Clinical Trial Results:
A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab with a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients with BRAF V600E-mutant Metastatic Colorectal Cancer
Summary
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EudraCT number |
2015-005805-35 |
Trial protocol |
GB HU BE AT NL CZ DK ES NO DE IT |
Global end of trial date |
10 Nov 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Nov 2023
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First version publication date |
13 Nov 2023
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Other versions |
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 |
C4221009
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02928224 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
ARRAY-818-302: BEACON CRC | ||
Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Dec 2022
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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 |
10 Nov 2022
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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 |
Safety Lead-in-
- Assess the safety/tolerability of the combination of encorafenib + binimetinib + cetuximab in subjects with B-RAF proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).
Randomised Phase 3-
In subjects with BRAFV600E mCRC:
- Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or 5- fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI)/cetuximab (Control Arm) as measured by overall survival (OS)
- Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by Objective Response Rate (ORR) per Blinded Independent Central Review (BICR).
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Oct 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
6 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Argentina: 7
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Country: Number of subjects enrolled |
Australia: 36
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Country: Number of subjects enrolled |
Austria: 6
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Country: Number of subjects enrolled |
Belgium: 45
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Country: Number of subjects enrolled |
Brazil: 20
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Country: Number of subjects enrolled |
Canada: 7
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Country: Number of subjects enrolled |
Czechia: 10
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Country: Number of subjects enrolled |
Denmark: 10
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Country: Number of subjects enrolled |
France: 25
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Country: Number of subjects enrolled |
Germany: 29
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Country: Number of subjects enrolled |
Hungary: 6
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Country: Number of subjects enrolled |
Israel: 8
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Country: Number of subjects enrolled |
Italy: 85
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Country: Number of subjects enrolled |
Japan: 27
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Country: Number of subjects enrolled |
Mexico: 2
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Country: Number of subjects enrolled |
Netherlands: 39
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Country: Number of subjects enrolled |
Norway: 15
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Country: Number of subjects enrolled |
Poland: 11
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Country: Number of subjects enrolled |
Russian Federation: 27
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Country: Number of subjects enrolled |
Korea, Democratic People's Republic of: 41
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Country: Number of subjects enrolled |
Spain: 102
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Country: Number of subjects enrolled |
Taiwan: 17
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Country: Number of subjects enrolled |
Turkey: 7
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Country: Number of subjects enrolled |
Ukraine: 4
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Country: Number of subjects enrolled |
United Kingdom: 31
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Country: Number of subjects enrolled |
United States: 85
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Worldwide total number of subjects |
702
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EEA total number of subjects |
383
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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) |
450
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From 65 to 84 years |
252
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects were at least 18 years of age with confirmed metastatic colorectal cancer (CRC) whose disease had progressed after 1 or 2 prior regimens in the metastatic setting and whose tumor tissue was BRAF V600E-mutant as previously determined by a local assay at any time prior to screening. | ||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Combined Safety Lead-in | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Encorafenib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
300 milligrams (mg), once daily.
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Investigational medicinal product name |
Cetuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
400 mg/meter square initial dose (120-minute infusion), then 250 mg/meter square (60-minute infusion) thereafter, once weekly.
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Investigational medicinal product name |
Binimetinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
45 mg, twice daily
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Arm title
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Phase 3: Triplet Arm | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Encorafenib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Encorafenib: 300 mg, once daily.
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Investigational medicinal product name |
Cetuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
400 mg/meter square initial dose (120-minute infusion), then 250 mg/meter square (60-minute infusion) thereafter, once weekly.
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Investigational medicinal product name |
Binimetinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
45 mg, twice daily
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Arm title
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Phase 3: Doublet Arm | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Cetuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
400 mg/meter square initial dose (120-minute infusion), then 250 mg/meter square (60-minute infusion) thereafter, once weekly.
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Investigational medicinal product name |
Encorafenib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
300 mg, once daily.
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Arm title
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Phase 3:Control Arm | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible subjects could crossover to receive either triplet or doublet regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Irinotecan/cetuximab or FOLFIRI/cetuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
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Baseline characteristics reporting groups
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Reporting group title |
Combined Safety Lead-in
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Reporting group description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 3: Triplet Arm
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Reporting group description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 3: Doublet Arm
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Reporting group description |
Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 3:Control Arm
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Reporting group description |
Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible subjects could crossover to receive either triplet or doublet regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Combined Safety Lead-in
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Reporting group description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||
Reporting group title |
Phase 3: Triplet Arm
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Reporting group description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||
Reporting group title |
Phase 3: Doublet Arm
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Reporting group description |
Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care. | ||
Reporting group title |
Phase 3:Control Arm
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Reporting group description |
Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible subjects could crossover to receive either triplet or doublet regimen. | ||
Subject analysis set title |
Pharmacokinetic Population of Encorafenib
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
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End point title |
(Safety Lead-in) Number of Subjects with Dose-Limiting Toxicities (DLTs) [1] [2] | ||||||
End point description |
The dose-determining set (DDS) consisted of all combined safety lead-in (CSLI) subjects from the safety set who either completed a minimum exposure requirement (received >= 75% dose intensity of the planned dose for each binimetinib, encorafenib and cetuximab) and had sufficient safety evaluations or experienced a dose-limiting toxicity (DLT).
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End point type |
Primary
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End point timeframe |
Cycle 1 (up to 28 days)
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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: Only descriptive data was planned to be analysed. [2] - 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: Only descriptive data was planned to be analysed. |
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No statistical analyses for this end point |
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|||||||
End point title |
(Safety Lead-in) Number of Subjects with Adverse Events (AEs) [3] [4] | ||||||
End point description |
An AE is any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of subjects reporting AEs were reported in this endpoint. The Safety Set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)
|
||||||
Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analysed. [4] - 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: Only descriptive data was planned to be analysed. |
|||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Interim Analysis [5] [6] | ||||||
End point description |
An AE is any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of subjects with dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this endpoint. The Safety Set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)
|
||||||
Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analysed. [6] - 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: Only descriptive data was planned to be analysed. |
|||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Final Analysis [7] [8] | ||||||||||||
End point description |
An AE is any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of subjects according to incidence of dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this endpoint. The Safety Set consisted of all subjects who received at least 1 dose of study drug and had at least 1 posttreatment assessment, which may have included death. Subjects were analysed according to treatment received.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)
|
||||||||||||
Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analysed. [8] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis [9] | ||||||||||||
End point description |
OS was defined as the time from randomisation to death due to any cause. The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From randomisation to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.1 weeks for triplet arm and 52.4 weeks for control arm)
|
||||||||||||
Notes [9] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet Arm vs. Control Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
445
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Final Analysis [10] | ||||||||||||
End point description |
OS was defined as the time from randomisation to death due to any cause. The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From randomisation to death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)
|
||||||||||||
Notes [10] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
445
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm [11] | ||||||||||||
End point description |
ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of complete response (CR) or partial response (PR) divided by the total number of subjects, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 millimeter [mm] short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Duration of Phase 3, approximately 6 months (up to 28 days per cycle)
|
||||||||||||
Notes [11] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
218
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|
|||||||||
End point title |
(Safety Lead-in) Objective Response Rate (ORR) by Investigator [12] | ||||||||
End point description |
ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. The Safety Lead-in (SLI) Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [12] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Objective Response Rate (ORR) by BICR [13] | ||||||||
End point description |
ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [13] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Duration of Response (DOR) by Investigator [14] | ||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [14] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Duration of Response (DOR) by BICR [15] | ||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [15] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Time to Response by Investigator [16] | ||||||||
End point description |
Time to response was defined as the time from first dose to first radiographic evidence of response. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [16] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Time to Response by BICR [17] | ||||||||
End point description |
Time to response was defined as the time from first dose to first radiographic evidence of response. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [17] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Progression-free Survival (PFS) by Investigator [18] | ||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [18] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Progression-free Survival (PFS) by BICR [19] | ||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)
|
||||||||
Notes [19] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm [20] | ||||||||||||
End point description |
OS was defined as the time from randomisation to death due to any cause. The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 52.4 weeks for control arm)
|
||||||||||||
Notes [20] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Doublet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Doublet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
441
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm [21] | ||||||||||||
End point description |
OS was defined as the time from randomisation to death due to any cause. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 89.1 weeks for triplet arm)
|
||||||||||||
Notes [21] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Doublet Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3: Doublet Arm
|
||||||||||||
Number of subjects included in analysis |
444
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.5958 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per BICR [22] | ||||||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented disease progression (PD) or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to the earliest documented disease progression (PD) or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)
|
||||||||||||
Notes [22] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
445
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per Investigator [23] | ||||||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented disease progression (PD) or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to the earliest documented disease progression (PD) or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)
|
||||||||||||
Notes [23] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
445
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per BICR [24] | ||||||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)
|
||||||||||||
Notes [24] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Doublet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Doublet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
441
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per Investigator [25] | ||||||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)
|
||||||||||||
Notes [25] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Doublet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Doublet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
441
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR [26] | ||||||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)
|
||||||||||||
Notes [26] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Doublet Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3: Doublet Arm
|
||||||||||||
Number of subjects included in analysis |
444
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.1004 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator [27] | ||||||||||||
End point description |
PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)
|
||||||||||||
Notes [27] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Doublet Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3: Doublet Arm
|
||||||||||||
Number of subjects included in analysis |
444
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.3724 | ||||||||||||
Method |
Stratified Log-rank | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm per Investigator [28] | ||||||||||||
End point description |
ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Duration of Phase 3, approximately 6 months (up to 28 days per cycle)
|
||||||||||||
Notes [28] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
218
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR [29] | ||||||||||||
End point description |
ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Duration of Phase 3, approximately 6 months (up to 28 days per cycle)
|
||||||||||||
Notes [29] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Doublet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Doublet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
220
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator [30] | ||||||||||||
End point description |
ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Duration of Phase 3, approximately 6 months (up to 28 days per cycle)
|
||||||||||||
Notes [30] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Doublet vs Control Arm | ||||||||||||
Comparison groups |
Phase 3: Doublet Arm v Phase 3:Control Arm
|
||||||||||||
Number of subjects included in analysis |
220
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR [31] | ||||||||||||
End point description |
ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Duration of Phase 3, approximately 6 months (up to 28 days per cycle)
|
||||||||||||
Notes [31] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Doublet Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3: Doublet Arm
|
||||||||||||
Number of subjects included in analysis |
224
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.1928 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator [32] | ||||||||||||
End point description |
ORR per RECIST, v1.1, was defined as the number of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Duration of Phase 3, approximately 6 months (up to 28 days per cycle)
|
||||||||||||
Notes [32] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Triplet vs Doublet Arm | ||||||||||||
Comparison groups |
Phase 3: Triplet Arm v Phase 3: Doublet Arm
|
||||||||||||
Number of subjects included in analysis |
224
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0357 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per BICR [33] | ||||||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)
|
||||||||||||
Notes [33] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per Investigator [34] | ||||||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)
|
||||||||||||
Notes [34] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per Investigator [35] | ||||||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)
|
||||||||||||
Notes [35] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR [36] | ||||||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)
|
||||||||||||
Notes [36] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per BICR [37] | ||||||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)
|
||||||||||||
Notes [37] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator [38] | ||||||||||||
End point description |
DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)
|
||||||||||||
Notes [38] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per BICR [39] | ||||||||||||
End point description |
Time to response defined as the time from first dose to first radiographic evidence of response. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)
|
||||||||||||
Notes [39] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per Investigator [40] | ||||||||||||
End point description |
Time to response defined as the time from first dose to first radiographic evidence of response. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)
|
||||||||||||
Notes [40] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm per BICR [41] | ||||||||||||
End point description |
Time to response defined as the time from first dose to first radiographic evidence of response. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)
|
||||||||||||
Notes [41] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm per Investigator [42] | ||||||||||||
End point description |
Time to response defined as the time from first dose to first radiographic evidence of response. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)
|
||||||||||||
Notes [42] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR [43] | ||||||||||||
End point description |
Time to response defined as the time from first dose to first radiographic evidence of response. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)
|
||||||||||||
Notes [43] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator [44] | ||||||||||||
End point description |
Time to response defined as the time from first dose to first radiographic evidence of response. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)
|
||||||||||||
Notes [44] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
(Phase 3) Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Subjects (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [45] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EORTC QLQ-C30 questionnaire consisted of 30 questions generating 5 functional scores (physical, role, cognitive, emotional,& social); a global health (GH) status/global quality of life scale score; 3 symptom scale scores (fatigue, pain, & nausea & vomiting); & 6 standalone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, & diarrhea) & perceived financial burden. All items were graded by severity experienced during previous week & used 4-point-scale (1: not at all, 2: a little, 3: quite a bit, 4: very much). The scores were converted to health-related quality of life (HRQoL) scale ranging from 0-100. Higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity). The FAS for Phase 3 portion of study consisted of all randomised Phase 3 subjects. Here, ‘n’=subjects evaluable for the specified timepoints. 99999 indicated data could not be calculated due to insufficient subjects with events.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Cycle(C)1 Day(D)1 , C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)
|
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Notes [45] - 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: Only descriptive data was planned to be analysed. |
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|
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No statistical analyses for this end point |
|
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End point title |
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [46] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
FACT-C=Functional Assessment of Chronic Illness Therapy (FACIT) ,which assessed HRQoL of cancer subjects & subjects with other chronic illnesses. It consists of total 36 items (27 items of general version of FACT-C and disease-specific subscale containing 9 CRC-specific items), summarised to 5 subscales: physical well-being (7 items),functional well-being (7 items), social/family well-being (7 items);all 3 subscales range:0-28, emotional well-being (6 items)range:0-24, colorectal cancer subscale (9 items) range:0-36; higher subscale score=better QoL. All single-item measures range:0='Not at all' to 4='Very much'. Table summarises functional well-being subscale, individual questions are linearly scaled & combined to form functional well-being subscale score (range 0-28). High score represents better QoL.FAS for Phase 3 portion=all randomised Phase 3 subjects. Here, ‘n’=subjects evaluable for specified timepoints. 99999=data could not be calculated due to insufficient subjects.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)
|
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Notes [46] - 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: Only descriptive data was planned to be analysed. |
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|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [47] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EQ-5D-5L contains 1 item for each of 5 dimensions of health-related QoL (i.e., mobility, self-care, usual activities, pain or discomfort and anxiety or depression). Response options for each item varied from having no problems to moderate problems or extreme problems. The EQ-5D-5L (v4.0) is a standardised measure of health utility that provides a single index value for one’s health status. The EQ-5D-5L is frequently used for economic evaluations of health care and has been recognised as a valid and reliable instrument for this purpose. The EQ visual analog scale (VAS) is a score that is directly reported by the subject and ranges from 0 to 100 (higher is better quality health). The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, 'n' signifies subjects evaluable for the specified timepoints. 99999 indicated data could not be calculated due to insufficient subjects.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)
|
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Notes [47] - 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: Only descriptive data was planned to be analysed. |
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No statistical analyses for this end point |
|
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End point title |
(Phase 3) Change From Baseline in the Subject Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [48] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PGIC is a measure of subject's perceptions of change in their symptoms over time that can be used as an anchoring method to determine the minimal clinically important difference for other subject reported outcome (PROs). For this assessment, subjects answered the following question: “Since starting treatment, my colorectal cancer symptoms are: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse or (7) very much worse.” The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, 'n' signifies subjects evaluable for the specified timepoints. 99999 indicated data could not be calculated due to insufficient subjects.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [48] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Cetuximab [49] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [49] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Encorafenib [50] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [50] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Binimetinib [51] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [51] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Metabolite of Binimetinib (AR00426032) [52] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [52] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab [53] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib [54] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [54] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib [55] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [55] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032) [56] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [56] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib [57] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [57] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab [58] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [58] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib [59] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [59] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032) [60] | ||||||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||||||
Notes [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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib [61] | ||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||
Notes [61] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib [62] | ||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||
Notes [62] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab [63] | ||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||
Notes [63] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib [64] | ||||||||
End point description |
The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)
|
||||||||
Notes [64] - 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: Only descriptive data was planned to be analysed. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib | ||||||||
End point description |
The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from subjects enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register. The analysis set included all subjects in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Subjects were analysed according to the actual treatment and dose received.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib | ||||||||
End point description |
The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from subjects enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register. The analysis set included all subjects in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Subjects were analysed according to the actual treatment and dose received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
(Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab | ||||||||
End point description |
The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from subjects enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register. The analysis set included all subjects in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Subjects were analysed according to the actual treatment and dose received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Phase 3: Number of Subjects With Clinically Notable Shifts in Hematology and Coagulation Laboratory Parameters [65] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinically notable shifts was defined as worsening by at least 2 grades or to more than or equal to (>=) Grade 3 based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [65] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Phase 3: Number of Subjects With Clinically Notable Shifts in Serum Chemistry Laboratory Parameters [66] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinically notable shifts was defined as worsening by at least 2 grades or to >= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [66] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Phase 3: Number of Subjects With Clinically Notable Shifts in Urinalysis Laboratory Parameters [67] | ||||||||||||
End point description |
Clinically notable shifts was defined as worsening by at least 2 grades or to >= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)
|
||||||||||||
Notes [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: Only descriptive data was planned to be analysed. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
Phase 3: Number of Subjects With Newly Occurring Clinically Notable Vital Sign Abnormalities [68] | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Newly occurring clinically notable changes was defined as subjects not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: low/high systolic blood pressure (SBP): <= 90 millimeters of mercury(mmHg) with decrease from baseline of >= 20mmHg or >= 160mmHg with increase from baseline of >= 20mmHg, low/high diastolic blood pressure (DBP): <= 50mmHg with decrease from baseline of >= 15mmHg or >= 100mmHg with increase from baseline of >= 15mmHg, low/high pulse: <= 50 beats/min with decrease from baseline of >= 15 beats/min or >= 120 beats/min with increase from baseline of >= 15 beats/min, low/high temperature: <= 36 degree Celsius (deg C) or >= 37.5 deg C. Safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)
|
||||||||||||||||||||||||||||||||||||||||||||
Notes [68] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Phase 3: Number of Subjects With Newly Occurring Clinically Notable Electrocardiogram (ECG) Values [69] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Newly occurring clinically notable changes was defined as subjects not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: heart rate- decrease from baseline > 25% and to a value < 50 and increase from baseline > 25% and to a value > 100. QT interval- new > 450 (millisecond) msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec. QTcF- new > 450 msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [69] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Phase 3: Number of Subjects With Shift From Baseline to Worst Change from Baseline in Visual Acuity Logarithm of the Minimum Angle of Resolution (LogMAR) Score [70] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Visual acuity was measured using the Snellen visual acuity conversion chart. This was determined by establishing the smallest optotypes that could be identified correctly by the subject at a given observation distance. Snellen visual acuity was reported as a Snellen fraction (m/M) in which the numerator (m) indicated the test distance and the denominator (M) indicated the distance at which the gap of the equivalent Landolt ring subtends 1 minute of arc. The LogMAR score was calculated as – log(m/M). The maximum increase in score of <= 0, 0 to < 0.1, 0.1 to < 0.2, 0.2 to < 0.3 and >=0.3 relative to baseline in LogMAR were reported in this endpoint. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received.Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [70] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Phase 3: Number of Subjects With Shifts in Left Ventricular Ejection Fraction (LVEF) From Baseline to Maximum Grade On-treatment [71] | ||||||||||||||||||||||||||||||||
End point description |
Left ventricular ejection fraction (LVEF) abnormalities were defined according to CTCAE version 4.03 where Grade 0: Non-missing value below Grade 2, Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and < -20%, Grade 3: LVEF between 20% and 39% or absolute change from baseline <= -20%, Grade 4: LVEF lower than 20%. Categories with at least 1 non-zero data values showing any shift in Grade from baseline to 1 day after dose 1 (post-baseline) were reported. Subjects whose grade category was unchanged (e.g. Grade 0 to Grade 0) were not reported. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)
|
||||||||||||||||||||||||||||||||
Notes [71] - 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: Only descriptive data was planned to be analysed. |
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||
End point title |
Site of Metastases | |||||||||||||||||||||||||||||||||||
End point description |
Number of subjects with different sites of metastases were reported in this outcome measure. One subject may have more than one site of metastases. For CSLI: all subjects who received at least 1 dose of study drug and had at least 1 post treatment assessment, which may include death. For the randomised Phase 3 portion of the study: consisted of all randomised subjects.
|
|||||||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||||||||||||||||
End point timeframe |
At baseline
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
AEs = from initiation of study drug through 30 days after last dose of study drug. CSLI: maximum treatment exposure (MTE) of 280 weeks; Phase 3-Triplet: MTE of 277.4 Weeks; Phase 3- Doublet: MTE of 268 Weeks; Phase 3- Control: MTE of 108 Weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable signs,symptoms, or medical conditions that occur after subject's signed informed consent has been obtained. The safety set consisted of all subjects who received at least 1 dose of study drug & had at least 1 post-treatment assessment,which may have included death.
|
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Combined Safety Lead-in
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Reporting group description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 3: Triplet Arm
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Reporting group description |
Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 3: Doublet Arm
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Reporting group description |
Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 3:Control Arm
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Reporting group description |
Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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. | |||
Total number of deaths is reported for safety set under Adverse Events section. However, actual number of deaths were, for combined safety lead-in: 30; for Phase 3: Triplet arm: 209; for Phase 3: Doublet arm: 193 and for Phase 3: Control arm: 198. |