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Safety and Efficacy Study of mFOLFOX6 + Panitumumab Combination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Participants With Chemotherapy-naïve Unresectable Advanced Recurrent Colorectal Carcinoma (SAPPHIRE)

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ClinicalTrials.gov Identifier: NCT02337946
Recruitment Status : Completed
First Posted : January 14, 2015
Results First Posted : March 1, 2019
Last Update Posted : September 10, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Colorectal Carcinoma
Intervention Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab
Enrollment 164
Recruitment Details Participants took part in the study at 72 investigative sites in Japan from 16 October 2014 to 31 March 2017 (as Primary Completion Date). After that, overall study completion of this study was occurred on 31 August 2017.
Pre-assignment Details Participants with a diagnosis of colorectal carcinoma were enrolled to receive protocol treatment (1) up to cycle 6 followed by randomization, received 1 out of 2 treatments from protocol treatment (2) group A and group B.
Arm/Group Title Protocol Treatment 1 Protocol Treatment Period 2: Group A Protocol Treatment Period 2: Group B
Hide Arm/Group Description Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1. Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance. Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Period Title: Protocol Treatment 1 Period
Started 164 0 0
Completed 114 0 0
Not Completed 50 0 0
Reason Not Completed
Adverse Event             7             0             0
Major Protocol Deviation             1             0             0
Voluntary Withdrawal             6             0             0
Lack of Efficacy             15             0             0
Death During Protocol Treatment             3             0             0
Surgery Aimed at Curative Resection             9             0             0
Did not Meet Entrance Criteria             1             0             0
Reason not specified             8             0             0
Period Title: In-between Period
Started 114 0 0
Completed 113 0 0
Not Completed 1 0 0
Reason Not Completed
Without Informed Consent             1             0             0
Period Title: Protocol Treatment 2 Period
Started 0 56 57
Safety Population 0 56 54
Completed 0 5 7
Not Completed 0 51 50
Reason Not Completed
Adverse Event             0             9             9
Voluntary Withdrawal             0             3             1
Lack of Efficacy             0             29             29
Death During Protocol Treatment             0             1             0
Surgery Aimed at Curative Resection             0             5             7
Reason not specified             0             4             4
Arm/Group Title Entire Study Population
Hide Arm/Group Description Participants who received Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by either Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance or Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Baseline Participants 164
Hide Baseline Analysis Population Description
Enrolled participants included all participants who were enrolled and received protocol treatment 1.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 164 participants
66.6  (10.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Female
55
  33.5%
Male
109
  66.5%
Race and Ethnicity Not Collected   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants
[1]
Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Japan Number Analyzed 164 participants
164
Histological Type of Adenocarcinoma  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Well differentiated adenocarcinoma
47
  28.7%
Moderately differentiated adenocarcinoma
91
  55.5%
Poorly differentiated adenocarcinoma
15
   9.1%
Mucinous adenocarcinoma
3
   1.8%
Other
8
   4.9%
Information on Primary Lesion: Single, Multiple or Unknown  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Single
120
  73.2%
Multiple
4
   2.4%
Unknown
40
  24.4%
Information on Primary Lesion: Primary Lesion Site   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Cecum Number Analyzed 124 participants
8
   6.5%
Ascending colon Number Analyzed 124 participants
15
  12.1%
Transverse colon Number Analyzed 124 participants
10
   8.1%
Descending colon Number Analyzed 124 participants
4
   3.2%
Sigmoid colon Number Analyzed 124 participants
43
  34.7%
Rectosigmoid Number Analyzed 124 participants
12
   9.7%
Rectum Number Analyzed 124 participants
42
  33.9%
[1]
Measure Analysis Population Description: Primary tumor location data was collected/analyzed for 124 participants with multiple choices allowed, and total 134 data was available.
History of Surgery  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Had No History of Surgery
51
  31.1%
Had History of Surgery
113
  68.9%
History of Radiotherapy  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Had No History of Radiotherapy
163
  99.4%
Had History of Radiotherapy
1
   0.6%
History of Preoperative and/or Postoperative Adjuvant (Adj) Chemotherapy (CT)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Had No History of Pre/Postoperative Adj CT
151
  92.1%
Had History of Pre/Postoperative Adj CT
13
   7.9%
Number of Metastatic Organs at Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
0
3
   1.8%
1
72
  43.9%
≥2
89
  54.3%
Type of Metastatic Organs at Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Liver Number Analyzed 164 participants
119
  72.6%
Lung Number Analyzed 164 participants
57
  34.8%
Peritoneum Number Analyzed 164 participants
28
  17.1%
Lymph node Number Analyzed 164 participants
60
  36.6%
Bone Number Analyzed 164 participants
9
   5.5%
Adrenal gland Number Analyzed 164 participants
2
   1.2%
Other Number Analyzed 164 participants
13
   7.9%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [Cycle 1]   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
0
122
  74.4%
1
42
  25.6%
[1]
Measure Description: ECOG assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity but ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50 percent of waking hours), capable of all self-care but unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50 percent of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair.
Neuroblastoma Rat Sarcoma (NRAS) + Kirsten Rat Sarcoma (KRAS) Testing  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Mutant-type
10
   6.1%
Wild Type (WT)
152
  92.7%
Unknown
2
   1.2%
Worst Grade of Laboratory Tests/Clinical Findings During Protocol Treatment 1   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
None
103
  62.8%
Grade 2
21
  12.8%
Grade ≥3
40
  24.4%
[1]
Measure Description: Grade of Laboratory Tests/Clinical Findings was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 as follows: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe or medically significant but not immediately life threatening); Grade 4 (life-threatening consequences); Grade 5 (death related to Adverse Events (AE)).
Worst Grade of Peripheral Neuropathy During Protocol Treatment 1   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
None
100
  61.0%
Grade 1
51
  31.1%
Grade 2
12
   7.3%
Grade ≥3
1
   0.6%
[1]
Measure Description: Grade of Peripheral Neuropathy was evaluated based on NCI CTCAE version 4.03 as follows: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe or medically significant but not immediately life threatening); Grade 4 (life-threatening consequences); Grade 5 (death related to AE).
Number of Participants without Curative Resection During Protocol Treatment 1  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
164
 100.0%
Treatment Status for Protocol Treatment 1: Reduced or Not Reduced   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Reduced
59
  36.0%
Not Reduced
105
  64.0%
[1]
Measure Description: Treatment status was defined based on a presence or absence of any dose reduction.
Treatment Status for Protocol Treatment 1: Postponed or Not Postponed   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 164 participants
Postponed
121
  73.8%
Not Postponed
43
  26.2%
[1]
Measure Description: Treatment status was defined based on a presence or absence of any dose delays.
1.Primary Outcome
Title Progression-Free Survival Rate (PFS Rate) at 9 Months After Randomization
Hide Description PFS rate was defined as the gross percentage of participants who survived with no evidence of progression from the day of randomization (Day 0) until 9 months after Day 0. The presence/absence of progressive disease (PD) was determined based on imaging, consideration of clinical PD, or survival research results. PD based on response evaluation criteria in solid tumors (RECIST) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame Up to 9 months after randomization
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) was defined as all randomized participants.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 57
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
46.4
(38.1 to 54.9)
47.4
(39.1 to 55.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A, Group B
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of PFS rate between groups
Estimated Value 0.9
Confidence Interval (2-Sided) 95%
-17.2 to 19.0
Estimation Comments [Not Specified]
Other Statistical Analysis Agresti-Caffo method was used for estimation of 95% CI.
2.Secondary Outcome
Title Progression-Free Survival (PFS)
Hide Description The PFS is the period from the date of randomization (Day 0) until the date of judgment of progression from the date of randomization, or until death by all causes, whichever comes first. The presence/absence of progressive disease (PD) was determined based on imaging, consideration of clinical PD, or survival research results. PD based on response evaluation criteria in solid tumors (RECIST) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame Up to approximately 31 months
Hide Outcome Measure Data
Hide Analysis Population Description
FAS was defined as all randomized participants.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 57
Median (95% Confidence Interval)
Unit of Measure: months
9.1
(8.6 to 11.1)
9.3
(6.0 to 13.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A, Group B
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7349
Comments [Not Specified]
Method Regression, Multivariable Cox
Comments The Cox regression model was adjusted by stratification factors except for study sites.
Method of Estimation Estimation Parameter Adjusted Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.60 to 1.43
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from the day of randomization (Day 0) until death by all causes.
Time Frame Up to approximately 31 months
Hide Outcome Measure Data
Hide Analysis Population Description
FAS was defined as all randomized participants.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 57
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median and upper and lower limits of overall survival is not estimable at final analysis due to low number of participants with events.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A, Group B
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3485
Comments [Not Specified]
Method Regression, Multivariable Cox
Comments The Cox regression model was adjusted by stratification factors except for study sites.
Method of Estimation Estimation Parameter Adjusted Hazard Ratio (HR)
Estimated Value 1.41
Confidence Interval (2-Sided) 95%
0.69 to 2.88
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Response Rate (RR)
Hide Description RR was defined as the percentage of participants who had shown complete response (CR) or partial response (PR) as the best overall response in accordance with the RECIST 1.1 criteria after randomization. The best overall response was CR, followed by PR, stable disease (SD), progressive disease (PD), and not evaluable (NE). CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters as the best overall response after randomization., SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time Frame Up to approximately 31 months
Hide Outcome Measure Data
Hide Analysis Population Description
FAS was defined as all randomized participants.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 57
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
80.4
(68.0 to 88.8)
87.7
(76.4 to 94.2)
5.Secondary Outcome
Title Time to Treatment Failure (TTF)
Hide Description TTF was defined as the time from the day of randomization (Day 0) until the day of protocol treatment discontinuation determination, the day of PD decision during protocol treatment, or death from any cause, whichever came the earliest.
Time Frame Up to approximately 31 months
Hide Outcome Measure Data
Hide Analysis Population Description
FAS was defined as all randomized participants.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 57
Median (95% Confidence Interval)
Unit of Measure: months
8.1
(5.9 to 9.5)
6.1
(4.5 to 9.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A, Group B
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5901
Comments [Not Specified]
Method Regression, Multivariable Cox
Comments The Cox regression model was adjusted by stratification factors except for study sites.
Method of Estimation Estimation Parameter Multivariable Hazard Ratio (HR)
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.60 to 1.33
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Participants With Adverse Events
Hide Description Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.
Time Frame Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 54
Measure Type: Number
Unit of Measure: percentage of participants
100 100
7.Secondary Outcome
Title Percentage of Participants With Adverse Events by Severity Graded Using the Common Terminology Criteria for Adverse Events (CTCAE) Grade
Hide Description An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time Frame Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
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Hide Analysis Population Description
Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 54
Measure Type: Number
Unit of Measure: percentage of participants
Grade 1 0 0
Grade 2 19.6 27.8
Grade 3, 4 and 5 80.4 72.2
8.Secondary Outcome
Title Percentage of Participants With Grade 2 or Higher Peripheral Neuropathy
Hide Description Peripheral neuropathy was defined as events classified with a preferred term (PT) of "peripheral neuropathy" according to Standardized MedDRA Queries.
Time Frame Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 54
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
30.4
(19.8 to 43.4)
3.7
(0.3 to 13.3)
9.Secondary Outcome
Title Percentage of Participants With Grade 3 or Higher Skin Toxicity
Hide Description Skin toxicity was defined as events classified with an system organ class of "Skin and subcutaneous tissue disorders" or a preferred term of "paronychia".
Time Frame Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.
Arm/Group Title Group A Group B
Hide Arm/Group Description:
Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
Overall Number of Participants Analyzed 56 54
Measure Type: Number
Unit of Measure: percentage of participants
Skin and subcutaneous tissue disorders 17.9 18.5
Paronychia 7.1 9.3
Time Frame Up to approximately 34 months
Adverse Event Reporting Description At each visit the investigators had to record any occurrence of adverse events. Adverse events were any unfavorable or unintended sign (including clinically problematic abnormalities of laboratory test data), symptoms, or diseases that developed after the administration of a drug, irrespective of whether there was a causal relationship with the relevant treatment. Safety population included participants who received at least one dose of protocol treatment after randomization.
 
Arm/Group Title Group A Group B
Hide Arm/Group Description Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance. Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.
All-Cause Mortality
Group A Group B
Affected / at Risk (%) Affected / at Risk (%)
Total   2/56 (3.57%)      0/54 (0.00%)    
Hide Serious Adverse Events
Group A Group B
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   20/56 (35.71%)      18/54 (33.33%)    
Blood and lymphatic system disorders     
Febrile neutropenia † 1  4/56 (7.14%)  1/54 (1.85%) 
Neutropenia † 1  0/56 (0.00%)  1/54 (1.85%) 
Anaemia † 1  0/56 (0.00%)  1/54 (1.85%) 
Cardiac disorders     
Cardiac failure congestive † 1  0/56 (0.00%)  1/54 (1.85%) 
Ear and labyrinth disorders     
Vertigo positional † 1  0/56 (0.00%)  1/54 (1.85%) 
Gastrointestinal disorders     
Mechanical ileus † 1  0/56 (0.00%)  1/54 (1.85%) 
Duodenal ulcer haemorrhage † 1  1/56 (1.79%)  0/54 (0.00%) 
Enterocolitis haemorrhagic † 1  1/56 (1.79%)  0/54 (0.00%) 
Intestinal obstruction † 1  0/56 (0.00%)  1/54 (1.85%) 
Inguinal hernia † 1  1/56 (1.79%)  0/54 (0.00%) 
Stomatitis † 1  2/56 (3.57%)  1/54 (1.85%) 
Diarrhoea † 1  0/56 (0.00%)  2/54 (3.70%) 
Nausea † 1  1/56 (1.79%)  0/54 (0.00%) 
Colitis ischaemic † 1  1/56 (1.79%)  0/54 (0.00%) 
Anal fistula † 1  1/56 (1.79%)  0/54 (0.00%) 
Gastric ulcer haemorrhage † 1  0/56 (0.00%)  1/54 (1.85%) 
Ascites † 1  1/56 (1.79%)  0/54 (0.00%) 
Abdominal distension † 1  0/56 (0.00%)  1/54 (1.85%) 
Constipation † 1  0/56 (0.00%)  1/54 (1.85%) 
Vomiting † 1  0/56 (0.00%)  1/54 (1.85%) 
Proctalgia † 1  0/56 (0.00%)  1/54 (1.85%) 
General disorders     
Chest discomfort † 1  1/56 (1.79%)  0/54 (0.00%) 
Death † 1 [1]  1/56 (1.79%)  0/54 (0.00%) 
Pyrexia † 1  1/56 (1.79%)  0/54 (0.00%) 
Hepatobiliary disorders     
Hepatic failure † 1 [1]  1/56 (1.79%)  0/54 (0.00%) 
Cholangitis † 1  1/56 (1.79%)  0/54 (0.00%) 
Infections and infestations     
Pneumonia † 1  2/56 (3.57%)  0/54 (0.00%) 
Device related infection † 1  2/56 (3.57%)  0/54 (0.00%) 
Pelvic abscess † 1  0/56 (0.00%)  1/54 (1.85%) 
Biliary tract infection † 1  1/56 (1.79%)  0/54 (0.00%) 
Enteritis infectious † 1  0/56 (0.00%)  1/54 (1.85%) 
Urinary tract infection † 1  0/56 (0.00%)  1/54 (1.85%) 
Sepsis † 1  0/56 (0.00%)  1/54 (1.85%) 
Pulmonary tuberculosis † 1  1/56 (1.79%)  0/54 (0.00%) 
Injury, poisoning and procedural complications     
Femoral neck fracture † 1  0/56 (0.00%)  1/54 (1.85%) 
Heat illness † 1  0/56 (0.00%)  1/54 (1.85%) 
Investigations     
Nutritional condition abnormal † 1  0/56 (0.00%)  1/54 (1.85%) 
White blood cell count decreased † 1  1/56 (1.79%)  0/54 (0.00%) 
Amylase increased † 1  0/56 (0.00%)  1/54 (1.85%) 
Metabolism and nutrition disorders     
Decreased appetite † 1  3/56 (5.36%)  1/54 (1.85%) 
Dehydration † 1  1/56 (1.79%)  0/54 (0.00%) 
Musculoskeletal and connective tissue disorders     
Flank pain † 1  0/56 (0.00%)  1/54 (1.85%) 
Back pain † 1  0/56 (0.00%)  1/54 (1.85%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cancer pain † 1  0/56 (0.00%)  1/54 (1.85%) 
Nervous system disorders     
Epilepsy † 1  0/56 (0.00%)  1/54 (1.85%) 
Loss of consciousness † 1  1/56 (1.79%)  0/54 (0.00%) 
Transient ischaemic attack † 1  0/56 (0.00%)  1/54 (1.85%) 
Cerebral haemorrhage † 1  0/56 (0.00%)  1/54 (1.85%) 
Renal and urinary disorders     
Hydronephrosis † 1  1/56 (1.79%)  0/54 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Interstitial lung disease † 1  0/56 (0.00%)  1/54 (1.85%) 
Skin and subcutaneous tissue disorders     
Palmar-plantar erythrodysaesthesia syndrome † 1  0/56 (0.00%)  1/54 (1.85%) 
Vascular disorders     
Embolism † 1  1/56 (1.79%)  0/54 (0.00%) 
1
Term from vocabulary, MedDRA version 20.0
†
Indicates events were collected by systematic assessment
[1]
One treatment emergent death occurred during the treatment and is related to treatment.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Group A Group B
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   47/56 (83.93%)      45/54 (83.33%)    
Gastrointestinal disorders     
Stomatitis † 1  5/56 (8.93%)  5 5/54 (9.26%)  6
Nausea † 1  3/56 (5.36%)  3 3/54 (5.56%)  4
Vomiting † 1  4/56 (7.14%)  7 1/54 (1.85%)  1
General disorders     
Malaise † 1  4/56 (7.14%)  5 4/54 (7.41%)  4
Pyrexia † 1  4/56 (7.14%)  4 3/54 (5.56%)  3
Fatigue † 1  3/56 (5.36%)  3 0/54 (0.00%)  0
Immune system disorders     
Hypersensitivity † 1  6/56 (10.71%)  8 0/54 (0.00%)  0
Infections and infestations     
Paronychia † 1  14/56 (25.00%)  14 16/54 (29.63%)  16
Investigations     
Neutrophil count decreased † 1  18/56 (32.14%)  44 15/54 (27.78%)  19
White blood cell count decreased † 1  7/56 (12.50%)  12 9/54 (16.67%)  18
Platelet count decreased † 1  5/56 (8.93%)  17 2/54 (3.70%)  2
Metabolism and nutrition disorders     
Hypomagnesaemia † 1  10/56 (17.86%)  10 11/54 (20.37%)  12
Decreased appetite † 1  5/56 (8.93%)  5 4/54 (7.41%)  5
Musculoskeletal and connective tissue disorders     
Back pain † 1  3/56 (5.36%)  3 1/54 (1.85%)  1
Nervous system disorders     
Neuropathy peripheral † 1  8/56 (14.29%)  8 6/54 (11.11%)  6
Dysgeusia † 1  7/56 (12.50%)  7 4/54 (7.41%)  4
Peripheral sensory neuropathy † 1  3/56 (5.36%)  3 3/54 (5.56%)  3
Respiratory, thoracic and mediastinal disorders     
Interstitial lung disease † 1  3/56 (5.36%)  3 2/54 (3.70%)  2
Skin and subcutaneous tissue disorders     
Dry skin † 1  4/56 (7.14%)  4 3/54 (5.56%)  3
Palmar-plantar erythrodysaesthesia syndrome † 1  2/56 (3.57%)  2 4/54 (7.41%)  4
Dermatitis acneiform † 1  2/56 (3.57%)  2 3/54 (5.56%)  3
Pruritus † 1  1/56 (1.79%)  1 3/54 (5.56%)  4
1
Term from vocabulary, MedDRA version 20.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
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Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02337946    
Other Study ID Numbers: Panitumumab-2003
U1111-1161-8871 ( Registry Identifier: UTN (WHO) )
183/NRP-005 ( Other Identifier: Secondary Takeda ID )
JapicCTI-142668 ( Registry Identifier: JapicCTI )
First Submitted: September 30, 2014
First Posted: January 14, 2015
Results First Submitted: March 27, 2018
Results First Posted: March 1, 2019
Last Update Posted: September 10, 2019