Clinical Trial Results:
An Open label Randomized Multi-Centre Exploratory Phase II Study to Evaluate the Efficacy and Safety of the Combination of Panitumumab with FOLFOX 4 Chemotherapy or Panitumumab with FOLFIRI Chemotherapy in Subjects with Wild-Type KRAS Colorectal Cancer and Liver-only Metastases
Summary
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EudraCT number |
2008-006766-28 |
Trial protocol |
ES |
Global end of trial date |
31 Mar 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Dec 2018
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First version publication date |
14 Dec 2018
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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 |
TTD-08-04
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00885885 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
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Sponsor organisation address |
Téllez 30, Madrid, Spain, 28007
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Public contact |
Inmaculada Ruiz Mena, Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), 0034 913788275, ttd@ttdgroup.org
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Scientific contact |
Inmaculada Ruiz Mena, Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), 0034 913788275, ttd@ttdgroup.org
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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 |
26 May 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Nov 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Mar 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To compare the objective response rate (ORR) over the entire treatment period when panitumumab was administered in combination with either FOLFOX 4 or FOLFIRI chemotherapy as 1st line treatment in subjects with previously untreated KRAS Wild-Type colorectal cancer (mCRC) and liver-only metastases. To determine the optimal combination (panitumumab + FOLFOX 4 chemotherapy or panitumumab + FOLFIRI chemotherapy) based on efficacy and tolerability for further clinical trials in this population.
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Protection of trial subjects |
Treatment dose was adjusted in terms of adverse events. G-CSF as prophylaxis was not recommended; G-CSF could be used therapeutically at the Investigator’s discretion in patients with serious neutropenic complications. The use of topical, oral, and intravenous antibiotics to treat skin- and nail-related toxicities was allowed at the Investigator’s discretion.
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Background therapy |
None. | ||
Evidence for comparator |
While there have been few prospective studies of systemic chemotherapy in patients with non-resectable hepatic metastases, it seems clear that the use of FOLFOX and FOLFIRI combination chemotherapy regimens with biological therapies, especially EGFR inhibitors, can increase the response rate | ||
Actual start date of recruitment |
14 May 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 80
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Worldwide total number of subjects |
80
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EEA total number of subjects |
80
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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) |
45
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From 65 to 84 years |
35
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85 years and over |
0
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Recruitment
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Recruitment details |
80 patients were included; 3 of them did not receive any study treatment. The safety population included 38 patients in the Panitumumab + FOLFOX-4 arm and 39 patients in the Panitumumab + FOLFIRI arm. This was a national study with all patients being included at 15 Spanish sites | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Key inclusion criteria: Male or female > 18 years of age, histologically confirmed adenocarcinoma of the colon or rectum with liver-only metastases, no major contraindication to liver surgery, wild-type KRAS. 103 patients were assessed for eligibility, of whom 21 did not meet all the inclusion criteria and 2 met one of the exclusion criteria. | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Blinding implementation details |
Not applicable.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Panitumumab + FOLFOX 4 | |||||||||||||||||||||||||||||||||
Arm description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and commencement of FOLFOX 4 chemotherapy. FOLFOX 4 was administered every 2 weeks (± 3 days) as follows: Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Panitumumab
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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 |
The starting panitumumab dose was 6 mg/kg. The panitumumab dose was calculated based on the subject’s body weight at baseline (i.e. Cycle 1) and was not re-calculated unless the actual body weight changed by at least 10% relative to baseline. Panitumumab was diluted in 100 mL of pyrogen-free 0.9% sodium chloride solution. The maximum concentration of the diluted solution to be infused was not to exceed 10 mg/mL; if necessary, the volume of normal saline could be increased. Panitumumab was administered intravenously using an infusion pump.
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Investigational medicinal product name |
FOLFOX 4
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion, Injection
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Routes of administration |
Intravenous use, Intravenous bolus use
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Dosage and administration details |
FOLFOX 4 was administered as follows:
Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion.
Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22-hour (± 1 hour) continuous infusion.
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Arm title
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Panitumumab + FOLFIRI | |||||||||||||||||||||||||||||||||
Arm description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and FOLFIRI chemotherapy. FOLFIRI was administered every 2 weeks (± 3 days), on day 1 of each cycle, as follows: Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes (± 15 minutes). Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours (± 15 minutes) during Irinotecan infusion, but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as a 46 hour (± 2-hour) continuous infusion. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Panitumumab
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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 |
The starting panitumumab dose was 6 mg/kg. The panitumumab dose was calculated based on the subject’s body weight at baseline (i.e. Cycle 1) and was not re-calculated unless the actual body weight changed by at least 10% relative to baseline. Panitumumab was diluted in 100 mL of pyrogen-free 0.9% sodium chloride solution. The maximum concentration of the diluted solution to be infused was not to exceed 10 mg/mL; if necessary, the volume of normal saline could be increased. Panitumumab was administered intravenously using an infusion pump.
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Investigational medicinal product name |
FOLFIRI
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion, Injection
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Routes of administration |
Intravenous bolus use , Intravenous use
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Dosage and administration details |
FOLFIRI was administered on day 1 of each cycle as follows:
Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes ± 15 minutes. Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours ± 15 minutes during irinotecan infusion. but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as 46-hour ± 2-hour continuous infusion.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 3 patients in Panitumumab + FOLFIRI arm were withdrawn from the study without receiving study treatment: 1 patient had divergent KRAS results and 2 patients had metastases in locations other than the liver. These 3 patients are not included in the presentations of Subject disposition, Baseline characteristics, End points and Adverse events. |
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Period 2
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Period 2 title |
Treatment period
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Blinding implementation details |
Not applicable.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Panitumumab + FOLFOX 4 | |||||||||||||||||||||||||||||||||
Arm description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and commencement of FOLFOX 4 chemotherapy. FOLFOX 4 was administered every 2 weeks (± 3 days) as follows: Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22-hour (± 1 hour) continuous infusion. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Panitumumab
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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 |
The starting panitumumab dose was 6 mg/kg. The panitumumab dose was calculated based on the subject’s body weight at baseline (i.e. Cycle 1) and was not re-calculated unless the actual body weight changed by at least 10% relative to baseline. Panitumumab was diluted in 100 mL of pyrogen-free 0.9% sodium chloride solution. The maximum concentration of the diluted solution to be infused was not to exceed 10 mg/mL; if necessary, the volume of normal saline could be increased. Panitumumab was administered intravenously using an infusion pump.
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Investigational medicinal product name |
FOLFOX 4
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion, Injection
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Routes of administration |
Intravenous use, Intravenous bolus use
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Dosage and administration details |
FOLFOX 4 was administered as follows:
Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion.
Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22-hour (± 1 hour) continuous infusion.
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Arm title
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Panitumumab + FOLFIRI | |||||||||||||||||||||||||||||||||
Arm description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and FOLFIRI chemotherapy. FOLFIRI was administered every 2 weeks (± 3 days), on day 1 of each cycle, as follows: Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes ± 15 minutes. Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours ± 15 minutes during irinotecan infusion. but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as 46-hour ± 2 hour continuous infusion. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Panitumumab
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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 |
The starting panitumumab dose was 6 mg/kg. The panitumumab dose was calculated based on the subject’s body weight at baseline (i.e. Cycle 1) and was not re-calculated unless the actual body weight changed by at least 10% relative to baseline. Panitumumab was diluted in 100 mL of pyrogen-free 0.9% sodium chloride solution. The maximum concentration of the diluted solution to be infused was not to exceed 10 mg/mL; if necessary, the volume of normal saline could be increased. Panitumumab was administered intravenously using an infusion pump.
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Investigational medicinal product name |
FOLFIRI
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion, Injection
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Routes of administration |
Intravenous bolus use , Intravenous use
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Dosage and administration details |
FOLFIRI was administered on day 1 of each cycle as follows:
Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes ± 15 minutes. Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours ± 15 minutes during irinotecan infusion. but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as 46-hour ± 2-hour continuous infusion.
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Baseline characteristics reporting groups
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Reporting group title |
Panitumumab + FOLFOX 4
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and commencement of FOLFOX 4 chemotherapy. FOLFOX 4 was administered every 2 weeks (± 3 days) as follows: Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Panitumumab + FOLFIRI
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and FOLFIRI chemotherapy. FOLFIRI was administered every 2 weeks (± 3 days), on day 1 of each cycle, as follows: Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes (± 15 minutes). Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours (± 15 minutes) during Irinotecan infusion, but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as a 46 hour (± 2-hour) continuous infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Panitumumab + FOLFOX 4
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and commencement of FOLFOX 4 chemotherapy. FOLFOX 4 was administered every 2 weeks (± 3 days) as follows: Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. | ||
Reporting group title |
Panitumumab + FOLFIRI
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and FOLFIRI chemotherapy. FOLFIRI was administered every 2 weeks (± 3 days), on day 1 of each cycle, as follows: Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes (± 15 minutes). Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours (± 15 minutes) during Irinotecan infusion, but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as a 46 hour (± 2-hour) continuous infusion. | ||
Reporting group title |
Panitumumab + FOLFOX 4
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and commencement of FOLFOX 4 chemotherapy. FOLFOX 4 was administered every 2 weeks (± 3 days) as follows: Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22-hour (± 1 hour) continuous infusion. | ||
Reporting group title |
Panitumumab + FOLFIRI
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and FOLFIRI chemotherapy. FOLFIRI was administered every 2 weeks (± 3 days), on day 1 of each cycle, as follows: Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes ± 15 minutes. Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours ± 15 minutes during irinotecan infusion. but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as 46-hour ± 2 hour continuous infusion. | ||
Subject analysis set title |
Panitumumab + FOLFOX 4 (Safety Set)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects in the Panitumumab + FOLFOX 4 arm who received at least one dose of Panitumumab or FOLFOX 4 chemotherapy.
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Subject analysis set title |
Panitumumab + FOLFIRI (Safety Set)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects in the Panitumumab + FOLFIRI arm who received at least one dose of Panitumumab or FOLFIRI chemotherapy.
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Subject analysis set title |
Panitumumab + FOLFOX 4 (WT RAS Set)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects in the Panitumumab + FOLFOX 4 (Safety Set) analysis set whose RAS mutational status was evaluated and was found to be wild type.
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Subject analysis set title |
Panitumumab + FOLFIRI (WT RAS Set)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects in the Panitumumab + FOLFIRI (Safety Set) analysis set whose RAS mutational status was evaluated and was found to be wild type.
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Subject analysis set title |
All subjects (Safety Set)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects who received at least one dose of Panitumumab or FOLFOX 4 chemotherapy or FOLFIRI chemotherapy.
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Subject analysis set title |
All subjects (WT RAS Set)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects in the All patients (Safety Set) analysis set whose RAS mutational status was evaluated and was found to be wild type.
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End point title |
Overall response rate | |||||||||||||||||||||||||
End point description |
Complete response or partial response (modified RECIST)
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End point type |
Primary
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End point timeframe |
From treatment start to the decision to end both treatments (Panitumumab and chemotherapy).
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Statistical analysis title |
Chi-square test | |||||||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFIRI (Safety Set) v Panitumumab + FOLFOX 4 (Safety Set)
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Number of subjects included in analysis |
77
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||||||||||||||||||
P-value |
= 0.5012 | |||||||||||||||||||||||||
Method |
Chi-squared | |||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||
Statistical analysis title |
Chi-square test | |||||||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (WT RAS Set) v Panitumumab + FOLFIRI (WT RAS Set)
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Number of subjects included in analysis |
53
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||||||||||||||||||
P-value |
= 0.6909 | |||||||||||||||||||||||||
Method |
Chi-squared | |||||||||||||||||||||||||
Confidence interval |
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End point title |
Hepatic resection rate | |||||||||||||||||||||||||
End point description |
Proportion of subjects with R0 (with tumour free margins and without evidence of microscopic and macroscopic residual disease) and R1 (microscopic residual margin) resections
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End point type |
Secondary
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End point timeframe |
From treatment start to the decision to end both treatments (Panitumumab and chemotherapy).
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Statistical analysis title |
Fisher's exact test | |||||||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (Safety Set) v Panitumumab + FOLFIRI (Safety Set)
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Number of subjects included in analysis |
76
|
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Analysis specification |
Pre-specified
|
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Analysis type |
equivalence | |||||||||||||||||||||||||
P-value |
= 0.2853 | |||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||
Statistical analysis title |
Fisher's exact test | |||||||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (WT RAS Set) v Panitumumab + FOLFIRI (WT RAS Set)
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Number of subjects included in analysis |
53
|
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Analysis specification |
Pre-specified
|
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Analysis type |
equivalence | |||||||||||||||||||||||||
P-value |
= 0.0378 | |||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||
Confidence interval |
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End point title |
Time to resection | ||||||||||||||||||||
End point description |
Time to surgical resection in subjects who underwent metastatic surgery.
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End point type |
Secondary
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End point timeframe |
From enrolment to the date of surgical resection.
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Statistical analysis title |
Log-rank test | ||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (Safety Set) v Panitumumab + FOLFIRI (Safety Set)
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Number of subjects included in analysis |
40
|
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Analysis specification |
Pre-specified
|
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Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.2832 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
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End point title |
Duration of response | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From first confirmed response to first observed disease progression or death (whichever came first).
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Statistical analysis title |
Log-rank test | ||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (Safety Set) v Panitumumab + FOLFIRI (Safety Set)
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Number of subjects included in analysis |
29
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Analysis specification |
Pre-specified
|
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.7588 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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End point title |
Time to response | ||||||||||||||||||||
End point description |
For subjects with a best response of stable disease, the date of their last evaluable radiographic assessment was recorded. For subjects with a best response of progressive disease, the date of their last evaluation was recorded.
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End point type |
Secondary
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End point timeframe |
From treatment start to first confirmed complete response or partial response.
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Statistical analysis title |
Log-rank test | ||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (Safety Set) v Panitumumab + FOLFIRI (Safety Set)
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Number of subjects included in analysis |
73
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Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.842 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Statistical analysis title |
Log-rank test | ||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (WT RAS Set) v Panitumumab + FOLFIRI (WT RAS Set)
|
||||||||||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.9926 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
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End point title |
Time to treatment failure | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From enrolment to treatment failure.
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Statistical analysis title |
Log-rank test | ||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (Safety Set) v Panitumumab + FOLFIRI (Safety Set)
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Number of subjects included in analysis |
77
|
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Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.7027 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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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 |
From treatment start to first observed disease progression or death (whichever came first).
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Statistical analysis title |
Log-rank test | ||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (Safety Set) v Panitumumab + FOLFIRI (Safety Set)
|
||||||||||||||||||||
Number of subjects included in analysis |
77
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.7297 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Statistical analysis title |
Log-rank test | ||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (WT RAS Set) v Panitumumab + FOLFIRI (WT RAS Set)
|
||||||||||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.3047 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
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End point title |
Overall survival | ||||||||||||||||||||
End point description |
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End point type |
Secondary
|
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End point timeframe |
From treatment start to death.
|
||||||||||||||||||||
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Statistical analysis title |
Log-rank test | ||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (Safety Set) v Panitumumab + FOLFIRI (Safety Set)
|
||||||||||||||||||||
Number of subjects included in analysis |
77
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.9657 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Statistical analysis title |
Log-rank test | ||||||||||||||||||||
Comparison groups |
Panitumumab + FOLFOX 4 (WT RAS Set) v Panitumumab + FOLFIRI (WT RAS Set)
|
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Number of subjects included in analysis |
53
|
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Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.8237 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
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End point title |
Depth of response | ||||||||||||||||||||
End point description |
Maximum tumour size decrease (%) with respect to baseline measurements (sum of lesion diameters) during treatment, prior to hepatic surgery.
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End point type |
Secondary
|
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End point timeframe |
From treatment start to hepatic surgery.
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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 |
From day -7 during the screening period to 30 ± 3 days after the end of study treatment
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
|
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Reporting group title |
Panitumumab + FOLFOX 4
|
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and commencement of FOLFOX 4 chemotherapy. FOLFOX 4 was administered every 2 weeks (± 3 days) as follows: Day 1: Oxaliplatin (85 mg/m2, intravenous infusion) and folinic acid (200 mg/m2, intravenous infusion), both given over 120 minutes (± 15 minutes) at the same time; followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2, intravenous infusion), given as a 22 hour (± 1 hour) continuous infusion. Day 2: Folinic acid (200 mg/m2, intravenous infusion), given over 120 minutes (± 15 minutes); followed by 5-FU (400 mg/m2, intravenous bolus), given over 2 to 4 minutes; followed by 5-FU (600 mg/m2 intravenous infusion), given as a 22-hour (± 1 hour) continuous infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Panitumumab + FOLFIRI
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Reporting group description |
Panitumumab was administered by intravenous infusion on day 1 of each cycle, just prior to administration of chemotherapy. A treatment cycle was defined as the 14 day period following treatment with panitumumab and FOLFIRI chemotherapy. FOLFIRI was administered every 2 weeks (± 3 days), on day 1 of each cycle, as follows: Irinotecan (180 mg/m2, intravenous infusion) was administered over 90 minutes ± 15 minutes. Folinic acid (400 mg/m2, intravenous infusion) was administered over 2 hours ± 15 minutes during irinotecan infusion. but without mixing. Immediately afterwards, a 5-FU intravenous bolus (400 mg/m2) was administered and a 5-FU intravenous infusion (2400 mg/m2) was given as 46-hour ± 2-hour continuous infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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15 Dec 2008 |
Removal of "Administrative decision by the study sponsor" as a reason for withdrawal of patients from study treatment or from observation. In conjunction with this Amendment, the Patient Information Sheet and Informed Consent Form were updated. Notably, a Patient Information Sheet was created for the optional new marker study. These changes were made in response to feedback from the Independent Ethics Committees involved in this study. |
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03 Mar 2009 |
Update to the Patient Information Sheet based on new information regarding the administration/safety of one of the study treatments (Panitumumab). |
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15 Mar 2010 |
Addition of 2 new secondary objectives: (1) to assess the effects of the study treatments in terms of overall survival and (2) to assess hypomagnesaemia as a predictor of response to study treatment. Modification of the study endpoints to reflect the changes in the secondary objectives. Change of definition of the adjuvant treatment regimen to 12 complete cycles (including neoadjuvant treatment cycles received before surgery) of the allocated study treatment regimen. Correction of error in age of subjects eligible for enrollment. Inclusion criteria: metastases permitted to be resectable or non-resectable (not only non-resectable). Clarification of the definition of delay to surgery due to study treatment-related toxicity. Definition of end of study modified. Specification of version of RECIST to be used. Information regarding storage and handling of Panitumumab updated. Amendment/updating of the objectives of the parallel study of genetic factors. |
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24 Nov 2010 |
Inclusion criteria/screening procedures: removal of the requirement for KRAS gene analysis to be performed by the designated central laboratory (thus permitting it to be performed locally). The reason for this was minimize the delay in starting treatment in eligible patients, since Spanish hospitals perform a KRAS analysis as part of routine clinical practice in patients with metastatic colorectal cancer. |
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28 Feb 2011 |
Update to the "SAFETY - POTENTIAL RISKS AND DISCOMFORT" section of the Patient Information Sheet based on new information regarding the safety of combination treatment with Panitumumab plus chemotherapy. |
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15 May 2013 |
Change of Principal Investigator at 2 of the study sites. Creation of an addendum to the Patient Information Sheet detailing new safety information, which all patients included in the study were required to sign. This was because the phase III PRIME (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy) study had shown that patients with RAS mutations in regions other than codon 2 who received Panitumumab plus FOLFOX had lower progression-free survival and overall survival compared to patients treated with FOLFOX alone. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |