Clinical Trial Results:
RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAS-102 PLUS BEST SUPPORTIVE CARE (BSC) VERSUS PLACEBO PLUS BSC IN PATIENTS WITH METASTATIC COLORECTAL CANCER REFRACTORY TO STANDARD CHEMOTHERAPIES
Summary
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EudraCT number |
2012-000109-66 |
Trial protocol |
GB DE SE AT ES IE CZ BE IT |
Global end of trial date |
23 May 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Jun 2017
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First version publication date |
01 Jun 2017
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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 |
TPU-TAS-102-301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01607957 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Taiho Oncology, Inc.
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Sponsor organisation address |
101 Carnegie Center, Suite 101, Princeton, United States, NJ 08540
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Public contact |
Robert Winkler, MD, Taiho Oncology, Inc., 001 609/455.3893, rwinkler@taihooncology.com
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Scientific contact |
Robert Winkler, MD, Taiho Oncology, Inc., 001 609/455.3893, rwinkler@taihooncology.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 |
31 Jan 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jan 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
23 May 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Objectives: To compare the following endpoints for the TAS-102 (experimental) arm with the placebo (control) arm in patients with refractory metastatic colorectal cancer:
Primary
Overall survival (OS)
Key Secondary
Progression-free survival (PFS)
Safety and tolerability
Other Secondary
Time to treatment failure (TTF)
Overall response rate (ORR)
Disease control rate (DCR)
Duration of response (DR)
Subgroup analysis by KRAS status on OS and PFS
Exploratory (Pharmacokinetic assessments performed at selected sites)
To explore the effect of intrinsic and extrinsic factors on the pharmacokinetics (PK) of TAS-102
To explore the relationship between plasma concentrations of TAS-102 components (FTD and TPI)
and safety and efficacy parameters
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Protection of trial subjects |
The study was conducted in accordance with Good Clinical Practices (GCP), ICH Guidelines, the ethical principles that have their origin in the Declaration of Helsinki, and all applicable regulatory requirements.
The Investigator (according to applicable regulatory requirements) or a person designated by the Investigator and under the Investigator’s responsibility fully informed patients of all pertinent aspects of the clinical trial. All participants were informed to the fullest extent possible about the study in a language and in terms they are able to understand.
Prior to participation in the trial, the written ICF was signed and personally dated by the patient or by the patient’s legal representative and by the person who conducted the ICF discussion. A copy of the signed and dated ICF was provided to the patient. The ICF used had had prior approval by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
An independent data monitoring committee (DMC) monitored the safe conduct of the study.
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Background therapy |
- | ||
Evidence for comparator |
A placebo-controlled design was selected for this study since, at the time the study was initiated, there were no standard therapies for patients with metastatic colorectal cancer who had been previously treated with fluoropyrimidines, oxaliplatin, irinotecan, monoclonal anti-VEGF and anti-EGFR antibodies for KRAS wild-type patients, and had become refractory or intolerant to those chemotherapies. Regorafenib became authorised for the treatment of patients with metastatic colorectal cancer in all participating RECOURSE countries (Australia, EU, Japan and the US) only after most of the study enrollment was complete (>80%). Patients in both the TAS-102 and placebo treatment groups received best supportive care in addition to study medication. | ||
Actual start date of recruitment |
17 Jun 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
12 Months | ||
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 |
Sweden: 6
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Country: Number of subjects enrolled |
United Kingdom: 9
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Country: Number of subjects enrolled |
Austria: 20
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Country: Number of subjects enrolled |
Spain: 112
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Country: Number of subjects enrolled |
Belgium: 64
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Country: Number of subjects enrolled |
Czech Republic: 4
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Country: Number of subjects enrolled |
France: 50
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Country: Number of subjects enrolled |
Germany: 22
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Country: Number of subjects enrolled |
Ireland: 8
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Country: Number of subjects enrolled |
Italy: 108
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Country: Number of subjects enrolled |
Australia: 32
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Country: Number of subjects enrolled |
United States: 99
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Country: Number of subjects enrolled |
Japan: 266
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Worldwide total number of subjects |
800
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EEA total number of subjects |
403
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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) |
448
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From 65 to 84 years |
352
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85 years and over |
0
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Recruitment
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Recruitment details |
800 patients were randomized at a total of 101 study centers in 13 countries United States (21), Japan (20), Spain (11), Italy (9), Germany (8), Belgium (6), France (6), Australia (5), United Kingdom (5), Austria (4), Ireland (3), Sweden (2), Czech Republic (1). The first patient was randomized on 17 June 2012 and the last on 08 October 2013. | |||||||||||||||
Pre-assignment
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Screening details |
A total of 1002 patients provided signed informed consent for participation in the study. Of these, 800 were randomized and 202 (20%) did not meet eligibility criteria and were not randomised (ie, screen failures). | |||||||||||||||
Period 1
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Period 1 title |
Baseline Period
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Investigator, Monitor, Subject | |||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Experimental Arm | |||||||||||||||
Arm description |
TAS-102 plus Best supportive care (BSC) | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
TAS-102
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Investigational medicinal product code |
TAS-102
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Other name |
Lonsurf
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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 |
TAS-102 was supplied as an immediate-release film coated tablet in 2 strengths (expressed as FTD (trifluridine) content):
• 15-mg white, round tablet containing 15 mg FTD and 7.065 mg TPI (tipiracil hydrochloride) as active ingredients.
• 20-mg pale-red, round tablet containing 20 mg FTD and 9.420 mg TPI as active ingredients.
TAS-102 dosing was based on body surface area (BSA). The starting dose was 35 mg/m2/dose administered twice daily (BID) after morning and evening meals for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest (1 treatment cycle), repeated every 4 weeks.
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Arm title
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Control Arm | |||||||||||||||
Arm description |
Placebo plus best supportive care (BSC) | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
NA
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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 |
Manufactured to look identical to the TAS-102 15-mg (white, round) and 20-mg (pale-red, round) tablets.
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Period 2
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Period 2 title |
On-treatment period
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Is this the baseline period? |
No | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||||||||
Blinding implementation details |
TAS-102 tablets (15-mg / 20-mg) and the corresponding placebo tablets were identical in appearance and were packaged in identical containers. Unblinding of the study treatment by the Investigator was not to occur unless needed to manage a patient’s medical condition. In this emergency, the Investigator could unblind the patient by calling the IWRS to obtain the patient’s treatments. If unblinding occurred, the Investigator was not to disclose the unblinding information.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Experimental arm | |||||||||||||||
Arm description |
TAS-102 plus Best supportive care (BSC) | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
TAS-102
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Investigational medicinal product code |
TAS-102
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Other name |
Lonsurf
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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 |
TAS-102 was supplied as an immediate-release film coated tablet in 2 strengths (expressed as FTD content):
• 15-mg white, round tablet containing 15 mg FTD and 7.065 mg TPI as active ingredients.
• 20-mg pale-red, round tablet containing 20 mg FTD and 9.420 mg TPI as active ingredients.
TAS-102 dosing was based on body surface are (BSA). The starting dose was 35 mg/m2/dose administered twice daily (BID) after morning and evening meals for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest (1 treatment cycle), repeated every 4 weeks.
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Arm title
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Control arm | |||||||||||||||
Arm description |
Placebo plus best supportive care (BSC) | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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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 |
Manufactured to look identical to the TAS-102 15-mg (white, round) and 20-mg (pale-red, round) tablets.
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Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Number of subjects starting the on-treatment period does not include 1 patient in each arm (TAS-102 and placebo) that was not treated. |
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Baseline characteristics reporting groups
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Reporting group title |
Experimental Arm
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Reporting group description |
TAS-102 plus Best supportive care (BSC) | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control Arm
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Reporting group description |
Placebo plus best supportive care (BSC) | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Experimental Arm
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Reporting group description |
TAS-102 plus Best supportive care (BSC) | ||
Reporting group title |
Control Arm
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Reporting group description |
Placebo plus best supportive care (BSC) | ||
Reporting group title |
Experimental arm
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Reporting group description |
TAS-102 plus Best supportive care (BSC) | ||
Reporting group title |
Control arm
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Reporting group description |
Placebo plus best supportive care (BSC) |
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End point title |
Overall Survival | ||||||||||||
End point description |
Tumour assessments were performed throughout the study based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, 2009. Computed tomography (CT) scans were performed at the end of every 8 weeks until disease progression. If a patient discontinued study medication for reasons other than radiologic disease progression (eg, with intolerable side effects), the patient was followed for tumour response until radiologic disease progression or initiation of new anticancer therapy (whichever occurred first). All patients were followed for survival at scheduled 8-week time intervals until death. Patients were followed until 12 months after the first dose of study medication for the last patient randomised, even if consent for study participation had been withdrawn.
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End point type |
Primary
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End point timeframe |
Overall survival data: 24 January 2014 (observation of the 571st death in the study)
The time from the date of randomization to the death date.
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Statistical analysis title |
Overall Survival | ||||||||||||
Comparison groups |
Experimental arm v Control arm
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Number of subjects included in analysis |
798
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||
Method |
Stratified log-rank test p-value | ||||||||||||
Confidence interval |
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Notes [1] - (1-sided and 2-sided) |
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End point title |
Progression-Free Survival | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
All clinical data except overall survival: 31 January 2014
The time (in months) from the date of randomization until the date of the investigator-assessed radiological disease progression or death due to any cause.
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Statistical analysis title |
Progression-Free Survival | ||||||||||||
Comparison groups |
Experimental arm v Control arm
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Number of subjects included in analysis |
798
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Stratified log-rank test p-value | ||||||||||||
Confidence interval |
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Notes [2] - (1-sided and 2-sided) |
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End point title |
Safety and Tolerability | |||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
All clinical data except overall survival: 31 January 2014
The time from when patient signs ICF through the period of patient follow-up (30 days after the last dose of study medication or until the start of new antitumor therapy, whichever is earlier)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
AEs will be reported from the time a patient signs informed consent through the period of patient follow-up (30 days after the last dose of study medication or until the start of new antitumor therapy,
whichever is earlier).
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Adverse event reporting additional description |
Document all AEs in the source documents. Documentation should include onset and resolution/stabilization dates, severity/grade, relationship to study medication, and outcome
of the event. All AEs should be entered in the CRF within 10 business days or as soon as possible from the time the Investigator first becomes aware of them.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16
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Reporting groups
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Reporting group title |
Experimental Arm
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Reporting group description |
TAS-102 plus Best supportive care (BSC) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control Arm
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Reporting group description |
Placebo plus best supportive care (BSC) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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28 Mar 2012 |
• v1.0 - ROW, v2.0 Japan
• Names of Sponsor’s Medical Monitors updated/added.
• Clarification of the following: stratification variables; duration of survival
follow-up; duration of baseline period; definition of end of treatment;
definition of non-target lesions; definition of best overall response; definition
of population evaluable for tumour response; and size of population for PK
analysis.
• Modification of Inclusion Criterion #8 to specify that verification of adequate
organ function should be based on laboratory data obtained within 7 days
prior to Day 1 of Cycle 1; and specified an exception to requirement of total
serum bilirubin of ≤1.5 mg/dL (ie, except for Grade 1 hyperbilirubinaemia
due solely to a medical diagnosis of Gilbert’s syndrome).
• Addition of Exclusion Criterion #1j for patients with autoimmune disorders
and/or requiring immunosuppressive therapy
• Specified requirement for fractionation (direct/indirect) in case of elevation
of total bilirubin. |
||
22 Apr 2012 |
• v2.0 ROW, v3.0 Japan
• Addition of mobile phone number of Medical Monitor for Japan.
• Removal of carbon dioxide from required serum chemistry tests. |
||
13 Nov 2012 |
• v3.0 ROW, v4.0 Japan, v4.0 Sweden, v5.0 Germany
• Addition of generic name and updated chemical name for TPI
• Clarification of timing of end of treatment assessments of ECG, urinalysis,
and tumour measurements.
• Modification of Exclusion Criterion #4 regarding unresolved toxicities
associated with prior therapies.
• Addition of a caution statement when using human thymidine analogues
concomitantly with TAS-102.
• Clarification of procedures to be followed in case of need to break the study
blind. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
NA |