis populations due to critical audit findings. | ||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||
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Arms
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Arm title
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Vemurafenib | ||||||||||||||||||||||||||||
Arm description |
Participants received continuous oral doses of vemurafenib 960 milligrams (mg) (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Vemurafenib
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Investigational medicinal product code |
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Other name |
RO5185426, Zelboraf
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor.
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Baseline characteristics reporting groups
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Reporting group title |
Vemurafenib
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Reporting group description |
Participants received continuous oral doses of vemurafenib 960 milligrams (mg) (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor. | ||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Vemurafenib
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Reporting group description |
Participants received continuous oral doses of vemurafenib 960 milligrams (mg) (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor. | ||
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End point title |
Percentage of Participants Experiencing Any Grade 3 or 4 Adverse Events (AEs) as determined by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.0 [1] | ||||||||
End point description |
The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the NCI-CTCAE version 4.0, where Grade
1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: Grade 3 means
"Severe"; Inability to work or perform normal daily activity; treatment or medical intervention is indicated in order to improve the overall wellbeing or symptoms; delaying the onset of treatment is not putting the survival of the participant at direct risk. Grade 4 means "Life-threatening,
Disabling"; based on extreme limitation in activity; significant medical intervention/therapy required; and hospitalization probable. Analysis was performed on the safety population (all participants who received at least one dose of study medication).
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End point type |
Primary
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End point timeframe |
Baseline up to 28 days post end of treatment (maximum up to 46 months)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With at Least 1 AE Leading to Study Drug Interruption or Drug Discontinuation [2] | ||||||||||||
End point description |
An AE was considered as any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Pre existing conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Percentage of participants with dose interruption or discontinuation due to AE was presented. Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
Baseline up to 28 days post end of treatment (maximum up to 46 months)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants with AEs of Special Interest [3] | ||||||||||||||||||||||||||||||||||
End point description |
AEs of special interest included cutaneous squamous cell carcinoma (SCC), rash, photosensitivity, liver injury, arthralgia, fatigue, gastrointestinal (GI) polyps, pancreatitis, Potentiation of radiation toxicity, prolongation of cardiac repolarization or arrhythmia, non-cutaneous SCC and other primary malignancies (other than cutaneous SCC or new primary melanoma). Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
Baseline up to 28 days post end of treatment (maximum up to 46 months)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
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End point title |
Mean Cumulative Dose of Vemurafenib [4] | ||||||||
End point description |
Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
Baseline up to end of treatment or death (maximum up to 46 months)
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Vemurafenib Treatment [5] | ||||||||||||
End point description |
Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose taken due to adverse events, noncompliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation. Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
Baseline up to end of treatment or death (maximum up to 46 months)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean Total Vemurafenib Dose Per Day [6] | ||||||||||||
End point description |
Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose taken due to adverse events, noncompliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation. Average total dose per day: total actual dose taken divided by total actual days on treatment. Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
Baseline up to end of treatment or death (maximum up to 46 months)
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Dose Intensity of vemurafenib [7] | ||||||||
End point description |
Dose intensity was defined as (total actual doses taken/total planned doses) *100, where total planned doses = prescribed doses * planned days on treatment, where planned days on treatment were defined as the interval between date of first dose and date of last dose. Analysis was performed on the safety population.
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End point type |
Primary
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End point timeframe |
Baseline up to end of treatment or death (maximum up to 46 months)
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Improvement in Eastern Cooperative Group (ECOG) Performance Status | ||||||||||||
End point description |
ECOG Performance Status was measured on therapy assessed participant's performance status on 5 point scale: 0 = fully active/able to carry on all pre disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than [>] 50% of waking hours [hrs]), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead. Percentage of participants who had at least one point improvement from baseline at any assessment visit as well as at last study visit was reported. Analysis was performed on the safety population.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 1 of each 28 day cycle up to end of treatment (up to 46 months)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants who Received any Concomitant Medications | ||||||||
End point description |
Concomitant medications were all medications taken during the study, including those started before but ongoing at first dose. No medications for Melanoma were included. Percentage of participants who received at least one concomitant medication was reported. Analysis was performed on the safety population.
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End point type |
Secondary
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End point timeframe |
Baseline up to 46 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Best Overall Response (BOR) of Confirmed Complete Response or Partial Response, as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | ||||||||
End point description |
BOR was assessed by the investigator according to RECIST v1.1. BOR was defined as having confirmed CR or PR. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to less than (<) 10 millimeter (mm) in short axis; PR: 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 lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging greater than or equal to (>=) 4 weeks after initial response. Analysis was performed on the safety population. Number of subjects analyzed = participants with measurable disease at baseline
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End point type |
Secondary
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End point timeframe |
Baseline until first documentation of confirmed CR or PR (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response | ||||||||
End point description |
The duration of response was defined as the time between the date of first confirmed CR or PR and date of first progression of disease (PD), or death, from any cause. Responses were assessed as per RECIST v1.1. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to < 10 mm in short axis; PR: 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 lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging >= 4 weeks after initial response. PD: 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 lesion. Analysis was performed on the safety population. Number of subjects analyzed=participants who achieved CR or PR.
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End point type |
Secondary
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End point timeframe |
From 1st documentation of confirmed CR or PR to PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until end of the study [up to 46 months])
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Response | ||||||||
End point description |
Time to response was defined as the time between the date of first treatment and date of first confirmed CR or PR (assessed as per RECIST v1.1). CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to < 10 mm in short axis; PR: 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 lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging >= 4 weeks after initial response. Analysis was performed on the safety population. Number of subjects analyzed = participants with measurable disease at baseline.
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End point type |
Secondary
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End point timeframe |
Baseline until first documentation of confirmed CR or PR, whichever occurred first (assessed at baseline, at Weeks 8, 16,
as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46
months])
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With PD Assessed According to RECIST v1.1 or Death | ||||||||
End point description |
PD was assessed according to RECIST v1.1. 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 lesion. Analysis was performed on the safety population.
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End point type |
Secondary
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End point timeframe |
Baseline until PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression Free Survival (PFS) | ||||||||
End point description |
PFS was defined as the time between the date of the first treatment and the date of first progression or death from any cause. PD was assessed according to RECIST v1.1. 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 lesion. Analysis was performed on the safety population.
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End point type |
Secondary
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End point timeframe |
Baseline until PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Died | ||||||||
End point description |
Analysis was performed on the safety population.
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End point type |
Secondary
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End point timeframe |
Baseline until death (maximum up to 46 months)
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
Overall Survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. Analysis was performed on the safety population.
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End point type |
Secondary
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End point timeframe |
Baseline until death (maximum up to 46 months)
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline up to 28 days post end of treatment (maximum up to 46 months)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Vemurafenib
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Reporting group description |
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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28 Apr 2011 |
• Based on result of a different study similar participant population was allowed to be enrolled in this study and therefore participants with surgically incurable and unresectable Stage IIIC or Stage IV (AJCC) and participants who had not received prior treatment for metastatic melanoma were allowed into the study (in addition to participants who had received prior treatment).
• Included participants at least 16 years of age due to the assumed similarities between the biological/physiological and pharmacokinetic/pharmacodynamic characteristics of 16 to 18-year-old participants.
• Excluded participants with a known hypersensitivity to vemurafenib or another BRAF inhibitor.
• Excluded participants with congenital long QT syndrome considering the recent data of effect of vemurafenib on the QT interval.
• Clarified the type of concomitant medication that was prohibited or must be used with caution.
• Included ECG monitoring to be 28 days after starting treatment with vemurafenib, every 4 weeks for the following 3 months, every 12 weeks thereafter and at the end of study/follow-up visit, following the new safety information.
• Clarified the definition of the date at which the Screening Period started to be the date at which the first archival tumor tissue sample was sent to the central testing laboratory for BRAF mutation testing, except when a study procedure was performed prior to sending the tumor sample to the testing laboratory, when this date was recorded as the date of the start of Screening.
• Clarified the reporting of SCC to allow for the proper coding to the preferred term cutaneous SCC and clarified that SCC should be reported as an serious AE only if it meets the definition of an serious AE. |
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30 Nov 2011 |
• Included a long term follow-up safety phase for 24 months after the last participant enrolled.
• Added information to the study background.
• Included tolerability as part of the primary objective of the study, together with safety.
• Clearly defined the end of treatment visit and the 28 day follow-up visit after discontinuation of vemurafenib and updated the sections referring to visits.
• Increased the number of participants to be screened and enrolled.
• Clarified that only a protocol violation that endangered a participant’s safety would mandate discontinuation of study treatment.
• Added the option for participants who developed disease progression but who in the opinion of the investigator would still benefit from continuing vemurafenib treatment, could do so after discussion with the Sponsor.
• Included that for participants who developed any other suspicious lesions (in addition to SCC), tissue from the lesions was also to be provided for confirmation of diagnosis by a designated central pathology laboratory.
• Clarified when the study enrolment would end in relation to local regulatory approval and reimbursement of vemurafenib for the treatment of metastatic melanoma.
• Increased the number of study centers.
• Clarified the exclusion criteria
• Clarified the use of limited field radiotherapy to include all palliative reasons if the limited field radiotherapy was not considered a target lesion for the RECIST assessments.
• Increased the follow-up of chest CT for evaluation of non cutaneous SCC.
• Clarified that the participants with known or suspected bone metastases should undergo radionuclide bone scan or PET scan at baseline if clinically indicated.
• Clarified the definition of AE and SAEs.
• Amended the statistical analyses. |
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15 Aug 2012 |
• Added that participant recruitment has been higher than expected with additional countries and sites than originally planned being included. The protocol has been updated to reflect the higher number of participant and revised statistical assumptions. It was estimated that approximately 7400 participants will be screened and approximately 3300 participants with the BRAF V600 mutation will be enrolled in the study and receive treatment with vemurafenib.
• Increased the visit window to +/- 5 days to allow flexibility and to be more realistic to clinical routine, and the follow-up visit to after 28 days.
• Included an additional head and neck examination for monitoring of non cutaneous SCCs to align with the monitoring guidance of the Zelboraf® (marketed name of vemurafenib) Summary of Product Characteristics, to the Long Term Safety Follow-up Phase, to be performed at 6 months following study drug discontinuation or until initiation of another neo plastic therapy.
• Added a dermatological evaluation at 6 months following study drug discontinuation or until initiation of another anti neoplastic therapy for monitoring of cutaneous SCCs to align with the monitoring guidance of the vemurafenib Summary of Product Characteristics
• Included for consistency throughout the protocol that as well as cutaneous SCC, BCC and keratoacanthoma and other second primary malignancies were defined as events requiring close monitoring. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
