Clinical Trial Results:
A Phase I/II, open-label, dose escalation trial to evaluate the safety, pharmacokinetics, and pharmacodynamics of RAF265 (CHIR-265) administered orally to patients with locally advanced or metastatic melanoma
Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
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Summary
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EudraCT number |
2007-005367-10 |
Trial protocol |
NL |
Global end of trial date |
30 Nov 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Jul 2018
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First version publication date |
07 Jul 2018
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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 |
CRAF265A2101
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00304525 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Nov 2013
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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 |
30 Nov 2013
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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 |
The primary objectives of this study were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD), dose limiting toxicities (DLTs), and the safety profile of RAF265 when administered orally to patients with locally advanced or metastatic melanoma; to determine the plasma pharmacokinetics (PK) of orally administered RAF265; and to evaluate potential pharmacodynamic effects of RAF265 using tumor/nevus biopsies, peripheral blood samples, and imaging.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Apr 2006
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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 |
United States: 97
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Country: Number of subjects enrolled |
Switzerland: 7
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Worldwide total number of subjects |
104
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EEA total number of subjects |
0
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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) |
0
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Adults (18-64 years) |
70
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From 65 to 84 years |
34
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were screened over a period of 28 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Arm 1 - PK Run-in/Dose escalation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received a run-in dose then daily and weekly doses of RAF265 for at least one 28-day cycle. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
RAF265
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Investigational medicinal product code |
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Other name |
CHIR-265
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered a run-in dose of 10 mg of a 50mg/ml solution, then received the same dose daily for 11 days, followed by a dose of 10 mg weekly after a hold. One subject had the run-in dose then proceeded to 10 mg/week after the hold. Subjects mixed RAF265 with 20 or 40 mL of juice, and were requested to consume no more than 8 oz. of additional liquid for the next 2 hours.
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Arm title
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Arm 2 - PK Run-in/Dose escalation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Seven cohorts of subjects received run-in, loading, and daily doses of RAF265 for at least one 28-day cycles; the last (eighth) cohort did not receive a run-in dose. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
RAF265
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Investigational medicinal product code |
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Other name |
CHIR-265
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Pharmaceutical forms |
Oral liquid, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Cohorts 1-7.1 received RAF265 as a single oral dose of a 50 mg/ml solution on Day 1 of the PK run-in period (cohorts 1-7 only) followed 7 to 10 days later by one loading dose on cycle 1 day 1, and then by lower once daily doses starting on cycle 1 day 2; until progression or toxicity. Run-in doses were 10-403 mg; loading doses were 8-322 mg; daily doses were 2-67 mg. Four subjects transitioned from oral solution to tablets. The dose was based on the tablet equivalent to the subject’s current liquid dose rounded to the nearest 10 mg by using 10 and 50 mg tablets. For the oral solution, subjects mixed RAF265 with 20 or 40 mL of juice, and were requested to consume no more than 8 oz. of additional liquid for the next 2 hours. For tablets, subjects were instructed to take their daily dosing at approximately the same time each day with a glass of water and to consume it over as short a time as possible. Subjects were also instructed to ingest RAF265 at least 2 hours before or after a meal.
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Arm title
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Arm 3 - Dose escalation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Four cohorts of subjects received RAF265 weekly for at least one 28-day cycle. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
RAF265
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Investigational medicinal product code |
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Other name |
CHIR-265
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
Four cohorts received a weekly dose of RAF265 from Cycle 1 until disease progression or unacceptable toxicity required discontinuation of treatment. Doses for all cycles were 10 to 40 mg of a 50 mg/ml solution. Subjects mixed RAF265 with 20 or 40 mL of juice, and were requested to consume no more than 8 oz. of additional liquid for the next 2 hours.
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Arm title
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Arm 4 - Bioequivalence | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Arm 4 was added to establish the bioequivalency of the oral liquid formulation to the tablet, but was later closed. Bioavailability was instead assessed in a separate study. While three subjects underwent prescreening, none were treated in this arm. For two subjects, no data were entered into the case report form (CRF) due to withdrawal of consent or failure of prescreening. The remaining subject was recruited into Arm 5. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Bioequivalence | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Arm 5 - Dose escalation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Two cohorts of subjects received RAF265 daily for 2 weeks with a 1-week dose holiday, for at least one 21-day cycle. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
RAF265
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Investigational medicinal product code |
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Other name |
CHIR-265
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Pharmaceutical forms |
Oral liquid, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Cohorts 1 and 2 received a daily dose of RAF265 for 14 days of each 21-day cycle, from Cycle 1 until disease progression or unacceptable toxicity required discontinuation of treatment. Doses for all cycles were 67 or 94 mg of a 50 mg/ml solution. Three subjects were transitioned from oral solution to tablets. The dose was based on the tablet equivalent to the subject’s current liquid dose rounded to the nearest 10 mg by using 10 and 50 mg tablets. For the oral solution, subjects mixed RAF265 with 20 or 40 mL of juice, and were requested to consume no more than 8 oz. of additional liquid for the next 2 hours. For tablets, subjects were instructed to take their daily dosing at approximately the same time each day with a glass of water and to consume it over as short a time as possible. Subjects were also instructed to ingest RAF265 at least 2 hours before or after a meal.
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Baseline characteristics reporting groups [1]
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Reporting group title |
Overall study
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Reporting group description |
- | ||||||||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: Arm 4 was added to establish the bioequivalency of the oral liquid formulation to the tablet, but was later closed. One subject was recruited into Arm 5. |
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End points reporting groups
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Reporting group title |
Arm 1 - PK Run-in/Dose escalation
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Reporting group description |
Subjects received a run-in dose then daily and weekly doses of RAF265 for at least one 28-day cycle. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||
Reporting group title |
Arm 2 - PK Run-in/Dose escalation
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Reporting group description |
Seven cohorts of subjects received run-in, loading, and daily doses of RAF265 for at least one 28-day cycles; the last (eighth) cohort did not receive a run-in dose. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||
Reporting group title |
Arm 3 - Dose escalation
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Reporting group description |
Four cohorts of subjects received RAF265 weekly for at least one 28-day cycle. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||
Reporting group title |
Arm 4 - Bioequivalence
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Reporting group description |
Arm 4 was added to establish the bioequivalency of the oral liquid formulation to the tablet, but was later closed. Bioavailability was instead assessed in a separate study. While three subjects underwent prescreening, none were treated in this arm. For two subjects, no data were entered into the case report form (CRF) due to withdrawal of consent or failure of prescreening. The remaining subject was recruited into Arm 5. | ||
Reporting group title |
Arm 5 - Dose escalation
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Reporting group description |
Two cohorts of subjects received RAF265 daily for 2 weeks with a 1-week dose holiday, for at least one 21-day cycle. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity. | ||
Subject analysis set title |
Arm 2 Dose Level 1
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 10 mg (run-in), 8 mg (loading dose), and 2 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Level 2
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 20 mg (run-in), 16 mg (loading dose), and 3 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Level 3
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 30-36 mg (run-in), 24-29 mg (loading dose), and 4-6 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Level 4
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 40-72 mg (run-in), 32-58 mg (loading dose), and 5-12 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Level 5
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 50-144 mg (run-in), 40-115 mg (loading dose), and 6-24 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Level 6
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 60-288 mg (run-in), 48-230 mg (loading dose), and 7-48 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Level 7
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 70-403 mg (run-in), 56-322 mg (loading dose), and 8-67 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Level 7.1
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 288 mg (loading dose split into 3 doses of 96 mg each) and 67 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 3 Dose Level 1
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 10 mg of RAF265 each week. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 3 Dose Level 2
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 20 mg of RAF265 each week. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 3 Dose Level 3
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 30 mg of RAF265 each week. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 3 Dose Level 4
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This subject received 40 mg of RAF265 each week. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 5 Dose Level 1
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 67 mg of RAF265 daily for 14 days followed by a 1-week dose holiday. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 5 Dose Level 2
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 94 mg of RAF265 daily for 14 days followed by a 1-week dose holiday. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Levels 1-4
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received 10-72 mg (run-in), 8-58 mg (loading dose), and 2-12 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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Subject analysis set title |
Arm 2 Dose Levels 7-7.1
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received no run-in or 70-403 mg (run-in), 56-322 mg (loading dose), and 8-67 mg (daily maintenance dose) of RAF265. Subjects entered the assigned dose level and continued until disease progression or unacceptable toxicity.
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End point title |
Observed Maximum Plasma Concentration (Cmax) of RAF265 After a Run-in Dose-Arm 2 [1] | ||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
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End point type |
Primary
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End point timeframe |
Pre-dose and 1, 2, 3, 4, 6, 8, 24,48, 72, and 96 hours post-dose
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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 statistical analysis was planned for this primary outcome measure. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Time to Maximum (Tmax), Last Quantifiable (Tlast), And Half-Life (T1/2) Concentration of CRAF265 After a Run-in Dose-Arm 2 [2] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
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End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose, 1, 2, 3, 4, 6, 8, 24, 48, 72, and 96 hours post dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [3] - n's were: Tmax, 3; Tlast, 3; T1/2, 2 [4] - n's were: Tmax, 3; Tlast, 3, T1/2, 1 [5] - n's were: Tmax, 4; Tlast, 4; T1/2, 2 [6] - n's were: Tmax, 10; Tlast, 7; T1/2, 5 [7] - n's were: Tmax, 15; Tlast, 15; T1/2, 11 [8] - n's were: Tmax, 22; Tlast, 20; T1/2, 13 [9] - n's were: Tmax, 9; Tlast, 9; T1/2, 4 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Area Under The Plasma Concentration-time Curve From Time Zero to The Time of The Last Quantifiable Measurement (AUC0-tlast) of CRAF265 After a Run-in Dose-Arm 2 [10] | ||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose, 1, 2, 3, 4, 6, 8, 24, 48, 72, and 96 hours post dose
|
||||||||||||||||||||||||||||||||
| Notes [10] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Cmax of RAF265 on Day 1 of Cycle 1-All Arms [11] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, 4, 6 (all arms), and 8 (Arms 3 and 5 only) hours post-dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [11] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Tmax and Tlast of RAF265 on Day 1 of Cycle 1-All Arms [12] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, 4, 6 (all arms), and 8 (Arms 3 and 5 only) hours post-dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [12] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [13] - n's were: Tmax, 3; Tlast, 3 [14] - n's were: Tmax, 3; Tlast, 3 [15] - n's were: Tmax, 4; Tlast, 4 [16] - n's were: Tmax, 10; Tlast, 9 [17] - n's were: Tmax, 15; Tlast, 14 [18] - n's were: Tmax, 22; Tlast, 21 [19] - n's were: Tmax, 9; Tlast, 8 [20] - n's were: Tmax, 10; Tlast, 10 [21] - n's were: Tmax, 3; Tlast, 2 [22] - n's were: Tmax, 7; Tlast, 7 [23] - n's were: Tmax, 5; Tlast, 5 [24] - n's were: Tmax, 1; Tlast, 1 [25] - n's were: Tmax, 3; Tlast, 3 [26] - n's were: Tmax, 6; Tlast, 5 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
AUC0-tlast of RAF265 on Day 1 of Cycle 1-All Arms [27] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, 4, 6 (all arms), and 8 (Arms 3 and 5 only) hours post-dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [27] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Cmax of RAF265 on Day 15 of Cycle 1-Arm 2 [28] | ||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, 4, and 6 hours post-dose
|
||||||||||||||||||||||||||||||||||||
| Notes [28] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Tmax and Tlast of RAF265 on Day 15 of Cycle 1-Arm 2 [29] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, 4, and 6 hours post-dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [29] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [30] - n's were: Tmax, 3; Tlast, 3 [31] - n's were: Tmax, 3; Tlast, 3 [32] - n's were: Tmax, 4; Tlast, 4 [33] - n's were: Tmax, 8; Tlast, 7 [34] - n's were: Tmax, 15; Tlast, 14 [35] - n's were: Tmax, 19; Tlast, 16 [36] - n's were: Tmax, 9; Tlast, 9 [37] - n's were: Tmax, 9; Tlast, 9 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
AUC0-tlast of RAF265 on Day 15 of Cycle 1-Arm 2 [38] | ||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, 4, and 6 hours post-dose
|
||||||||||||||||||||||||||||||||||||
| Notes [38] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Cmax of RAF265 on Day 14 of Cycles 1 and 2-Arm 5 [39] | ||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, and 8 hours post-dose
|
||||||||||||||||||
| Notes [39] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||
|
|||||||||||||||||||
| Notes [40] - n's were: Cycle 1, 3; Cycle 2, 3 [41] - n's were: Cycle 1, 5; Cycle 2, 5 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Tmax of RAF265 on Day 14 of Cycles 1 and 2-Arm 5 [42] | ||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, and 8 hours post-dose
|
||||||||||||||||||
| Notes [42] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||
|
|||||||||||||||||||
| Notes [43] - n's were: Cycle 1, 3; Cycle 2, 3 [44] - n's were: Cycle 1, 5; Cycle 2, 5 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Tlast of RAF265 on Day 14 of Cycles 1 and 2-Arm 5 [45] | ||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, and 8 hours post-dose
|
||||||||||||||||||
| Notes [45] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||
|
|||||||||||||||||||
| Notes [46] - n's were: Cycle 1, 2; Cycle 2; 2 [47] - n's were: Cycle 1, 4; Cycle 2, 5 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
AUC0-tlast of RAF265 on Day 14 of Cycles 1 and 2-Arm 5 [48] | ||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||
End point timeframe |
Pre-dose and 1, 2, 3, and 8 hours post-dose
|
||||||||||||||||||
| Notes [48] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||
|
|||||||||||||||||||
| Notes [49] - n's were: Cycle 1, 2; Cycle 2, 2 [50] - n's were: Cycle 1, 4; Cycle 2, 5 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Observed Mimimum Plasma Concentration (Cmin) of RAF265 at Steady State-Arms 2, 3, and 5 [51] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Four mls of blood were collected to determine the concentration of RAF265 in plasma. Unbound RAF265 plasma concentration vs. time data were used to determine RAF265 pharmacokinetic (PK) parameters. PK analysis was performed by non-compartmental methods.
This endpoint analyzed the PK Analysis Set, defined as all subjects who had sufficient and interpretable PK assessments (sufficient samples collected for calculating noncompartmental or compartmental PK parameters, as appropriate) treated in the study (Arms 2, 3 and 5).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1 pre-dose of Cycle 2 and all subsequent cycles
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [51] - 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 statistical analysis was planned for this primary outcome measure. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline of Tissue Biomarker Expression (H-score) and Response Evaluation Criteria in Solid Tumors (RECIST) Tumor Response at Day 8 of Cycle 2-Arm 2 [52] [53] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
By using established immunohistochemical methods, tumor tissue (and nevi, if available), were assessed for baseline levels and, in instances of paired pre- and on-treatment biopsies, relative changes in the levels of core pharmacodynamic and response markers. A negative value indicates less expression.
pMEK = phosphorylated MAPK/ERK kinase, pERK = phosphorylated extracellar signal-regulated kinase, Ki67 = proliferation-associated antigen Ki-67, BIM= a pro-apoptotic member of the BCL-2 family, PARP = Poly(ADP-ribose)polymerase, Cyclin D1 = cell cycle gene, MITF = microphthalmia-associated transcription factor, CKIT=c-KIT, P53= Tumor Protein 53/TP53, PAKT473= Phospho Akt S 473, PS6=Phosphoserine 240-S6 ribosomal protein, PTEN=Phosphatase and Tensin homolog.
This endpoint analyzed the Full Analysis Set (FAS), defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 8 of Cycle 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [52] - 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 statistical analysis was planned for this primary outcome measure. [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1, 4 and 5; data for Arms 2 and 3 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [54] - n's were: 23, 13, 14, 8, 19, 19, 18, 21, 23, 14, 23, 21, 20, 20 [55] - n's were: 2, 2, 1, 0, 1, 1, 2, 2, 2, 0, 3, 2, 2, 2, [56] - n's were: 6, 5, 2, 1, 4, 6, 5, 5, 6, 3, 5, 6, 5, 4 [57] - n's were: 11, 2, 8, 4, 11, 8, 8, 10, 11, 8, 10, 9, 9, 10 [58] - n's were: 4, 4, 3, 3, 3, 4, 3, 4, 4, 3, 5, 4, 4, 4 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline of Tissue Biomarker Expression (H-score) and RECIST Tumor Response at Day 28 of Cycle 2-Arm 3 [59] [60] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
By using established immunohistochemical methods, tumor tissue (and nevi, if available), were assessed for baseline levels and, in instances of paired pre- and on-treatment biopsies, relative changes in the levels of core pharmacodynamic and response markers. A negative value indicates less expression.
Abbreviations: pMEK = phosphorylated MAPK/ERK kinase, pERK = phosphorylated extracellar signal-regulated kinase, Ki67 = proliferation-associated antigen Ki-67, BIM= a pro-apoptotic member of the BCL-2 family, PARP = Poly(ADP-ribose)polymerase, Cyclin D1 = cell cycle gene, MITF = microphthalmia-associated transcription factor, CKIT=c-KIT, P53= Tumor Protein 53/TP53, PAKT473= Phospho Akt S 473, PS6=Phosphoserine 240-S6 ribosomal protein, PTEN=Phosphatase and Tensin homolog.
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 28 of Cycle 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [59] - 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 statistical analysis was planned for this primary outcome measure. [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1, 4 and 5; data for Arms 2 and 3 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [61] - , n's were: 15, 13, 2, 16, 16, 11, 17, 17, 15, 16, 14, 14, 14 [62] - n's were: 3, 3, 1, 3, 3, 0, 3, 3, 2, 3, 2, 2, 3 [63] - n's were: 5, 5, 1, 7, 6, 6, 7, 7, 7, 7, 5, 6, 6, [64] - n's were: 6, 5, 0, 5, 6, 4, 6, 6, 5, 5, 6, 5, 4 [65] - n's were: 1, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in The Concentrations of Soluble Markers at Day 15 of Cycle 1-Arm 2 [66] [67] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Plasma samples were analyzed by ELISA for changes in the circulating levels of soluble vascular endothelial growth factor (VEGF), soluble VEGF receptor type 1 (sVEGFR-1), soluble VEGF receptor type 2 (sVEGFR-2), basic fibroblast growth factor (bFGF), placental growth factor (PLGF), and melanoma inhibitory activity protein (MIA).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose serum and plasma samples of subjects in the dose escalation phase were collected on the first day of the PK run-in and on Day 15 of Cycle 1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [66] - 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 statistical analysis was planned for this primary outcome measure. [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1, 4 and 5; data for Arms 2 and 3 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [68] - n's were: 68, 68, 68, 68, 68, 50, 68 [69] - n's were: 13, 13, 13, 13, 13, 12, 13 [70] - n's were: 19, 19, 19, 19, 19, 18, 19 [71] - n's were: 19, 19, 19, 19, 19, 2, 19 [72] - n's were: 17, 17, 17, 17, 17, 18, 17 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in The Concentrations of Soluble Markers at Day 15 of Cycle 1-Arm 3 [73] [74] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Plasma samples were analyzed by ELISA for changes in the circulating levels of soluble vascular endothelial growth factor (VEGF), soluble VEGF receptor type 1 (sVEGFR-1), soluble VEGF receptor type 2 (sVEGFR-2), basic fibroblast growth factor (bFGF), placental growth factor (PLGF), and melanoma inhibitory activity protein (MIA).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose serum and plasma samples of subjects in the dose escalation phase were collected on the first day of the PK run-in and on Day 15 of Cycle 1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [73] - 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 statistical analysis was planned for this primary outcome measure. [74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1, 4 and 5; data for Arms 2 and 3 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [75] - n's were: 15, 15, 15, 15, 15, 2, 15 [76] - n's were: 3, 3, 3, 3, 3, 0, 3 [77] - n's were: 6, 6, 6, 6, 6, 1, 6 [78] - n's were: 5, 5, 5, 5, 5, 0, 5 [79] - n's were: 1, 1, 1, 1, 1, 1, 1, |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Metabolic Response as Assayed by 18[F}-Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET)-Arm 2 [80] [81] | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Metabolic response was defined as either complete metabolic response (CMR; complete resolution of tumor FDG-PET uptake so the maximum standardized uptake value [SUVmax] is the same as background) or partial metabolic response (PMR; a decrease in tumor sSUVmax of >=25% from the baseline scan). Scans were preferably obtained 3 to 8 hours after RAF265 oral administration, but not later than 48 hours after dosing.
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
FDG-PET scans were done at baseline ( within 14 days prior to treatment), Cycle 1 Day 8, Cycle 1 Day 15 (± 2 days), Cycle 1 Day 28 (± 2 days), and the end of treatment
|
||||||||||||||||||||||||||||||||||||||||||
| Notes [80] - 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 statistical analysis was planned for this primary outcome measure. [81] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Metabolic Response as Assayed by FDG-PET-Arm 3 [82] [83] | ||||||||||||||||||||||||||||||
End point description |
Metabolic response was defined as either complete metabolic response (CMR; complete resolution of tumor FDG-PET uptake so the maximum standardized uptake value [SUVmax] is the same as background) or partial metabolic response (PMR; a decrease in tumor sSUVmax of >=25% from the baseline scan). Scans were preferably obtained 3 to 8 hours after RAF265 oral administration, but not later than 48 hours after dosing.
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||
End point timeframe |
FDG-PET scans were done at baseline ( within 14 days prior to treatment), Cycle 1 Day 8 and the end of treatment
|
||||||||||||||||||||||||||||||
| Notes [82] - 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 statistical analysis was planned for this primary outcome measure. [83] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Number of Subjects With Metabolic Response as Assayed by FDG-PET-Arm 5 [84] [85] | ||||||||||||||||||||||||
End point description |
Metabolic response was defined as either complete metabolic response (CMR; complete resolution of tumor FDG-PET uptake so the maximum standardized uptake value [SUVmax] is the same as background) or partial metabolic response (PMR; a decrease in tumor sSUVmax of >=25% from the baseline scan). Scans were preferably obtained 3 to 8 hours after RAF265 oral administration, but not later than 48 hours after dosing.
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
FDG-PET scans were done at baseline ( within 14 days prior to treatment), Cycles 1 and 2 Day 14 and the end of treatment
|
||||||||||||||||||||||||
| Notes [84] - 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 statistical analysis was planned for this primary outcome measure. [85] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
Number of Subjects With Both Metabolic Response as Assayed by FDG-PET And Response as Defined by RECIST-Arms 2, 3, and 5 [86] [87] | ||||||||||||
End point description |
Metabolic response was defined as either complete metabolic response (CMR; complete resolution of tumor FDG-PET uptake so the maximum standardized uptake value [SUVmax] is the same as background) or partial metabolic response (PMR; a decrease in tumor sSUVmax of >=25% from the baseline scan).
RECIST Response was defined as partial response (PR) or complete response (CR). PR and CR were defined by using Response Evaluation Criteria in Solid Tumors (RECIST criteria). PR was defined as a decrease of at least 30% from baseline in the sum of the longest diameter (LD) of target lesions, and CR as disappearance of all target lesions. An additional confirmatory computed tomography scan was required > 28 days after initial response (partial response or complete response).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Through Cycle 2
|
||||||||||||
| Notes [86] - 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 statistical analysis was planned for this primary outcome measure. [87] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With a Dose-Limiting Toxicity (DLT) During The First 28 Days of Treatment--Arms 2, 3, and 5 [88] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
A DLT was defined as any adverse event or abnormality judged by the investigator to be related to RAF265, and not related to an intercurrent illness, disease progression, other medication or procedure. Grading of laboratory abnormalities was done according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 of the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP; Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 2003).
This endpoint analyzed the Dose Determining Set (DDS), defined as subjects who received at least 75% (21 days in Arm 2 and 5 or 3 doses in Arm 3) of the scheduled doses in the first cycle for Arm 2 and 3, first 28 days for Arm 5 (with or without DLT) or had experienced a DLT any time in the first cycle for Arm 2 and 3, first 28 days for Arm 5.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to 28 days after the start of treatment
|
|||||||||||||||||||||||||||||||||||||||||||||
| Notes [88] - 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 statistical analysis was planned for this primary outcome measure. |
||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Response as Assayed by Central Radiology by Mutations Status of The BRAF Gene-Arm 2 [89] | ||||||||||||||||||||||||||||||||||||
End point description |
Response was defined as partial response (PR) or complete response (CR). PR and CR were defined by using Response Evaluation Criteria in Solid Tumors (RECIST criteria). PR was defined as a decrease of at least 30% from baseline in the sum of the longest diameter (LD) of target lesions, and CR as disappearance of all target lesions. An additional confirmatory computed tomography scan was required > 28 days after initial response (partial response or complete response).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 28 of every two cycles of treatment and end of study
|
||||||||||||||||||||||||||||||||||||
| Notes [89] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Response as Assayed by Central Radiology by Mutations Status of The BRAF Gene-Arm 3 [90] | ||||||||||||||||||||||||||||||||||||
End point description |
Response was defined as partial response (PR) or complete response (CR). PR and CR were defined by using Response Evaluation Criteria in Solid Tumors (RECIST criteria). PR was defined as a decrease of at least 30% from baseline in the sum of the LD of target lesions, and CR as disappearance of all target lesions. An additional confirmatory computed tomography scan was required > 28 days after initial response (partial response or complete response).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 28 of every two cycles of treatment and end of study
|
||||||||||||||||||||||||||||||||||||
| Notes [90] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Number of Subjects With Response as Assayed by Central Radiology by Mutations Status of The BRAF Gene-Arm 5 [91] | ||||||||||||||||||||||||
End point description |
Response was defined as partial response (PR) or complete response (CR). PR and CR were defined by using Response Evaluation Criteria in Solid Tumors (RECIST criteria). PR was defined as a decrease of at least 30% from baseline in the sum of the LD of target lesions, and CR as disappearance of all target lesions. An additional confirmatory computed tomography scan was required > 28 days after initial response (partial response or complete response).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Day 28 of every two cycles of treatment and end of study
|
||||||||||||||||||||||||
| Notes [91] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Percent of Subjects With Stable Disease or Better After 12 Months as Assayed by Central Radiology-Arm 2 [92] | ||||||||||||||||||||||||
End point description |
Stable disease (SD) or better was defined as SD, partial response (PR), or complete response (CR). SD, PR, and CR were defined by using Response Evaluation Criteria in Solid Tumors (RECIST criteria). SD was defined as neither sufficient decrease to meet the definition of PR nor sufficient
increase to meet the definition of progressive disease (PD); PR as a decrease of at least 30% from baseline in the sum of the longest diameter of target lesions, and CR as disappearance of all target lesions. An additional confirmatory computed tomography scan was required > 28 days after initial response (partial response or complete response).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
12 months after the start of treatment
|
||||||||||||||||||||||||
| Notes [92] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Percent of Subjects With Stable Disease or Better After 12 Months as Assayed by Central Radiology-Arm 3 [93] | ||||||||||||||||||||||||
End point description |
Stable disease (SD) or better was defined as SD, partial response (PR), or complete response (CR). SD, PR, and CR were defined by using Response Evaluation Criteria in Solid Tumors (RECIST criteria). SD was defined as neither sufficient decrease to meet the definition of PR nor sufficient
increase to meet the definition of progressive disease (PD); PR as a decrease of at least 30% from baseline in the sum of the longest diameter of target lesions, and CR as disappearance of all target lesions. An additional confirmatory computed tomography scan was required > 28 days after initial response (partial response or complete response).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
12 months after the start of treatment
|
||||||||||||||||||||||||
| Notes [93] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Percent of Subjects With Stable Disease or Better After 12 Months as Assayed by Central Radiology-Arm 5 [94] | ||||||||||||||||
End point description |
Stable disease (SD) or better was defined as SD, partial response (PR), or complete response (CR). SD, PR, and CR were defined by using Response Evaluation Criteria in Solid Tumors (RECIST criteria). SD was defined as neither sufficient decrease to meet the definition of PR nor sufficient
increase to meet the definition of progressive disease (PD); PR as a decrease of at least 30% from baseline in the sum of the longest diameter of target lesions, and CR as disappearance of all target lesions. An additional confirmatory computed tomography scan was required > 28 days after initial response (partial response or complete response).
This endpoint analyzed the FAS, defined as all subjects who received at least one full or partial dose of RAF265.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
12 months after the start of treatment
|
||||||||||||||||
| Notes [94] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Data for this endpoint were not collected from subjects in Arms 1 and 4; data for Arms 2, 3 and 5 are reported in separate endpoints. |
|||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Reporting groups
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Reporting group title |
Arm 2
|
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Reporting group description |
Arm 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 5
|
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Reporting group description |
Arm 5 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 3
|
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Reporting group description |
Arm 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Feb 2006 |
This amendment introduced the following changes:
-Added blood pressure (BP) assessment Cycle 2 Day 8 (C2D8)
-Added serum lipase required safety lab
-Reworded exclusion criteria 3 (mutation status) and clarified consent and destruction of patient samples
-Adjusted PK/Pharmacodynamic timepoints and clarified collection of PK/Pharmacodynamic only through Cycle 6
-Additional text added to clarify original intent of protocol and tables adjusted accordingly |
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03 Aug 2006 |
This amendment introduced the following changes:
- Changed Chiron Corporation to Novartis Pharmaceuticals due to acquisition of Chiron
- Added RAF265 compound name and protocol name
- Changed to Novartis (NVS) SAE reporting process
- Changed “subject” to “patient” throughout protocol
- Updated window period for tumor biopsy on C1D15 to day of dosing
- Added treatment Arm 2 (PK runin/ loading dose/daily maintenance dose) and Arm 3 (once a week dosing) and increased total number of patient enrolled
-Added the Multinomial Two-Stage Design to be used in the statistical analysis for the MTD dose expansion segment of the study, and added two clinical study reports to be written: one for the dose escalation segment as soon as the MTD has been determined on both arms 2 and 3, and a final clinical study report at the end of the study.
- Added biomarkers to Arm 2 and 3 in dose escalation and expansion
- Removed urine PK
- Added multinomial two-stage design for stats analysis for MTD dose expansion; two CSRs planned (dose escalation as soon as MTD reached in both Arm 2 and 3; and final CSR at end of study)
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19 Jul 2007 |
This amendment made the following changes:
-Clarified single “PK run-in” dose given in Arm 2 and its relationship to the targeted and actual loading doses given on C1D1
- Allow option of expanding either the MTD or an “optimal biologic dose” (OBD).
- Changes were made to dose escalation:
1. The dose of RAF265 was doubled from one cohort of patients to the next until two or more patients experience grade 2 drug-related toxicity, or until any 1 patient experiences grade 3 or higher toxicity. Thereafter increases in dose can be no greater than 40% from one cohort of patients to the next.
2. Bayesian logistic regression analysis with overdose control was implemented in Arm 2 (daily dosing regimen).
3. The observation period before new patients are enrolled at the next highest dose level of RAF265 was changed from 8 weeks to 4 weeks.
- Changes to simplify procedures and better assess the pharmacodynamics of RAF265
1. Include DCE- Magnetic resonance imaging (MRI) and FDG-PET to assess RAF265’s potential effects on tumor tissue
2. Added collection of plasma and serum samples for exploratory studies including circulating tumor DNA
3. Added optional collection of peripheral blood mononuclear cells (pre- and post-treatment) in separately consented individuals during the expansion phase for HLA typing, kinase studies and immunological studies
4. Sites may collect fine needle aspirate (FNA) biopsies during the dose expansion phase of the study to
permit enrollment of patients whose tumor cannot be accessed by core, punch or excisional biopsy at the first timepoint. Only after consultation with NVS clinical team.
5. Modified the number and frequency of certain procedures in both Arm 2 and Arm 3
6. Inclusion criteria were modified
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06 Feb 2008 |
This amendment introduced the following changes:
- Added Arm 4 (tablet formulation); 12 patients to be treated exclusively with tablet formulation at a dose calculated to produce the same average steady state plasma concentration as the liquid formulation MTD
- If needed, the PK run-in dose (in Arm 2) and the loading dose (in Arms 2 and 4) can be split evenly into 2-3 doses, given
8-12 hours apart. If this strategy is adopted, the PK sampling scheme will be altered accordingly.
- Changed the requirement of pre- and post-treatment biopsies; a minimum of 6 patients treated at the MTD will have pre- and on-treatment biopsies. NVS reserved option to conduct pre- and ontreatment paired tumor biopsies at any dose if needed to choose the optimaldose for phase II or other studies.
Mutational status from archival tumor tissue for all other patients. If no archival tumor tissue can be obtained,
mutation status must be determined from a pre-treatment biopsy of tumor tissue.
- A window of 3 days allowed for the performance of all study procedures except for PK sampling or unless otherwise specified in the protocol. |
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15 May 2009 |
This amendment introduced the following changes:
- Addition of complete eye exam including: visual acuity testing, visual field testing, color vision testing, IOP, split lamp exam of anterior eye segment, dilated funduscopy at baseline, C2D1, then every 3 cycles, and EOT. Additionally, eye exams should be done as soon as patient complains of visual disturbance and repeated as clinically indicated
- Added eligibility criteria to exclude patents with history or current evidence of retinal disease as confirmed by eye exam
- Updated dose limiting toxicity table to include visual toxicity and adjusted dose modification criteria for visual toxicity
- Eliminated loading dose in expansion phase of study
- Allowed for 12 additional patients to be enrolled in Arm 4 if initial data indicates new/different correction factor for tablets is required for cancer patients
- Updated PK timepoints for Arm 2 and Arm 4 |
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11 Dec 2009 |
This amendment introduced the following changes:
-Eliminated PK run-in
- Loading dose established at 288mg administered into 3 doses (96mg every 8 hours); only daily maintenance dose will be escalated
- Addition of Treatment Arm 5 alternate dosing schedule: 2 weeks continuous dosing followed by 1 week off (21 day cycle) without loading dose starting at 67mg daily maintenance dose
- Allow only patients with documented BRAF mutations in phase II; 30 evaluable patients with BRAF mutation, including at least 20 V600E will be
enrolled in the phase II expansion portion of this study |
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11 Nov 2011 |
This amendment introduced the following changes:
- Protocol synopsis updated. Figures and tables were updated to reflect tablet transition and continued drug access for ongoing patients.
- References to Arm 4 were removed to reflect closure of this study arm in the Ethics section.
- Exploratory biomarkers and Arm 4 objective were removed from study objectives, Investigation Plan, was updated to reflect closure of treatment arms after Phase I of study, removal of dose expansion (Phase II) portions of study, and addition of tablet transition and drug access for ongoing patients.
- Exploratory biomarker studies were removed. Table 5-10 in the protocol was updated to reflect removal of expansion portions of the study, and DCE-MRI was removed as it only pertained to the removed expansion arms.
- Tumor response section was updated to reflect continued drug access.
- Safety section was updated to reflect continued drug access.
- Removal of Patients from treatment or assessment was updated to reflect continued drug access.
- Treatments administered section, was updated to reflect removal of expansion portion of the study.
- Directions for administration, was updated to reflect tablet transition and continued drug access.
- Exploratory biomarker variables were removed from the Efficacy and safety section.
- Statistical and analytical plans section was updated to indicate that the final analysis of data will be done after every patient has been followed for at least 6
cycles or has discontinued from study due to disease progression or death; data collected from patients receiving continued drug access after study enrollment is closed will not be summarized but will be listed in an addendum to the CSR. Removed the expansion (Phase II) portion of the study and sample size considerations for the dose expansion section.
- Removed sample size considerations for DCEMRI section.
-RECIST quick reference was updated to correct definition of progressive disease. |
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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. | |||
| Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results. | |||
