Conditions: Colorectal Carcinoma
Keywords: Metastatic colorectal cancer, Panitumumab, mFOLFOX6, First-line
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 164
Healthy volunteers: no

Brief summary:
The purpose of this study is to exploratorily examine efficacy and safety in the participants with chemotherapy-naïve unresectable, advanced/recurrent colorectal carcinoma of Kirsten rat sarcoma-2 virus (KRAS) wild-type who have been treated with 6 cycles (2 weeks/cycle) of first-line mFOLFOX6 + panitumumab combination therapy and then assigned to two groups i.e., a group receiving 5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + panitumumab combination therapy.

Detailed description:
The drug being tested in this study is called panitumumab. Panitumumab is being tested to treat people who have advanced/recurrent colorectal carcinoma of KRAS wild-type. This study will look at the efficacy and safety of 5-FU/LV + panitumumab(Pmab) combination therapy or mFOLFOX6 + Pmab combination therapy in the participants.

The study will enroll 164 patients. All participants will receive 6 cycles of Protocol Treatment \[1\]: 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.

Then they will be randomly assigned (by chance, like flipping a coin) to one of the treatment groups.

* Group A
* Group B

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 20 months.

Arms:
arm 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. arm 2: 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.

Interventions: intervention 1: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab intervention 2: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab
Intervention descriptions: intervention 1: oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion intervention 2: None

Protocol document:
Prot_001.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 
Note; This document was translated into English and the language in original document was Japanese.


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CONFIDENTIAL 
 
 
 
 
SAPPHIRE study 
(A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + 
panitumumab combination therapy and 5-FU/LV + panitumumab combination therapy in 
the patients with chemotherapy-naïve unresectable advanced recurrent colorectal 
carcinoma of KRAS wild-type after 6 cycles of combination therapy with mFOLFOX6 + 
panitumumab) 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
183/NRP-005 
Version number 
Version 3  
Product name 
Panitumumab 
Creation date 
October 20, 2016 
 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Takeda.  


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1.0 
STUDY ADMINISTRATIVE STRUCTURE AND PRINCIPLES 
1.1 Study Administrative Structure 
See Appendix for the contacts and study-related responsibilities. 
1.2 Principles of the study 
This study will be conducted with the highest respect for the individual participants in accordance with 
the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki 
• 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws, conflict of 
interest guidelines and Ethical Guideline for Clinical Research (the Ministry of Health, Labour and 
Welfare, revised in 2008) 


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TABLE OF CONTENTS 
1.0 
STUDY ADMINISTRATIVE STRUCTURE AND PRINCIPLES .......................................... 2 
1.1 
Study Administrative Structure .......................................................................................... 2 
1.2 
Principles of the study......................................................................................................... 2 
2.0 
STUDY SUMMARY ................................................................................................................ 9 
3.0 
LIST OF ABBREVIATIONS ................................................................................................. 14 
4.0 
INTRODUCTION ................................................................................................................... 16 
4.1 
Background ....................................................................................................................... 16 
4.1.1 
Etiology of target disease ........................................................................................... 16 
4.1.2 
Standard treatment for target disease ......................................................................... 16 
4.1.3 
Efficacy and safety of mFOLFOX6 in patients with unresectable, advanced/recurrent 
colorectal cancer ........................................................................................................ 17 
4.1.4 
Efficacy and safety of panitumumab in patients with unresectable, advanced or 
recurrent colorectal cancer ......................................................................................... 17 
4.1.5 
Adverse reactions to OXA ......................................................................................... 20 
4.1.6 
Examination of the method of administration of OXA in first-line therapy .............. 21 
4.2 
Rationale for the proposed study ...................................................................................... 21 
5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY .............................................................. 22 
5.1 
Objective ........................................................................................................................... 22 
5.2 
Endpoints .......................................................................................................................... 22 
5.2.1 
Primary endpoint ........................................................................................................ 22 
5.2.2 
Secondary endpoints .................................................................................................. 22 
5.2.3 
Additional endpoint ................................................................................................... 22 
5.3 
Rationale for the endpoints ............................................................................................... 23 
5.3.1 
Primary endpoint ........................................................................................................ 23 
5.3.2 
Secondary endpoints .................................................................................................. 23 
6.0 
STUDY DESIGN .................................................................................................................... 24 
6.1 
Study design...................................................................................................................... 24 
6.2 
Rationale for study design, dose and endpoints ................................................................ 25 
6.2.1 
Study population ........................................................................................................ 25 
6.2.2 
Treatment regimens and planned number of subjects ................................................ 25 
6.3 
Discontinuation of entire study or discontinuation at a study site .................................... 25 
6.3.1 
Criteria for discontinuation of entire study ................................................................ 25 


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6.3.2 
Procedures of study suspension and discontinuation of entire study or study at a study 
site 26 
6.4 
Procedures for revision of the protocol ............................................................................. 26 
7.0 
SELECTION OF STUDY SUBJECTS ................................................................................... 27 
7.1 
Inclusion criteria ............................................................................................................... 27 
7.1.1 
Inclusion criteria for enrollment ................................................................................ 27 
7.1.2 
Inclusion criteria for randomization ........................................................................... 28 
7.2 
Exclusion criteria .............................................................................................................. 28 
7.2.1 
Exclusion criteria for enrollment ............................................................................... 28 
7.2.2 
Exclusion criteria for randomization .......................................................................... 29 
8.0 
TREATMENT ......................................................................................................................... 30 
8.1 
Protocol treatment ............................................................................................................. 30 
8.1.1 
Protocol Treatment [1] ............................................................................................... 30 
8.1.2 
Protocol Treatment [2] ............................................................................................... 30 
8.2 
Treatment regimen ............................................................................................................ 30 
8.2.1 
Protocol Treatment [1] ............................................................................................... 30 
8.2.2 
Protocol Treatment [2] ............................................................................................... 31 
8.3 
Recommended dose of protocol treatment ....................................................................... 32 
8.4 
Criteria for initiation of protocol treatment (common for Protocol Treatment [1] and [2])
 32 
8.5 
Criteria for dose change .................................................................................................... 33 
8.5.1 
Protocol Treatment [1] ............................................................................................... 33 
8.5.2 
Protocol Treatment [2] ............................................................................................... 35 
8.6 
Criteria for dose increase of protocol treatment................................................................ 37 
8.7 
Overdose of panitumumab ................................................................................................ 37 
8.8 
Criteria for discontinuation of protocol treatment ............................................................ 37 
8.9 
Contraindicated drugs/therapies........................................................................................ 38 
8.10 
Allowed supportive care and combination medications ................................................... 39 
8.11 
Handling of surgery aimed at curative resection (complete resection: R0 resection) of 
colorectal cancer ............................................................................................................... 40 
8.12 
Recommended follow-up therapy ..................................................................................... 40 
8.12.1 Recommended second-line treatment ........................................................................ 40 
8.12.2 Recommended third-line or subsequent treatment ..................................................... 40 


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9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR OBSERVATIONS ....... 41 
9.1 
Study calendar .................................................................................................................. 41 
9.2 
Collection/test/observation items and procedures during the study .................................. 42 
9.2.1 
Informed consent procedure ....................................................................................... 42 
9.2.2 
Procedures for registration and allocation of drugs ................................................... 43 
9.2.3 
Subject demographics ................................................................................................ 44 
9.2.4 
Medical history .......................................................................................................... 44 
9.2.5 
Current medical condition .......................................................................................... 45 
9.2.6 
Clinical findings (physical examination) ................................................................... 45 
9.2.7 
Body weight and height ............................................................................................. 45 
9.2.8 
Vital signs .................................................................................................................. 45 
9.2.9 
ECOG-PS ................................................................................................................... 45 
9.2.10 Treatment compliance (Protocol Treatment [1] and [2] implementation status) ....... 46 
9.2.11 Laboratory tests .......................................................................................................... 46 
9.2.12 Imaging test (thoracoabdominal-pelvic CT/MRI)...................................................... 48 
9.2.13 NRAS test ................................................................................................................... 49 
9.2.14 Surgery aimed at curative resection (complete resection: R0 resection) of colorectal 
cancer ......................................................................................................................... 50 
9.2.15 Survival survey .......................................................................................................... 50 
9.2.16 Follow-up therapy ...................................................................................................... 51 
9.3 
Records of subjects who discontinued before enrollment ................................................ 51 
10.0 
ADVERSE EVENTS .............................................................................................................. 52 
10.1 
Definitions ........................................................................................................................ 52 
10.1.1 Adverse events ........................................................................................................... 52 
10.1.2 Items to be considered concerning adverse events..................................................... 52 
10.1.3 Serious adverse events ............................................................................................... 53 
10.1.4 Noteworthy adverse events for the sponsor ............................................................... 54 
10.1.5 Severity of adverse events.......................................................................................... 54 
10.1.6 Causality of adverse events ........................................................................................ 55 
10.1.7 Date of onset .............................................................................................................. 55 
10.1.8 Date of resolution ....................................................................................................... 56 
10.1.9 Incidence .................................................................................................................... 56 


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10.1.10 Action taken for protocol treatment ........................................................................... 56 
10.1.11 Outcome ..................................................................................................................... 56 
10.2 
Procedures......................................................................................................................... 57 
10.2.1 Collection and reporting of adverse events ................................................................ 57 
10.2.2 Collection and reporting of serious adverse events .................................................... 58 
10.2.3 Notification of unexpected serious adverse event to joint study sites ........................ 58 
10.3 
Follow-up of serious adverse events ................................................................................. 58 
10.4 
Reporting of additional information on adverse events .................................................... 59 
10.5 
Notification of serious adverse events to IRB such as an ethics review committee and 
regulatory authorities ........................................................................................................ 59 
11.0 
COMMIITTEES ESTABLISHED FOR ADMINISTRATIVE STRUCTURE AND THIS 
STUDY .................................................................................................................................... 60 
11.1 
Research steering committee ............................................................................................ 60 
11.2 
Data Monitoring Committee ............................................................................................. 60 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS .................................................. 61 
12.1 
Case report form ............................................................................................................... 61 
12.2 
Time limit for data input into the EDC ............................................................................. 61 
12.3 
Storage of records ............................................................................................................. 62 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................................... 63 
13.1 
Statistical and analytical plans .......................................................................................... 63 
13.1.1 Analysis set ................................................................................................................ 63 
13.1.2 Analysis of demographic and other baseline characteristics ...................................... 63 
13.1.3 Efficacy analysis ........................................................................................................ 63 
13.1.4 Safety analysis ........................................................................................................... 66 
13.1.5 Predetermined subgroup analysis ............................................................................... 66 
13.2 
Criteria for interim analysis and premature discontinuation ............................................. 67 
13.3 
Determination of the planned number of subjects ............................................................ 67 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................................... 68 
14.1 
Monitoring of study sites .................................................................................................. 68 
14.1.1 Central monitoring ..................................................................................................... 68 
14.1.2 Site visit monitoring ................................................................................................... 68 
14.2 
Protocol deviations ........................................................................................................... 68 
14.3 
Quality assurance and regulatory agency inspections ....................................................... 68 


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15.0 
ETHICAL CONDUCT OF A STUDY .................................................................................... 69 
15.1 
Conflict of interests ........................................................................................................... 69 
15.2 
Approval by the institutional review board including the ERC ........................................ 69 
15.3 
Written information and subject’s consent ....................................................................... 69 
15.4 
Subject confidentiality ...................................................................................................... 70 
15.5 
Advantages and disadvantages to subjects ....................................................................... 70 
15.5.1 Advantage to subjects ................................................................................................ 70 
15.5.2 Disadvantage to subjects ............................................................................................ 70 
15.6 
Publication, disclosure, and clinical trial registration policy ............................................ 71 
15.6.1 Publication and disclosure ......................................................................................... 71 
15.6.2 Clinical trial registration ............................................................................................ 71 
15.6.3 Clinical trial results disclosure ................................................................................... 71 
15.7 
Attribution of study results and intellectual property rights ............................................. 71 
15.8 
Insurance and compensation for injury ............................................................................. 71 
16.0 
REFERENCES ........................................................................................................................ 72 
 
Figures and Tables List 
Figure 6.a  Outline of study design ...................................................................................................... 24 
Figure 8.a  mFOLFOX6 + panitumumab combination therapy ........................................................... 31 
Figure 8.b  5-FU/LV + panitumumab combination therapy ................................................................ 32 
 
Table 4.a  Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study ......... 18 
Table 4.b  Adverse Drug Reactions (ADRs) of special interest on Post-marketing survey in Japan ... 20 
Table 8.a  Treatment regimen of mFOLFOX6 + panitumumab combination therapy ......................... 30 
Table 8.b  Treatment regimen of 5-FU/LV + panitumumab combination therapy .............................. 31 
Table 8.c  Criteria for initiation of treatment cycle .............................................................................. 33 
Table 8.d  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [1]) ............................ 33 
Table 8.e  Doses of OXA and 5-FU (Protocol Treatment [1]) ............................................................. 34 
Table 8.f  Criteria for dose reduction of panitumumab ........................................................................ 34 
Table 8.g  Dose of panitumumab ......................................................................................................... 35 
Table 8.h  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [2]) ............................ 35 
Table 8.i  Doses of OXA and 5-FU (Protocol Treatment [2]) ............................................................. 36 


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Table 9.a  Study calendar (Protocol Treatment [1]) ............................................................................. 41 
Table 9.b  Study calendar (Protocol Treatment [2]) ............................................................................. 42 
Table 9.c  Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) ........................... 45 
Table 9.d  Laboratory tests performed at the time of enrollment ......................................................... 46 
Table 9.e  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment 
[1]) ............................................................................................................................. 47 
Table 9.f  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment 
[2]) ............................................................................................................................. 47 
Table 9.g  Laboratory tests performed at the time of discontinuation.................................................. 48 
Table 9.h  EXON and codon verified on NRAS test ............................................................................. 50 
Table 9.i  Residual tumor after surgical treatment ............................................................................... 50 
 


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2.0 
STUDY SUMMARY 
Sponsor: Takeda Pharmaceutical Company Limited 
Investigational product: Panitumumab 
Study title: 
SAPPHIRE study (A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + 
panitumumab combination therapy and 5-FU/LV + panitumumab combination therapy in the patients with 
chemotherapy-naïve unresectable advanced recurrent colorectal carcinoma of KRAS wild-type after 6 cycles of 
combination therapy with mFOLFOX6 + panitumumab) 
Protocol number: 183/NRP-005 
Study type: Exploratory study 
Study design: 
 
 
Patinets will be assigned to the Protocol Treatment through minimization using the following as stratification 
factors: study site, age at enrollment (≥ 20 and ≤ 69, or > 70), the number of metastasized organs (≤ 1, or ≥ 2) 
and response evaluated in accordance with the Response Evaluation Criteria in Solid Tumors version 1.1 
(hereinafter referred to as "RECIST 1.1") criteria as Complete Response (CR), Partial Response (PR) or Stable 
Disease (SD). 
Objective: 
To exploratorily examine the efficacy and safety in patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type who receive 6 cycles (2 weeks per cycle) of 
first-line mFOLFOX6 + panitumumab combination therapy and are to be assigned to either of the 2 groups, i.e., 
a group receiving 5-FU/LV + panitumumab combination therapy or a group receiving mFOLFOX6 + 
panitumumab combination therapy. 
Study population: 
The patients with chemotherapy-naïve unresectable, advanced/recurrent colorectal carcinoma of KRAS wild-type 
Planned number of subjects: 
100, as the allocated sample size 
Group A: 50 
Group B: 50 


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Number of study sites: 40 (planned) 
Method of administration: 
In both Protocol Treatment [1] and Protocol Treatment [2] (Group A and Group B), 1 cycle consists of 2 weeks, 
and the respective study drugs will be administered at the following doses according to the following schedule. 
Protocol Treatment [1] 
mFOLFOX6 + panitumumab combination therapy, once every 2 weeks, 6 cycles 
Oxaliplatin (OXA): 85 mg/m2/day 1 
Levofolinate calcium (l-LV): 200 mg/m2/day 1 
Bolus 5-FU: 400 mg/m2/day 1 
Infusional 5-FU civ: 2400 mg/m2/day 1-3 
Panitumumab: 6 mg/kg 
Protocol Treatment [2] 
Group A: mFOLFOX6 + panitumumab combination 
therapy, once every 2 weeks 
OXA: 85 mg/m2/day 1 
l-LV: 200 mg/m2/day 1 
Bolus 5-FU: 400 mg/m2/day 1 
Infusional 5-FU civ: 2400 mg/m2/day 1-3 
Panitumumab: 6 mg/kg 
(same treatment as the Protocol Treatment [1]) 
Group B: 5-FU/LV + panitumumab combination 
therapy, once every 2 weeks 
l-LV: 200 mg/m2/day 1 
Bolus 5-FU: 400 mg/m2/day 1 
Infusional 5-FU civ: 2400 mg/m2/day 1-3 
Panitumumab: 6 mg/kg 
Duration of treatment (approximately): 
12 months (assumed duration from the day of first administration in Protocol Treatment [1] until becoming 
Progressive Disease [PD] or intolerance) 
Inclusion criteria 
Inclusion criteria for enrollment: 
(1) Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the 
appendix and anal canal cancer) 
(2) Patients with measurable lesion(s) according to the RECIST 1.1criteria (refer to Appendix B) 
(3) Chemotherapy-naïve patients. Patients who experience relapse more than 6 months after the final dose of 
perioperative adjuvant chemotherapy* with fluoropyrimidine agents may be enrolled. 
*: Patients who received perioperative adjuvant chemotherapy using OXA may not be enrolled. 
(4) Patients aged ≥20 years at enrollment 
(5) Patients with confirmed KRAS wild-type* tumors 
However, the criteria will be changed to all patients with confirmed KRAS or Neuroblastoma Rat Sarcoma 
(NRAS) wild-type tumors, when the KRAS and NRAS tests come to be covered by National Health 
Insurance, and the tests become feasible at medical institutions. 
*: Patients with no mutation in any of the codons shown below are considered wild-type. 
KRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
NRAS** 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
**: To be considered when the test comes to be covered by insurance and becomes feasible at medical 
institutions. 
(6) Patients who satisfy the following criteria for the major organ function in tests performed within 14 days 
prior to enrollment 
1) 
Neutrophil count ≥ 1.5 × 103/μL 
2) 
White blood cell count ≥ 3.0× 103/μL 


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3) 
Platelet count ≥ 10.0 × 104/μL 
4) 
Hemoglobin ≥ 9.0 g/dL 
5) 
Total bilirubin ≤ 2.0 mg/dL 
6) 
Aspartate aminotransferase (AST) ≤ 100 U/L (≤ 200 U/L if liver metastases are present) 
7) 
Alanine aminotransferase (ALT) ≤ 100 U/L (≤ 200 U/L if liver metastases are present) 
8) 
Serum creatinine ≤ 1.5 mg/dL 
(7) Patients graded as 0 or 1in accordance with the Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) scale 
(8) Patients with life expectancy of ≥ 6 months after enrollment 
(9) Patients who provide written informed consent after detailed explanation of the study prior to enrollment 
Inclusion criteria for randomization: 
(1) Patients who have received 6 cycles* of mFOLFOX6 + panitumumab combination therapy (Protocol 
Treatment [1]) 
*: Defined as the use of 5-FU/l-LV without dose interruption in all 6 cycles (2 weeks/cycle) of Protocol 
Treatment [1], in adherence to the specified Protocol Treatment [1] regimen. However, bolus 5-FU and 
panitumumab may be excluded. 
(2) Patients graded as 0 or 1 in accordance with the ECOG-PS during the 6th cycle 
(3) Patients whose imagings within 14 days (2 weeks) after the administration day in the 6th cycle are 
definitely evaluated as other than PD and Not Evaluable in accordance with the RECIST 1.1 criteria (refer 
to Appendix B) 
Exclusion criteria 
Exclusion criteria for enrollment: 
(1) Patients who have received radiotherapy for a measurable lesion(s) 
(2) Patients who received radiotherapy for a lesion(s) other than measurable lesions within 28 days (4 weeks) 
prior to enrollment. However, the treatment to relieve the pain of metastatic bone tumors is allowed. 
(3) Patients with known or strongly suspected brain metastasis 
(4) Patients with synchronous or metachronous cancers (other than colorectal cancer) with a disease-free period 
of ≤ 5 years, excluding mucosal cancers cured or possibly cured by regional resection (esophageal, 
stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.). 
(5) Patients with body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) 
(6) Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant, 
breast-feeding or pregnancy positive 
(7) Patients with active hemorrhage requiring blood transfusion 
(8) Patients with diseases requiring systemic steroids for treatment (excluding topical steroids) 
(9) Patients who have undergone intestinal resection and colostomy within 14 days (2 weeks) prior to 
enrollment 
(10) Patients with history of, or obvious and extensive computerized tomography (CT) findings of interstitial 
pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) 
(11) Patients with serious drug hypersensitivity 
(12) Patients with local or systemic active infection requiring treatment, or with a fever indicating infection 
(13) Patients with intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating 
symptoms despite adequate treatment) 
(14) Patients with active hepatitis B and/or C 
(15) Patients with known HIV infection 
(16) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study 


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Exclusion criteria for randomization: 
(1) Patients in whom interstitial pneumonia has been newly diagnosed during the period from enrollment to 
randomization 
(2) Patients who have received radiotherapy for a measurable lesion(s) during the period from enrollment to 
randomization. However, the treatment to relieve the pain of metastatic bone tumors is allowed 
(3) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study 
Endpoints: 
[Primary endpoint] 
 Efficacy 
Progression-Free Survival (PFS) rate at 9 months after randomization 
[Secondary endpoints] 
 Efficacy 
 PFS duration 
 Overall survival (OS) 
 Response rate (RR) 
 Time to treatment failure (TTF) 
 Safety 
 Incidence rate of adverse events (AEs) and the severity by incidence rate 
 Incidence rate of peripheral nerve disorders 
 Incidence rate of skin disorders 
 Additional endpoint 
 Duration of Performance Status Maintenance (DPSM) 
 Duration of OXA continuation in mFOLFOX6 + panitumumab group (Group A) 
 Duration of panitumumab continuation in both groups 
Statistical method: 
The primary objective of this study is to explore the worthiness of a confirmatory study verifying the 
non-inferiority of the 5-FU/LV + panitumumab arm versus mFOLFOX6 + panitumumab arm, setting the PFS 
rate at 9 months after randomization as the primary endpoint. 
The PFS rate at 9 months after randomization serves as a primary endpoint and is defined as the gross 
proportion of subjects who survive with no evidence of progression during from the day of randomization (Day 
0) until at 9 months after the Day 0. For each treatment group, a binomial test will be performed for the null 
hypothesis that the PFS rate to determine invalidity will be equal to or less than 30%, based on the PFS rate 
observed at 9 months after randomization. The main analysis will be at the one-sided 10% significance level. A 
two-sided 80% confidence interval using Agresti-Coull Method will be applied to the interval estimation. 
The PFS duration is defined as the time from the day of randomization (Day 0) until the first evidence of 
progression, or until death from any cause, whichever comes earlier. For each treatment group, the PFS duration 
will be illustrated with Kaplan-Meier curves, and the quartile of PFS and its 95% confidence interval (two-sided) 
will be culculated. At the same time, for the sake of reference, the hazard ratio of Group B versus Group A and 
its 95% confidence interval (two-sided) will be calculated on the basis of the stratified Cox regression model, 
and a log-rank test will be performed. 
Rationale for planned number of subjects: 
This study will be designed as a phase II randomized screening comparative study where direct comparisons are 
excluded from the primary analysis. 


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In the phase III study (PRIME Study) in which FOLFOX4 therapy was combined with bi-weekly administration 
of panitumumab 6 mg/kg as a first-line therapy, the median PFS duration in the patients of KRAS wild-type as 
the primary endpoint was reported as 9.6 months. Moreover, in the PEAK Study in which panitumumab and 
bevacizumab were compared as the drugs to be administered in combination with mFOLFOX6 therapy, the 
median PFS duration in the mFOLFOX6 therapy + panitumumab group was reported as 10.9 months. In these 2 
studies, the incidence of events or study withdrawals within 3 months was approximately 10% of the total. 
The subject population of this study is patients who can continue OXA administration following 3-month 
mFOLFOX6 + panitumumab combination therapy. Since the 45% point of PFS duration in the PRIME Study 
and PEAK Study was approximately 12 months, the median PFS duration in the Group A in this study is 
expected to be approximately 9 months, which is obtained by subtracting 3 months from the said point. The 
median PFS duration in the Group B is assumed to be comparable to that in the Group A. Therefore, the 
expected PFS rates at 9 months after randomization in the 2 groups are both set as 50%. In the meantime, a 
threshold to consider the worthiness of the study is set as 30%, based on the data previously reported. 
In the primary analysis, a binominal test will be performed for the null hypothesis, "a true PFS rate at 9 months 
after randomization will be equal to or lower than the threshold PFS rate to determin invalidity," in the 
respective groups based on the PFS rates observed at 9 months after randomization. Given that the threshold PFS 
rate at 9 months after randomization is 30%, the expected PFS rate is 50%, one-sided significance level is 10% 
and the power of test is 90%, the required sample size for the both groups will be 44 subjects each. Considering 
dropouts and study withdrawals, the target sample size to be randomised shall be designed as 50 patients for each 
group (100 patients in total). 


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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Unabbreviated expression 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ALP 
alkaline phosphatase 
ASCO 
American society of clinical oncology 
BRAF 
v–raf murine sarcoma viral oncogene homolog B1 
BSC 
best supportive care 
CEA 
carcinoembryonic antigen 
COI 
conflict of interest 
CR 
complete response 
CRO 
contract research organization 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
deepness of response 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EGF 
epidermal growth factor 
EGFR 
epidermal growth factor receptor 
ETS 
early tumor shrinkage 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FFPE 
Formalin-Fixed Paraffin-Embedded 
G-CSF 
granulocyte colony stimulating factor 
γ-GTP 
γ-glutamyl transpeptidase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
IRB 
institutional review board 
JCOG 
Japan Clinical Oncology Group 
KRAS 
Kirsten rat Sarcoma-2 virus 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
l-LV 
Leucovorin 
mCRC 
metastatic colorectal cancer 


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Abbreviation 
Unabbreviated expression 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NE 
Not Evaluable 
NRAS 
 
OS 
Overall survival 
OXA 
Oxaliplatin 
PD 
progressive disease 
PFS 
Progression free survival 
PPS 
per-protocol analysis set 
PR 
partial response 
PS 
performance status 
PT 
Preferred Term 
PI3K 
Phosphoinositide 3-kinase 
RAS 
rat sarcoma 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TTF 
Time to Treatment Failure 
ULN 
upper limit of normal 
UMIN-CTR 
University Hospital Medical Information Network - Clinical Trials 
Registry 
UPC 
urine protein creatinine 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell 
WT 
wild type 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 
Etiology of target disease 
According to “Cancer Statistics 2013,”1) and “Site-specific Cancer Prevalence” in 2008 in Japan, 
colon cancer was the third most prevalent cancer in men (15.0%) and the second in women (15.1%). 
According to “Site-specific Cancer Deaths (2012),” in men, lung cancer was the leading cause of 
cancer death (accounting for 23.9% of cancer deaths), followed by gastric cancer (15.0%) and hepatic 
cancer (9.3%); colorectal cancer (colon cancer and rectal cancer combined) accounted for 11.9% of 
cancer deaths which exceeded the death rate of hepatic cancer, representing that colorectal cancer is 
the third leading cause of cancer death. In women, lung cancer (13.8%) was also the leading cause of 
cancer death, followed by gastric cancer (11.6%) and pancreatic cancer (9.9%); deaths from colorectal 
cancer (colon cancer and rectal cancer combined) accounted for 14.9% of cancer deaths, representing 
that colorectal cancer is the first leading cause of cancer death. 
4.1.2 
Standard treatment for target disease 
The “Guidelines for Treatment of Colorectal Cancer (2014)”2) classify the standard treatment of 
colorectal cancer according to staging as follows: endoscopic resection for Stage 0, in which the lesion 
is limited in the mucosa; surgical resection for Stage I to III with postoperative adjuvant chemotherapy 
for Stage III involving lymph nodes; and surgical resection for Stage IV and recurrent disease if liver 
or lung metastasis is resectable, and systemic chemotherapy if not.  
The first-line chemotherapy regimens for the patients with unresectable, advanced/recurrent colorectal 
carcinoma necessitating powerful treatment that have been demonstrated to be useful in clinical 
studies and are currently covered by national health insurance in Japan are presented below. There is a 
consensus that cetuximab and panitumumab should be used only for KRAS wild-type (WT) colorectal 
cancer. 
(1) FOLFOX therapy or CapeOX therapy +bevacizumab*1 
FOLFOX therapy: combination chemotherapy with fluorouracil (hereinafter referred to as 
5-FU), Isovorin (hereinafter referred to as l-LV), and oxaliplatin (hereinafter referred to as 
OXA) 
CapeOX therapy: combination chemotherapy with capecitabine and OXA 
(2) FOLFIRI therapy + bevacizumab*1 
FOLFIRI therapy: combination chemotherapy with irinotecan (hereinafter referred to as IRI), 
5-FU, and l-LV 
(3) FOLFOX therapy + cetuximab*1, 2 or panitumumab*1, 2 
(4) FOLFIRI therapy + cetuximab*1, 2 or panitumumab*1, 2 
(5) FOLFOXIRI therapy  
FOLFOXIRI therapy: combination chemotherapy with OXA, IRI, 5-FU and l-LV 
(6) FL*3, CapeOX + bevacizumab*1 or UFT + LV 
UFT: combination preparation of tegafur and uracil 
*1: Combination with molecular-targeted drugs such as bevacizumab and epidermal 
growth factor receptor (EGFR) antibody is recommended, but if this cannot be 
indicated, chemotherapy alone will be provided. 
*2:  Indicated only for KRAS wild-type. 
*3: infusional 5-FU + l-LV 


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FOLFOX-based therapy is more frequently selected as first-line chemotherapy than FOLFIRI-based 
therapy, and bevacizumab is widely used for KRAS wild-type colorectal cancer as well. As a result, 
FOLFOX + bevacizumab combination therapy is the most common first-line treatment in Japan 
(in-house document).  
It is recommended that in principle, a regimen not used in first-line treatment should be used for 
second-line treatment. More specifically, IRI-based regimens are recommended as a second-line 
treatment of patients who have received an OXA-based regimen as a first-line treatment, while 
OXA-based regimens are recommended for patients who have received an IRI-based regimen. 
This principle also applies to molecular-targeted drugs concomitantly used for second-line treatment. 
For KRAS wild-type colorectal cancer, bevacizumab is recommended as a second-line treatment of 
patients who have received an anti-EGFR antibody as a first-line treatment, while switching to an 
anti-EGFR antibody or continued use of bevacizumab is an option as a second-line treatment of 
patients who have received bevacizumab as a first-line treatment. 
For third-line treatment, regorafenib, trifluridine/ tipiracil hydrochloride (TAS-102) or symptomatic 
therapy is recommended for cases on anti-EGFR antibodies as the first-line treatment. 
4.1.3 
Efficacy and safety of mFOLFOX6 in patients with unresectable, 
advanced/recurrent colorectal cancer 
As therapy for unresectable, advanced/recurrent colorectal cancer, regimens mainly based on 
fluoropyrimidine anticancer agents are considered to be the standard for a long term3). Based on the 
evidence showing that 5-FU combined with l-LV is superior to 5-FU monotherapy, the combination 
therapy with 5-FU and l-LV (hereinafter referred to as 5-FU/LV therapy) had been considered as 
standard chemotherapy for colorectal cancer for a long time. The type I topoisomerase inhibitor IRI 
and the third generation of platinum-based anticancer drug OXA were then developed, and have been 
shown to improve treatment outcome in a number of large scale controlled trials4) to 9). At present, 
continuous infusion of 5-FU/LV in combination with OXA (FOLFOX therapy) or in combination with 
IRI (FOLFIRI therapy) is the standard chemotherapy regimen for advanced/recurrent colorectal 
cancer3), 10). FOLFOX and FOLFIRI therapies were compared in the GERCOR V308 study9,) in which 
the median final overall survival (hereinafter referred to as OS) was similar between the precedent 
FOLFIRI and the precedent FOLFOX arms (21.5 months vs. 20.6 months), and thereby both of the 
therapies are used as the standard for unresectable colorectal cancer. The development of these 
therapies provided improvement of the median survival time of unresectable advanced colorectal 
cancer from 12 months with 5-FU/LV therapy to 20 months or more with 5-FU/LV therapy in 
combination with IRI or OXA. 
Among several FOLFOX regimens, FOLFOX4 therapy and modified FOLFOX6 (hereinafter referred 
to as mFOLOFX6) therapy, which include OXA at the approved dosage (85 mg/m2) in Japan, are 
covered by national health insurance, and simpler and easier mFOLFOX6 therapy is more frequently 
used. 
4.1.4 
Efficacy and safety of panitumumab in patients with unresectable, advanced 
or recurrent colorectal cancer 
4.1.4.1 
Panitumumab 
EGFR, a member of the ErbB family of transmembrane receptor tyrosine kinases constantly 
expressed in epithelial-derived tissues, has been shown to be overexpressed in various types of 
solid tumors. Colorectal cancer is characterized by high EGFR expression, and the EGFR signaling 
pathway has been shown to play in the pathogenesis and progression of tumors. Binding of 
epidermal growth factor (EGF), the major ligand of EGFR, to EGFR is considered to induce 
auto-phosphorylation of EGFR and activation of various signaling pathways, resulting in induction 
of cellular proliferation, inhibition of apoptosis, and increased production of inflammatory 


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cytokines and angiogenesis factors. Panitumumab is a human IgG2 monoclonal antibody that binds 
to EGFR with specificity and high affinity, and inhibits the proliferation of tumor cells by 
competitively inhibiting the binding of the ligand to EGFR. 
4.1.4.2 
Clinical study results for panitumumab in the U.S. and Europe 
As a clinical trial of panitumumab monotherapy for colorectal cancer, a phase III study was 
conducted to compare best supportive care (BSC) vs. BSC + panitumumab therapy in patients with 
unresectable, recurrent or advanced, EGFR-positive colorectal cancer that became resistant to 
fluoropyrimidine agents, OXA, and IRI (BSC arm, 232 patients; BSC + panitumumab arm, 231 
patients) 11). The primary endpoint of median PFS duration was 8 weeks and significantly longer in 
the BSC + panitumumab therapy, showing the efficacy of panitumumab therapy as compared with 
7.3 weeks in the BSC alone arm (hazard ratio [HR], 0.54; two-sided 95% confidence interval [CI], 
0.44 to 0.66; p<0.0001). The secondary endpoint of OS was not significantly different between the 
two arms (HR, 1.00; two-sided 95% CI, 0.82 to 1.22; p = 0.81); however, this may be primarily due 
to the fact that 173 subjects (75%) in the BSC arm received follow-up therapy with panitumumab. 
With regard to combination of chemotherapy and panitumumab, a phase III clinical study (PRIME 
Study) has been reported, in which FOLFOX4 monotherapy vs. FOLFOX4 therapy + panitumumab 
(given at a dose of 6 mg/kg every 2 weeks) as a first-line treatment was compared in a total of 
1,180 patients (590 in each arm)12). The primary endpoint of median PFS in KRAS wild-type 
patients was 9.6 months and significantly longer in the FOLFOX4 + panitumumab arm as 
compared with 8.0 months in the FOLFOX4 alone arm (HR, 0.80; two-sided 95% CI, 0.66 to 0.97; 
p = 0.02). Of Grade 3/4 AEs, panitumumab-related adverse events such as dermatologic toxicities, 
diarrhoea, and hypomagnesaemia occurred more frequently in the FOLFOX4 + panitumumab arm, 
but there were no major differences in the incidence of other adverse events between the two arms. 
Grade 3 infusion reaction occurred in 2 patients (Table 4.a). 
Table 4.a  Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study 
Adverse event 
FOLFOX4 + panitumumab 
(n = 322) 
FOLFOX4 alone 
(n = 327) 
n 
(%) 
N 
(%) 
Any adverse drug reaction 
270 
84 
227 
69 
Leukopenia 
136 
42 
134 
41 
Skin disorder 
116 
36 
7 
2 
Diarrhoea 
59 
18 
29 
9 
Nerve disorder 
52 
16 
51 
16 
Hypokalaemia 
32 
10 
15 
5 
Malaise 
30 
9 
10 
3 
Stomatitis 
28 
9 
2 
<1 
Hypomagnesaemia 
20 
8 
1 
<1 
Paronychia 
11 
3 
0 
0 
Pulmonary embolism 
9 
3 
5 
2 
Febrile neutropenia 
8 
2 
7 
2 
Infusion reaction 
2 
<1 
- 
- 
With regard to second-line treatment, a phase III clinical study (Study 20050181) has been 
conducted, in which FOLFIRI monotherapy vs. FOLFIRI therapy + panitumumab (given at a dose 
of 6 mg/kg every 2 weeks) was compared 13). The primary endpoints were PFS duration and OS in 
KRAS wild-type patients. In KRAS wild-type patients, the median PFS duration was 5.9 months and 
significantly longer in the FOLFIRI + panitumumab arm than 3.9 months in the FOLFIRI alone 
arm (HR, 0.73; two-sided 95% CI, 0.59 to 0.90; p = 0.004). On the other hand, OS in the same 
population was 14.5 months in the FOLFIRI + panitumumab arm and 12.5 months in the FOLFIRI 
alone arm, with no statistically significant difference between the two arms (HR, 0.85; two-sided 
95% CI, 0.70 to 1.04; p = 0.12). The RR was 35% and higher in the FOLFIRI + panitumumab arm 


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as compared with 10% in the FOLFIRI alone arm. Of Grade 3/4 adverse events, the incidence of 
dermatologic toxicities was higher and the incidences of diarrhoea and hypomagnesaemia tended to 
be higher in the FOLFIRI + panitumumab arm; however, there were no major differences in the 
incidence of toxicities including hematologic toxicities between the two arms, and the incidence of 
infusion reaction was not more than 1%. 
Both the PRIME Study12) and Study 2005018113) described above, in which KRAS mutation status 
was prospectively studied, showed that combination therapy containing panitumumab was not 
effective in KRAS-mutant patients, suggesting that KRAS mutation is predictive of poor response to 
anti-EGFR antibody therapy. 
4.1.4.3 
Clinical study results for panitumumab in Japan 
In a Japanese phase I clinical study of panitumumab, panitumumab was administered at the same 
dosing regimens with which the drug was confirmed to be safe and effective in overseas studies; 
i.e., a dose of 2.5 mg/kg once weekly, 6 mg/kg once every 2 weeks, and 9 mg/kg once every 3 
weeks. Each of these dosing regimens was evaluated in 6 patients. Again, in this study, 
panitumumab showed a good tolerability profile. 
In a Japanese phase II clinical study of panitumumab monotherapy14), 52 patients with previously 
treated, unresectable colorectal cancer were enrolled. In this study, the 6-mg/kg biweekly regimen 
of panitumumab, which was the recommended dosing regimen in the overseas phase III clinical 
study, was well tolerated, and the incidence of adverse events was similar to that observed in the 
U.S. and Europe (Table 4.b). In addition, 7 patients (13.5%) had partial response (hereinafter 
referred to as PR), and this Japanese study yielded an RR of 13.5% (two-sided 95% CI: 5.6 to 
25.8),a time to treatment failure of 11.4 weeks (two-sided 95% CI: 8.4 to 15.0), a median PFS of 
8.0 weeks (two-sided 95% CI: 7.4 to 11.4), and a median OS of 9.3 months (two-sided 95% CI: 7.1 
to 12.8), similar to those observed in clinical studies in the U.S and Europe. 
On the basis of the above results, panitumumab was approved in April 2010 for the treatment of 
incurable/unresectable, advanced/recurrent colorectal cancer in Japan as well. 
Table 4.b  Common adverse events (≥ 20%) noted in a Japanese phase II clinical study of 
Panitumumab monotherapy 
Adverse Events 
Panitumumab Monotherapy (n = 52) 
All 
≥ Grade 3 
n 
% 
N 
% 
Any adverse drug reaction  
51 
98 
6 
12 
Skin disorder 
51 
98 
3 
6 
Acne 
42 
81 
1 
2 
Dry skin 
32 
62 
0 
 
Skin rash 
24 
46 
1 
2 
Pruritus 
17 
33 
0 
 
Paronychia 
17 
33 
1 
2 
Hypomagnesaemia 
17 
33 
0 
 
Malaise 
13 
25 
0 
 
Stomatitis 
12 
23 
0 
 
Anorexia 
11 
21 
1 
2 
 
4.1.4.4 Result of the post-marketing Surveillance (overall survey) in Japan 
In a study conducted during a certain post-marketing period by enrolling all patients15), the median 
treatment duration (first day of administration to last day of administration) in 3,085 patients 
included in safety evaluation was 113 days (range: 1-559 days), and the incidence rate of adverse 


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drug reactions was 84.1% (≥Grade 3, 25.8%). The incidence rate in 1,254 patients in the group 
treated with panitumumab monotherapy was 80.1% (≥Grade 3, 19.7%) and that in 1,831 patients in 
the group treated with panitumumab + chemotherapy was 86.9% (≥Grade 3, 30.0%). The status of 
occurrence of adverse drug reactions of special interest is shown in Table 4.b.  
Table 4.b  Adverse Drug Reactions (ADRs) of special interest on Post-marketing survey in Japan 
Overall incidence of 
Post-marketing survey 
Panitumumab Monotherapy 
(n=1,254) 
Combination therapy (n=1,831) 
All 
≥ Grade 3 
All 
≥ Grade 3 
ADRs of special interest 
n 
% 
n 
% 
n 
% 
N 
% 
Skin and subcutaneous 
tissue disorders (SOC) 
918 
73.2 
118 
9.4 
1446 
79.0 
274 
15.0 
Paronychia 
272 
21.7 
33 
2.6 
459 
25.1 
99 
5.4 
Interstitial lung disease* 
16 
1.3 
- 
- 
23 
1.3 
- 
- 
Infusion reaction 
17 
1.4 
1 
0.1 
30 
1.6 
5 
0.3 
Hypomagnesemia 
257 
20.5 
61 
4.9 
263 
14.4 
62 
3.4 
Hypocalcemia 
59 
4.7 
16 
1.3 
77 
4.2 
26 
1.4 
Cardiac disorders (SOC) 
2 
0.2 
0 
0.0 
5 
0.3 
1 
0.1 
SOC: System Organ Class 
*：Based on the evaluation of the Interstitial Lung Disease (ILD) subcommittee 
 
4.1.5 
Adverse reactions to OXA 
Major dose-limiting toxicities of OXA are neurological manifestations, which are peripheral sensory 
nerve disorders characterized by dysaesthesia or paraesthesia in four limbs. They may accompany 
convulsion and are induced by exposure to coldness. Hochster et al.16) reported that these symptoms 
appeared in 85% to 95% of the patients who received FOLFOX therapy in combination with 
bevacizumab, that the duration became longer as the administration frequency increased, and that the 
incidence of functional disorders after administration of a cumulative dose of 800 mg/m2 was 
approximately 15%. In many cases, these neurological manifestations remit or disappear after 
discontinuation of administration. Acute sensory neurological manifestations appear within several 
hours after administration, and are induced by exposure to coldness. They may appear as transient 
paraesthesia, dysaesthesia, hypoaesthesia or acute laryngopharyngeal dysaesthesia syndrome. 
In addition to nerve disorders, acute laryngopharyngeal dysaesthesia syndrome is estimated to occur 
with an incidence of 1% to 2%. It is characterized by respiratory disorders without cyanosis and 
hypoxia, sensation of dyspnoea without direct effects on the respiratory functions such as dysphagia, 
decreased SaO2, laryngospasm, and bronchospasm without wheezing in the upper and lower 
respiratory tracts. Convulsion in the jaw, abnormal feeling in the tongue, dysarthria, eye pain, and 
chest pressure sensation are also observed17). These symptoms improve reversely without treatment. 
The incidence of acute laryngopharyngeal dysaesthesia syndrome is suggested to decrease as the 
duration of administration becomes longer. 
Among these adverse reactions, nerve disorders in particular make continuous administration of OXA 
difficult, and may lead to modification of the FOLFOX therapy regimen involving molecular-targeted 
drugs. For the patients responding to the therapy, they may miss the patients of important 
opportunities of treatment (internal data). 
 


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4.1.6 
Examination of the method of administration of OXA in first-line therapy 
Reduction of neurological manifestations associated with FOLFOX as standard chemotherapy for 
unresectable, advanced/recurrent colorectal carcinoma is urgently needed for improvement of the 
QOL of patients and for realization of long-term treatment. The reports of Tournigand et al18). 
presented that neurological manifestations was able to recover by setting a certain period of sLV5FU2 
therapy without OXA after FOLFOX therapy in the OPTIMOX1 (Stop and Go method) Study. They 
also presented that hematological toxicity and non-hematological toxicity were highly likely to be 
reduced during this period. Concerning the treatment effect, the response rate was 59.2% and MST 
was 21.2 months. Furthermore, the final report of OPTIMOX2 by F Maindrault-Goebel et al.19) 
showed that the OS in the administration schedule of OPTIMOX1 (Stop and Go method) was 26 
months. 
 
4.2 
Rationale for the proposed study 
In Japan, mFOLFOX6 therapy is conducted most frequently as the first-line therapy for unresectable, 
advanced/recurrent colorectal carcinoma. Peripheral nerve disorders induced by OXA contained in 
mFOLFOX6 therapy may cause a clinical problem because they become a cause of deterioration of the 
patients' QOL, thereby making continuous treatment impossible. When peripheral nerve disorders as 
mentioned above have occurred, mFOLFOX6 therapy as the baseline therapy is switched to FOLFIRI 
therapy in some cases in spite of favorable responses to the first-line therapy, instead of discontinuing 
OXA which is the cause of peripheral nerve disorders. This is deemed to lead to a loss of the opportunity 
of treatment for the patients. In the meantime, long-term administration of OXA may induce peripheral 
nerve disorders. For patients who discontinue administration of OXA after having received the drug for a 
certain period and who have experienced no peripheral nerve disorders during the treatment period, 
re-introduction of OXA in the later stage of treatment may remain as a treatment option. With regard to 
the discontinuaiton and resumption of OXA administration in FOLFOX therapy as the first line therapy 
at present, the evaluation for efficacy and safety of OPTIMOX study18) have been presented. However, 
appropriate administration method of OXA in first-line therapy with mFOLFOX6 + panitumumab has 
not been revealed. 
For these reasons, this study was planned on the basis of the judgment that efficacy and safety in the 
group in which OXA is discontinued after 6 cycles of the treatment and the group in which OXA is 
continued need to be examined in the patients responding to mFOLFOX6 + panitumumab combination 
therapy. 


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5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY 
5.1 
Objective 
To exploratorily examine efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type who have been treated with 6 cycles of 
first-line mFOLFOX6 + panitumumab combination therapy and then assigned to two groups, i.e., a 
group receiving 5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + 
panitumumab combination therapy. 
 
5.2 
Endpoints 
See Section 13.1.3 for Efficacy analysis. 
5.2.1 
Primary endpoint 
• 
Efficacy 
 
PFS rate at 9 months after randomization 
 
5.2.2 
Secondary endpoints 
• 
Efficacy 
 
PFS duration 
 
OS 
 
RR 
 
TTF 
• 
Safety 
 
Incidence rate of AEs, and the severity by incidence rate 
 
Incidence rate of peripheral nerve disorders 
 
Incidence rate of skin disorders 
 
5.2.3 
 Additional endpoint 
• 
DPSM 
• 
Duration of OXA continuation in mFOLFOX6 + panitumumab group (Group A) 
• 
Duration of panitumumab continuation in both groups 
 


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5.3 
Rationale for the endpoints 
5.3.1 
Primary endpoint 
The PFS is known as a strong surrogate endpoint for predicting treatment effects in OS, as a true 
endpoint20). Accordingly, the PFS was selected as the best indicator for evaluation of efficacy of the 
regimen with and without OXA after 6 cycles (2 weeks/cycle) of mFOLFOX6 + panitumumab 
combination therapy without being affected by the after-treatment. In addition, possible reduction in 
evaluation bias by using the PFS rate with preset time points is known in open-label, phase II, 
randomized screening controlled studies21). Consequently, the PFS rate at 9 months after 
randomization was employed as the primary endpoint of this study. The time point of 9 months was 
designed based on the median PFS rate expected in this study population. 
 
5.3.2 
Secondary endpoints 
As a help for interpretation of primary efficacy results, PFS duration, OS as a true endpoint, RR and 
TTF were selected as secondary endpoints. 
Concerning safety, the appropriateness of continuing and discontinuing OXA and panitumumab was 
evaluated in an exploratory manner. The incidence rate of adverse events, the incidences of peripheral 
nerve disorders and skin disorders were selected as secondary endpoints because they are important 
factors for the choice of treatment. 
 


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6.0 
STUDY DESIGN 
6.1 
Study design 
This is a phase II, multi-center joint, open-label, parallel-group randomized screening controlled study to 
exploratorily examine the efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type after treating them with 6 cycles of 
mFOLFOX6 + panitumumab combination therapy and subsequently assigning them to a group 
continuing mFOLFOX6 + panitumumab combination therapy (Group A) and a group in which OXA is 
discontinued and 5-FU/LV + panitumumab combination therapy is provided (Group B). 
The investigator and staff involved in this study (hereinafter referred to as "subinvestigator") enroll 
patients considered eligible for the study based on the inclusion criteria at enrollment within 14 days (2 
weeks) before the first administration (1st cycle), and treat them with 6 cycles of mFOLFOX6 + 
panitumumab combination therapy (Protocol Treatment [1]). The patients for whom continuation of 
mFOLFOX6 + panitumumab combination therapy is considered appropriate on the basis of the 
examination before administration of the 7th cycle and imagings within 14 days after administration of 
the 6th cycle, who satisfy the inclusion criteria for randomization, and who do not fall under any of the 
exclusion criteria for randomization will be randomly assigned to either the mFOLFOX6 + panitumumab 
combination group (Group A) or the 5-FU/LV + panitumumab combination group (Group B) at the ratio 
of 1:1 before administration of the 7th cycle. After randomization, treatment in Group A or Group B will 
be continued according to the administration standards for Protocol Treatment [2] until the "8.8. Criteria 
for discontinuation of protocol treatment" are met. The reasons for randomization criteria failure will be 
documented. The patients who fail to meet the administration standards for Protocol Treatment based on 
the examination before administration of the 7th cycle will be examined again after an appropriate 
interval. The patients who satisfy the subject inclusion criteria on the re-examination will receive the 
protocol treatment of the assigned group. Both inpatients and outpatients are eligible. Refer to "8.2 
Treatment regimen" for details about the protocol treatment ([1] and [2]). 
Patinets will be randomized through minimization using the following as stratification factors: study site, age 
at enrollment (≥ 20 and ≤ 69, or > 70), the number of metastasized organs (≤ 1, or ≥ 2) and response 
evaluated in accordance with the RECIST 1.122) criteria as CR, PR or SD. 
See "13.3 Determination of the planned number of subjects" for the number of subjects. 
 
 
Figure 6.a  Outline of study design 
 


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6.2 
Rationale for study design, dose and endpoints 
6.2.1 
Study population 
The timing at which OXA-induced peripheral nerve disorders occurs most frequently has been 
reported to be the time point at which the accumulated amount of OXA administered reaches 780-850 
mg/m2 20). This amount is equivalent to 9 or 10 doses when converted using the dose of 85 mg/m2 of 
OXA administered at a time in Protocol Treatment [1] and [2]. According to the report by Hochster et 
al16). who investigated the mean number of doses administered continuously in FOLFOX therapy in 
initial therapy in routine medical care, the number was 10 times in the FOLFOX + bevacizumab 
combination therapy in first-line therapy (TREE2). In the report by Giantonio et al.21), the mean 
number of doses administered continuously in FOLFOX±bevacizumab combination therapy in the 
second-line therapy (ECOG3200) for the patients with a history of chemotherapy was 7 to 10 times. 
This study aims at comparing efficacy and safety in the group continuing OXA from the 7th cycle and 
the group discontinuing OXA in the patients receiving first-line mFOLFOX6 + panitumumab 
combination therapy before the occurrence of peripheral nerve disorders. Since the above-described 
status of the frequency of OXA administration also seems to suggest that discontinuation of OXA after 
6th administration in Protocol Treatment [1] does not greatly deviate from the situation in routine 
medical care, the number of cycles of OXA administration given before randomization was set at 6. 
Moreover, since no significant differences were seen in the duration of disease control and PFS 
duration in OPTIMOX study, the response duration of treatment is not expected to differ significantly 
between the two groups even when OXA is discontinued after 6 cycles of mFOLFOX6 + 
panitumumab therapy while 5-FU/LV + panitumumab combination therapy is continued. Furthermore, 
although concomitant administration of panitumumab does not cause differences in time to treatment 
failure and PFS duration, discontinuation of OXA before the occurrence of peripheral nerve disorders 
enables re-introduction of OXA. Therefore, differences larger than in OPTIMOX study may be 
expected for OS. In addition, it may become possible to propose, for combination therapy of 
mFOLFOX6 and panitumumab, an approach which enables long-term continuation of treatment 
through prevention of the occurrence of OXA-induced peripheral nerve disorders. 
 
6.2.2 
Treatment regimens and planned number of subjects 
See "13.3 Determination of the planned number of subjects" for details. 
 
6.3 
Discontinuation of entire study or discontinuation at a study site 
6.3.1 
Criteria for discontinuation of entire study 
The sponsor should immediately discontinue the study when it is notified by the DMC and/or the 
research steering committee that at least one of the following criteria is applicable. 
• 
Occurrence of serious event/violation which endangers safety of subjects. 
• 
When new information or other evaluation on the safety or efficacy of protocol treatment 
becomes available which shows a change in the known risk/benefit profile of the concerned 
compound, and risks/benefits are no longer tolerable for subject participation in the study. 


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6.3.2 
Procedures of study suspension and discontinuation of entire study or study 
at a study site 
When the sponsor or the Institutional Review Board (IRB) such as the Ethics Review Committee 
(ERC) determines suspension or discontinuation of the entire study or the study at a certain study site, 
the sponsor will instruct the procedures specified for the relevant study. The relevant study site should 
observe the procedures for study suspension or discontinuation. 
 
6.4 
Procedures for revision of the protocol 
When a need arises to revise the protocol, the sponsor will consult with the research steering committee 
members to make a decision. 
Details of the protocol revision will be notified to investigators of all study sites. 
When the investigator of each study site receives the notification, he should arrange the revised protocol 
to be reviewed by the IRB such as the ERC again as necessary according to the stipulation at each study 
site and obtain approval of the head of the study site. 


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7.0 
SELECTION OF STUDY SUBJECTS 
7.1 
Inclusion criteria 
7.1.1 
Inclusion criteria for enrollment 
Patients who satisfy all the criteria below will be enrolled in this study. 
(1) Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma 
of the appendix and anal canal cancer) 
(2) Patients with measurable lesion(s) according to the RECIST 1.1criteria (refer to Appendix B) 
(3) Chemotherapy-naïve patients. Patients who experience relapse more than 6 months after the final 
dose of perioperative adjuvant chemotherapy* with fluoropyrimidine agents may be enrolled. 
*: Patients who received perioperative adjuvant chemotherapy using OXA may not be enrolled. 
(4) Patients aged ≥20 years at enrollment 
(5) Patients with confirmed KRAS wild-type* tumors 
(6) However, the criteria will be changed to all patients with confirmed KRAS or Neuroblastoma Rat 
Sarcoma (NRAS) wild-type tumors, when the KRAS and NRAS tests come to be covered by 
National Health Insurance, and the tests become feasible at medical institutions. 
*: Patients with no mutation in any of the codons shown below are considered wild-type. 
KRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
NRAS** 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
**: To be considered when the test comes to be covered by insurance and becomes feasible at medical 
institutions. 
(7) Patients who satisfy the following criteria for the major organ function in tests performed within 14 
days prior to enrollment 
1) 
Neutrophil count ≥ 1.5 × 103/μL 
2) 
White blood cell count ≥ 3.0× 103/μL 
3) 
Platelet count ≥ 10.0 × 104/μL 
4) 
Hemoglobin ≥ 9.0 g/dL 
5) 
Total bilirubin ≤ 2.0 mg/dL 
6) 
Aspartate aminotransferase (AST) ≤ 100 U/L (≤ 200 U/L if liver metastases are present) 
7) 
Alanine aminotransferase (ALT) ≤ 100 U/L (≤ 200 U/L if liver metastases are present) 
8) 
Serum creatinine ≤ 1.5 mg/dL 
(8) Patients graded as 0 or 1in accordance with the Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) scale 
(9) Patients with life expectancy of ≥ 6 months after enrollment 
(10) Patients who provide written informed consent after detailed explanation of the study prior to 
enrollment 


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7.1.2 
Inclusion criteria for randomization 
Patients who satisfy all the criteria below will be randomized. If possible, randomization will be 
conducted immediately before administration of the 7th cycle. 
(1) Patients who have received 6 cycles* of mFOLFOX6 + panitumumab combination therapy 
(Protocol Treatment [1]) 
*: 
Defined as the use of 5-FU/l-LV without dose interruption in all 6 cycles (2 weeks/cycle) of 
Protocol Treatment [1], in adherence to the specified Protocol Treatment [1] regimen. 
However, bolus 5-FU and panitumumab may be excluded. 
(2) Patients graded as 0 or 1 in accordance with the ECOG-PS during the 6th cycle 
(3) Patients whose imagings within 14 days (2 weeks) after the administration day in the 6th cycle 
are definitely evaluated as other than PD and Not Evaluable in accordance with the RECIST 1.1 
criteria (refer to Appendix B) 
7.2 
Exclusion criteria 
7.2.1 
Exclusion criteria for enrollment 
A subject who meets any of the criteria below will not be included in this study. 
(1) Patients who have received radiotherapy for a measurable lesion(s) 
(2) Patients who received radiotherapy for a lesion(s) other than measurable lesions within 28 days 
(4 weeks) prior to enrollment. However, the treatment to relieve the pain of metastatic bone 
tumors is allowed. 
(3) Patients with known or strongly suspected brain metastasis 
(4) Patients with synchronous or metachronous cancers (other than colorectal cancer) with a 
disease-free period of ≤5 years, excluding mucosal cancers cured or possibly cured by regional 
resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, 
etc.). 
(5) Patients with body cavity fluid that requires treatment (pleural effusion, ascites, pericardial 
effusion, etc.) 
(6) Patients who do not want to use contraception to prevent pregnancy, and women who are 
pregnant, breast-feeding or pregnancy positive 
(7) Patients with active hemorrhage requiring blood transfusion 
(8) Patients with diseases requiring systemic steroids for treatment (excluding topical steroids) 
(9) Patients who have undergone intestinal resection and colostomy within 14 days (2 weeks) prior 
to enrollment 
(10) Patients with history of, or obvious and extensive computerized tomography (CT) findings of 
interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) 
(11) Patients with serious drug hypersensitivity 
(12) Patients with local or systemic active infection requiring treatment, or with a fever indicating 
infection 
(13) Patients with intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea 
(incapacitating symptoms despite adequate treatment) 
(14) Patients with active hepatitis B and/or C 
(15) Patients with known HIV infection 
(16) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the 
study 


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7.2.2 
Exclusion criteria for randomization 
Patients who meet any of the criteria below will not be randomized. 
(1) Patients in whom interstitial pneumonia has been newly diagnosed during the period from 
enrollment to randomization 
(2) Patients who have received radiotherapy for a measurable lesion(s) during the period from 
enrollment to randomization. However, the treatment to relieve the pain of metastatic bone 
tumors is allowed 
(3) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the 
study 


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8.0 
TREATMENT 
The protocol treatment, contraindicated drugs/therapies, and recommended supportive care/combination 
therapies in this study are explained in this section. Commercially available drugs used at the study sites 
will be used in this study. See the latest package insert for details and handling of each drug. 
8.1 
Protocol treatment 
The study period in this study is defined as the period consisting of Protocol Treatment [1] (from 
obtaining informed consent to Cycle 6) and Protocol Treatment [2] (after randomization). 
8.1.1 
Protocol Treatment [1] 
mFOLFOX6 + panitumumab combination therapy 
OXA and infusional 5-FU will be administered in all of the specified 6 cycles (2 weeks/cycle). The 
dose can be reduced. 
Panitumumab will also be administered in all the possible 6 cycles; however dose interruption due to 
the occurrence of skin disorders will be allowed. 
 
8.1.2 
Protocol Treatment [2] 
Group A: mFOLFOX6 + panitumumab combination therapy 
Group B: 5-FU/LV + panitumumab combination therapy 
Dose reduction, interruption and discontinuation of every study drugs are allowed in accordance with 
"8.5 Criteria for dose change." If the study drugs are partially withdrawn, treatment with the other 
drugs will be continued unless any of the criteria specified in "8.8 Criteria for discontinuation of 
protocol treatment" is met. 
 
8.2 
Treatment regimen 
8.2.1 
Protocol Treatment [1] 
During the period of Protocol Treatment [1], mFOLFOX6 + panitumumab combination therapy will 
be given once in two weeks according to the following treatment regimen until any of the criteria 
specified in "8.8 Criteria for discontinuation of protocol treatment" is met (one administration will be 
regarded as one cycle). For administration of each drug, see "8.4 Criteria for initiation of protocol 
treatment (common for Protocol Treatment [1] and [2])" and "8.5 Criteria for dose change". 
For the patients aged 80 years or older at the time of enrollment, the drug can be administered at a 
dose one level lower than the designated dose from Cycle 1. 
Table 8.a  Treatment regimen of mFOLFOX6 + panitumumab combination therapy 
Drug 
Dose 
Method of 
administration 
(recommended) 
Date of administration 
Panitumumab 
6 mg/kg 
div 60 min* 
Day 1 
OXA 
85 mg/m2 
div 120 min 
Day 1 
l-LV 
200 mg/m2 
div 120 min 
Day 1 
5-FU (iv) 
400 mg/m2 
iv  <15 min 
Day 1 


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5-FU (civ) 
2400 mg/m2 
civ 46 hrs 
Day 1-2 
div: intravenous drip infusion, iv: intravenous infusion, civ: continuous intravenous infusion 
*:  When the dose at one time exceeds 1000 mg, intravenously administer it over 90 min or longer after dilution with 
JP physiological saline to make approximately 150 mL. 
 
 
Figure 8.a  mFOLFOX6 + panitumumab combination therapy 
 
8.2.2 
Protocol Treatment [2] 
If the dose of the drug has been reduced during the period of Protocol Treatment [1], the drug will be 
administered at the reduced dose from Cycle 7.  
 
8.2.2.1 
mFOLFOX6 + panitumumab combination therapy (Group A) 
See Section 8.2.1 for Protocol Treatment [1]. The term of Protocol Treatment [1] is regarded as 
Protocol Treatment [2]. 
8.2.2.2 
5-FU/LV + panitumumab combination therapy (Group B) 
During the period of Protocol Treatment [2], 5-FU/LV + panitumumab combination therapy will be 
given once in two weeks according to the following treatment regimen until any of the criteria 
specified in "8.8 Criteria for discontinuation of protocol treatment" is met (one administration will 
be regarded as one cycle). For administration of each drug, see "8.4 Criteria for initiation of 
protocol treatment (common for Protocol Treatment [1] and [2])" and "8.5 Criteria for dose 
change". 
Table 8.b  Treatment regimen of 5-FU/LV + panitumumab combination therapy 
Drug 
Dose 
Method of 
administration 
(recommended) 
Date of administration 
Panitumumab 
6 mg/kg 
div 60 min* 
Day 1 
l-LV 
200 mg/m2 
div 120 min 
Day 1 
5-FU (iv) 
400 mg/m2 
iv < 15 min 
Day 1 
5-FU (civ) 
2400 mg/m2 
civ 46 hrs 
Day 1-2 




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Protocol treatment should be discontinued when the subsequent cycle of treatment has not been started 
28 days later than scheduled (on Day 43 with the date of starting the previous cycle as Day 1). 
Postponement due to holidays is allowed. 
Table 8.c  Criteria for initiation of treatment cycle 
Item 
Criteria for initiation 
White blood cell count 
≥ 2,500/mm3 
Neutrophil count 
≥ 1,200/mm3 
Platelet count 
≥ 7.5 x 104/mm3 
Total bilirubin 
≤ 2.0 mg/dL 
Infection 
Absence of fever (≥ 38°C) indicating infection 
Nausea, vomiting, diarrhoea, stomatitis 
≤ Grade 1 
Initiation of treatment may be postponed at the discretion of the investigator or subinvestigator 
due to adverse events not listed above.  
 
8.5 
Criteria for dose change 
8.5.1 
Protocol Treatment [1] 
8.5.1.1 
Criteria for dose reduction/suspension of mFOLFOX6 
The criteria for dose reduction/suspension and the doses of OXA and 5-FU (bolus/infusional) 
during the period of Protocol Treatment [1] are shown in Table 8.d and Table 8.e, respectively. The 
dose of l-LV should not be changed. 
Table 8.d  Criteria for dose reduction/suspension of OXA and 5-FU (Protocol Treatment [1]) 
Adverse events in previous cycle 
Grade 
Dose adjustment of OXA and 5-FU 
Neutropenia, thrombopenia 
4 
Dose reduction of both OXA and 5-FU 
(bolus/infusional) by 1 level 
Grade 3 neutropenia or thrombopenia that 
persists for more than 7 days 
3 
Febrile neutropenia, infection, nausea, 
vomiting, diarrhoea, fatigue 
3 
Sensory nerve disorder* 
3 
Discontinuation of protocol treatment* 
2 
Discontinuation of protocol treatment* 
Or dose reduction of OXA by 1 level 
Allergic reaction 
3 
Discontinuation of protocol treatment* 
Dose reduction is allowed as necessary at the discretion of the investigator or subinvestigator due to 
stipulations/reasons other than above. However, protocol treatment will be discontinued at the time 
point of suspension of OXA and infusional 5-FU. 
*: 
When allergic reaction occurs during treatment with OXA, the treatment should be stopped immediately. The 
decision of restarting this cycle will be entrusted to the study site. If the allergic reaction is Grade 2 or less, protocol 
treatment with care is allowed under actions such as providing appropriate supportive care or slowing the infusion 
speed for the treatment after the next course. 
 


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Table 8.e  Doses of OXA and 5-FU (Protocol Treatment [1]) 
Dose reduction 
level 
OXA 
5-FU iv 
5-FU civ 
Initial dose 
85 mg/m2 
400 mg/m2 
2400 mg/m2 
-1 
65 mg/m2 
200 mg/m2 
2000 mg/m2 
-2 
50 mg/m2 
0 mg/m2 
(discontinuation**) 
1600 mg/m2 
-3 
Discontinuation of 
protocol treatment* 
0 mg/m2 
(discontinuation**) 
Discontinuation of 
protocol treatment* 
iv: intravenous infusion, civ: continuous intravenous infusion 
*: 
See "8.8 Criteria for discontinuation of protocol treatment" for details. 
**: The drug will be withdrawn; however, the Protocol Treatment [1] will be continued. 
 
8.5.1.2 
Criteria for dose reduction/suspension of panitumumab 
The criteria for dose reduction/suspension and the dose of panitumumab during the period of 
Protocol Treatment [1] are shown in Table 8.f and Table 8.g, respectively. 
Table 8.f  Criteria for dose reduction/suspension of panitumumab (Protocol Treatement [1]) 
Adverse events in 
previous cycle 
Grade 
Dose adjustment of panitumumab 
Skin disorder 
3 
Dose reduction by 1 level after a certain washout period. 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
milder within 6 weeks. 
2 
Dose suspension is allowed. (Suspension is not 
mandatory.) 
If the severity after the washout period recovers to the 
same or milder level than that at onset, the drug will be 
administered at the same dose before suspension. 
1 
Hypomagnesaemia* 
3 
Dose reduction by 1 level after a certain washout period. 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
milder within 6 weeks. 
Infusion reaction**, *** 
3 
Discontinuation of protocol treatment 
Dose reduction/suspension is allowed as necessary at the discretion of the investigator or 
subinvestigator due to stipulations/reasons other than above.  
*: 
When accompanied by abnormal ECG findings requiring treatment such as significant QTc prolongation, 
discontinuation or suspension of panitumumab should be considered irrespective of the severity of 
hypomagnesaemia. 
**: Allergic reaction, anaphylactoid reaction, and chills, fever, and dyspnea occurring within 24 hours after the initial 
dose 
***: The protocol treatment should be stopped immediately upon infusion reactions observed during infusion. The 
applicability of restarting this cycle should be considered at the study site's discretion. If the infusion reactions are 
Grade 2 or milder, the cautiously managed protocol treatment may be provided in and after the next cycle, such as 
providing appropriate supportive care or reducing the infusion rate by 50%. 
 


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Table 8.g  Dose of panitumumab (Protocol Treatement [1]) 
Dose reduction level 
Panitumumab 
Initial dose 
6 mg/kg 
-1 
4.8 mg/kg 
-2 
3.6 mg/kg 
-3 
0 mg/kg (discontinuation of protocol treatment) 
 
8.5.2 
Protocol Treatment [2] 
8.5.2.1 
Criteria for dose reduction/suspension of mFOLFOX6 
The criteria for dose reduction of OXA and 5-FU (bolus/infusional) during the period of Protocol 
Treatment [2] is shown in Table 8.h. Refer to Table 8.i for the doses of OXA and 5-FU 
(bolus/infusional), respectively. 
Table 8.h  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [2]) 
Adverse events in previous cycle 
Grade 
Dose adjustment of OXA and 5-FU 
Neutropenia, thrombopenia 
4 
Dose reduction of both OXA and 5-FU 
(bolus/infusional) by 1 level 
Grade 3 neutropenia or thrombopenia that 
persists for more than 7 days 
3 
Febrile neutropenia, infection, nausea, 
vomiting, diarrhoea, fatigue 
3 
Sensory nerve disorder 
3 
Discontinuation of OXA* (no 
resumption) 
2 
Discontinuation* of OXA (no 
resumption) 
Allergic reaction** 
3 
Discontinuation of OXA* (no 
resumption) 
Dose reduction/suspension is allowed as necessary at the discretion of the investigator or 
subinvestigator due to stipulations/reasons other than above. 
*: 
The protocol treatment will be continued until any criterion specified in "8.8 Criteria for discontinuation of protocol 
treatment" is met. 
**: The protocol treatment should be stopped immediately upon allergic reactions observed during administration. The 
applicability of restarting this cycle should be considered at the study site's discretion. If the allergic reactions are 
Grade 2 or milder, the cautiously managed protocol treatment may be provided in and after the next cycle, such as 
providing appropriate supportive care or reducing the dosing speed by 50%. 
 


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Table 8.i  Doses of OXA and 5-FU (Protocol Treatment [2]) 
Dose reduction 
level 
OXA 
5-FU iv 
5-FU civ 
Initial dose 
85 mg/m2 
400 mg/m2 
2400 mg/m2 
-1 
65 mg/m2 
200 mg/m2 
2000 mg/m2 
-2 
50 mg/m2 
0 mg/m2 
(discontinuation*) 
1600 mg/m2 
-3 
0 mg/m2 
(discontinuation) 
0 mg/m2 
(discontinuation*) 
0 mg/m2 
(discontinuation) 
iv: intravenous infusion, civ: continuous intravenous infusion 
*: 
The drug will be withdrawn; however, the Protocol Treatment [2] will be continued. 
 
8.5.2.2 
Criteria for dose reduction/suspension of panitumumab 
The criteria for dose reduction/suspension and the dose of panitumumab during the period of 
Protocol Treatment [2] are shown in Table 8.j and Table 8.k, respectively. 
Table 8.j  Criteria for dose reduction/suspension of panitumumab (Protocol Treatement [2]) 
Adverse events in 
previous cycle 
Grade 
Dose adjustment of panitumumab 
Skin disorder 
3 
Dose reduction by 1 level after a certain washout period. 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
milder within 6 weeks. 
2 
Dose suspension is allowed. (Suspension is not 
mandatory.) 
If the severity after the washout period recovers to the 
same or milder level than that at onset, the drug will be 
administered at the same dose before suspension. 
1 
Hypomagnesaemia* 
3 
Dose reduction by 1 level after a certain washout period. 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
milder within 6 weeks. 
Infusion reaction**, **** 
3 
Discontinuation of protocol treatment*** 
Dose reduction/suspension is allowed as necessary at the discretion of the investigator or 
subinvestigator due to stipulations/reasons other than above.  
*: 
When accompanied by abnormal ECG findings requiring treatment such as significant QTc prolongation, 
discontinuation or suspension of panitumumab should be considered irrespective of the severity of 
hypomagnesaemia. 
**: Allergic reaction, anaphylactoid reaction, and chills, fever, and dyspnea occurring within 24 hours after the initial 
dose 
***: The protocol treatment will be continued until any criterion specified in "8.8 Criteria for discontinuation of protocol 
treatment" is met. 
****: The protocol treatment should be stopped immediately upon infusion reactions observed during infusion. The 
applicability of restarting this cycle should be considered at the study site's discretion. If the infusion reactions are 
Grade 2 or milder, the cautiously managed protocol treatment may be provided in and after the next cycle, such as 
providing appropriate supportive care or reducing the infusion rate by 50%. 
 


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Table 8.k  Dose of panitumumab (Protocol Treatement [2]) 
Dose reduction level 
Panitumumab 
Initial dose 
6 mg/kg 
-1 
4.8 mg/kg 
-2 
3.6 mg/kg 
-3 
0 mg/kg (discontinuation*) 
*: 
The drug will be withdrawn; however, the Protocol Treatment [2] will be continued. 
 
8.6 
Criteria for dose increase of protocol treatment 
The dose should not be increased after dose reduction for any of the drugs. 
 
8.7 
Overdose of panitumumab 
Overdose of panitumumab is defined as below regardless of whether or not adverse events have 
occurred. 
(1) Administration at doses higher than the approved dose of panitumumab (6 mg/kg) 
(2) The next dose is administered within 10 days after the date of previous administration. 
Aiming at consistent entry of significant safety information regarding overdose in the database, the 
investigator or subinvestigator will record all cases of overdose (irrespective of the presence or absence 
of adverse events) in the page of overdose of the Case Report Forms (CRFs). Adverse events associated 
with overdose will be recorded in the page of "Adverse Events" in the CRFs according to "10.0 
ADVERSE EVENTS". 
Serious adverse events (SAEs) associated with overdose will be reported according to the procedure 
described in "10.2.2. Collection and reporting of serious adverse events." 
In the cases of overdose of panitumumab, the investigator or subinvestigator will provide treatment 
appropriate for the symptoms. 
 
8.8 
Criteria for discontinuation of protocol treatment 
The protocol treatment specified below should be discontinued when any of the criteria for 
discontinuation of protocol treatment listed below is met. The date of discontinuation of protocol 
treatment is defined as the date when the investigator decides on discontinuation of protocol treatment. 
The investigator should record the main reason for discontinuation of protocol treatment in the CRF 
according to the classification described below. See "9.3 Records of subjects who discontinued before 
enrollment"for subjects withdrawn from the study before enrollment. 
<Common for Protocol Treatment [1] and [2]> 
1. 
AE 
When the protocol treatment is discontinued due to AEs, or when the next protocol treatment cannot 
be resumed due to AEs for 44 days at longest after Day 1 of the last cycle of the protocol treatment. 
However, treatment delays due to holidays are allowed. 
2. 
Significant deviation from the protocol 
When study continuation may cause intolerable risk to the health of a subject because the subject 


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was found not to satisfy the inclusion criteria specified in the protocol after enrollment or 
randomization of protocol treatment has not been observed. 
3. 
Lost to follow-up 
When a subject fail to make visits and cannot be contacted. That attempts were made to contact the 
subject should be recorded in the source documents. 
4. 
Voluntary discontinuation 
When a subject wishes to discontinue study participation. Reasons for discontinuation should be 
documented in theCRF as long as they are recognizable. 
Note: Efforts to clarify the reasons for voluntary discontinuation should be made as possible. (A 
discontinuation due to AEs or lack of efficacy is not to be classified as "voluntary discontinuation.") 
5. 
Discontinuation of entire study 
When study discontinuation is decided by the sponsor, or IRB such as the ERC. 
6. 
Pregnancy 
When a female subject is found out to be pregnant. 
Note: Study participation should be immediately discontinued when pregnancy is known. 
7. 
Lack of efficacy 
When PD is evident in the clinical or imaging evaluation. The date of PD diagnosis should be 
documented in the CRF. 
In the case of a study withdrawal due to clinical PD, his/her CRF should include the dates of clinical 
PD diagnosis and subsequent imaging PD diagnosis. 
8. 
Death during protocol treatment 
Death before the consideration of protocol treatment discontinuation. 
9. 
When surgery aimed at curative resection (complete resection: R0 resection) of colorectal cancer is 
scheduledNote that PFS evaluation data (as described below) of a subject withdrawn from this study 
during the period of Protocol Treatment [2] should be collected to the extent possible. 
Data to be collected:  all imaging tests after curative resection (dates, methods and results of tests) 
10. Other 
When the investigator or subinvestigator consider that the protocol treatment should be 
discontinued. Details should be documented in the CRF. 
<Protocol Treatment [1] > 
11. When any of the inclusion criteria for randomization fails to be met or any of the exclusion criteria 
is met.<specify the applicable inclusion/exclusion criteria> 
 
8.9 
Contraindicated drugs/therapies 
The drugs and therapies shown below are contraindicated from informed consent until 28 days (4 weeks) 
after discontinuation of protocol treatment. The investigator and/or subinvestigator should instruct the 
patients not to use any drugs including over-the counter drugs other than the prescribed drugs without 
prior consultation. The following therapies are allowed to be started without waiting for the specified 
period only when the scheduled tests are performed until the next treatment upon starting it within 28 
days (4weeks) after discontinuation of protocol treatment. 
 
Chemotherapy other than protocol treatment 
 
Hormone therapy 
 
Immunotherapy 
 Cellular immunotherapy 


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 Vaccine therapy 
 Cytokine therapy 
 Biological response modifiers (BRM) 
 Antibody therapy 
 Gene therapy 
 
Other antibody therapy 
 
Radiotherapy 
However, the treatment to relieve the pain of metastatic bone tumor is allowed. 
 
Hyperthermia therapy 
 
Denosumab* 
*: Use of bisphosphonates is allowed. 
 
Study drug and unapproved drug 
 
8.10 
Allowed supportive care and combination medications 
The supportive care and concomitant medications shown below are recommended during the study 
period (from informed consent until discontinuation of protocol treatment). The absence of concomitant 
or supporting therapy does not constitute a protocol deviation. 
• 
Neutropenia 
Administration of G-CSF products is recommended. G-CSF products should be administered 
according to the NHI indications and should not be prophylactically used. 
• 
Nausea, vomiting 
Premedication including prophylactic administration of antiemetics is allowed. Premedication 
with 5-HT3 (serotonin) receptor antagonists, NK1 (neurokinin 1) receptor antagonists, steroids, 
and antihistamines may be carried out using the method employed at each study site. 
• 
Allergic reaction 
Treatment with adrenal corticosteroids, antihistamines, etc. may be considered at the time of 
onset or for premedication at the start of protocol treatment. Careful administration of 
panitumumab by slowing the infusion speed may be considered. 
• 
Interstitial pneumonia 
Interstitial pneumonia should be treated according to the severity (e.g., steroid pulse therapy).  
• 
Other 
Drugs for treatment of adverse events may be coadministered at the discretion of the investigator. 
Symptomatic therapies which have been continued from before the start of this study are allowed. 
In addition, it is recommended that the supportive care shown below be performed at the discretion of 
the investigator when any of panitumumab-related adverse events shown below is observed. The absence 
of supporting therapy does not constitute a protocol deviation. 
• 
It is recommended that oral minocycline, etc. be administered when skin disorder is observed. 
• 
At the time of onset of skin disorder 
External salicylic acid petrolatum (10%) 
External steroid therapy (example) 
Face: hydrocortisone butyrate (0.1%) 
Trunk: difluprednate (0.05%) 


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It is recommended the following skin care prophylactically against the skin disorder from the 
start of protocol treatment [1]. 
Moisturizer (example): heparin analog lotion 
Sunscreen (example): not containing 4-aminobenzoic acid, SPF (Sun Protection Factor) ≥30, PA 
(Protection grade of UVA) ≥ ++. Apply before going out to block ultraviolet rays (UVA and 
UVB). 
• 
At the time of onset of electrolyte abnormality (e.g., hypomagnesaemia, hypocalcaemia) 
ECG: ECG may be performed to determine whether there are abnormal ECG findings requiring 
treatment such as significant QTc prolongation. When any abnormal ECG findings requiring 
treatment are observed, suspension of panitumumab should be considered irrespective of the 
serum magnesium concentration. 
Magnesium supplementation (example): intravenous infusion of magnesium sulfate(10 mmol) 
over 60 min 
 
8.11 
Handling of surgery aimed at curative resection (complete resection: R0 
resection) of colorectal cancer 
Surgery is recommended for patients who can tolerate curative resection (complete resection: R0 
resection) thanks to the antitumor effect after initiation of protocol treatment. 
Protocol treatment should be discontinued when surgery aimed at curative resection (complete resection: 
R0 resection) of colorectal cancer is scheduled, and all tests and observation scheduled at discontinuation 
of protocol treatment should be conducted (see “9.1 Study calendar”). 
 
8.12 
Recommended follow-up therapy 
8.12.1 Recommended second-line treatment 
• 
Group A: Administration of bevacizumab in combination with IRI-based chemotherapy is 
recommended. 
• 
Group B: Readministration of bevacizumab in combination with OXA-based chemotherapy is 
recommended. 
 
8.12.2 Recommended third-line or subsequent treatment 
• 
Group A: All approved drugs (regorafenib, etc.) should be administered appropriately as best as 
possible. 
• 
Group B: Administration of bevacizumab in combination with the IRI-based chemotherapy is 
recommended. After that, all approved drugs (regorafenib, etc.) should be administered 
appropriately as best as possible. 
 


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9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR 
OBSERVATIONS 
9.1 
Study calendar 
The investigator should collect data according to the following procedures. The same investigator should 
perform tests/observation/evaluation of subjects in principle. 
Table 9.a  Study calendar (Protocol Treatment [1]) 
Item 
Enrollment Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Discontinuation of 
protocol treatment*7 
Informed consent 
●* 
 
 
 
 
 
 
 
Eligibility 
● 
 
 
 
 
 
 
 
Subject background 
● 
 
 
 
 
 
 
 
Clinical findings (physical 
examination) *1 
● 
● 
● 
● 
● 
● 
● 
● 
Vital signs*1 
 
● 
● 
● 
● 
● 
● 
● 
Height, body weight*1,*2 
● 
 
○ 
○ 
○ 
○ 
○ 
 
ECOG P.S. *1 
● 
● 
● 
● 
● 
● 
● 
● 
Treatment compliance 
 
● 
● 
● 
● 
● 
● 
 
Laboratory tests 
 
 
 
 
 
 
 
 
Hematology*1 
●*3 
● 
● 
● 
● 
● 
● 
● 
Serum chemistry*1 
●*3 
● 
● 
● 
● 
● 
● 
● 
Tumor markers*1 
●*3 
● 
 
 
 
 
 
○*4 
Imaging test *1 
(thoracoabdominal-pelvic 
CT/MRI) 
●*5 
● 
 
● 
 
 
 
○*6 
NRAS test 
●*8 
 
 
 
 
 
 
 
Adverse Event 
－ 
←    ●    → 
●: Mandatory, 〇: Perform as necessary 
*1: Consent should be obtained before enrollment 
*2: Perform before initiation of each cycle of protocol treatment. 
*3: The test in Cycle 1 may be skipped if laboratory tests at enrollmentare performed within 2 days before 
the treatment in Cycle 1. The tests in Cycle 1 should be performed before the treatment in Cycle 1 when 
the tests at enrollment are performed more than 3 days before the treatment in Cycle 1. 
*4: Measure body weight for dose-change. 
*5: Measure only when more than 56 days (8 weeks) have passed after the previous measurement. 
*6: If the imaging test before enrollment is performed within 14 days prior to Cycle 1, the test of first cycle 
can be omitted, but an imaging test should be preferably conducted immediately before administration 
of Cycle 1. 
*7: Perform the imaging test within 28 days (4 weeks) after decision on discontinuation for subjects 
withdrawn from the study for any reason other than PD. 
*8: Perform within 28 days (4 weeks) after discontinuation. Perform until the next treatment when it will be 
startied within 28 days (4weeks) after discontinuation. 
*9: Perform the test in the patients who agree to participate in the study before NRAS test comes to be 
covered by insurance, and the patients who agree to participate in the study after NRAS test comes to be 
covered by insurance but before the test becomes feasible at the study site and who give consents to the 
conduct of the test. The timing of submission of samples does not need to be upon registration. 
 


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Table 9.b  Study calendar (Protocol Treatment [2]) 
Item 
Randomization Cycle 
7§ 
Cycle 
8 
Cycle 
9 
Cycle 
10 
Cycle 
11~§ 
9 months after 
randomization 
Discontinuation 
of protocol 
treatment**7 
Follow-up 
period *10 
Eligibility 
● 
 
 
 
 
 
 
 
 
Clinical findings 
(physical examination)*1 
● 
● 
● 
● 
● 
● 
● 
● 
 
Vital signs *1 
 
● 
● 
● 
● 
● 
● 
● 
 
Height, body weight *3 
 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
ECOG P.S.*1 
 
● 
● 
● 
● 
● 
● 
● 
 
Treatment compliance 
(incluing the test at 
discontinuation) 
 
● 
● 
● 
● 
● 
● 
● 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
Hematology *1 
 
●*2 ● 
● 
● 
● 
● 
● 
 
Serum chemistry *1 
 
●*2 ● 
● 
● 
● 
● 
● 
 
Tumor markers§, *1 
 
●*2 
 
 
 
● 
○§ 
○*8 
 
Imaging test 
(thoracoabdominal-pelvic 
CT/MRI)§ 
●*4 
 
 
 
 
●*5 
●*6 
○*9 
○ 
Follow-up therapy 
 
 
 
 
 
 
 
 
● 
Survival survey 
 
 
 
 
 
 
 
 
● 
Adverse Event 
←    ●    → 
－ 
●: Mandatory, 〇: Perform as necessary 
§: As a rule, tests of tumor markers and imaging tests will be conducted in the (4n + 3)th administration 
cycle. However, when the administration interval becomes longer because of the criteria for extension of 
administration period, the tests will be conducted at appropriate timings. 
*1: Perform before the initiation of each cycle of protocol treatment. 
*2: The test in Cycle 7 may be skipped when the tests in Cycle 7 are performed within 2 days before 
treatment in Cycle 7. 
*3: Measure body weight for dose-change. 
*4: Masure between the day within 14 days (2 weeks) after administration in Cycle 6 and randomization. 
*5: Two years after the initiation of protocol treatment, the frequency of imaging test will be reduced to 
once every 112 ± 14 days (16 ± 2 weeks). 
*6:  Perform the imaging test at 9 months after randomization in addition to the cycles scheduled as the § 
rule above. 
*7: Perform within 28 days (4 weeks) after discontinuation , and also before the initiation of next treatment 
course if the next course starts within 28 days (4 weeks) after discontinuation. 
*8: Perform only when 56 days (8 weeks) or more have passed after the previous measurement. 
*9: Perform within 28 days (4 weeks) after discontinuation in only withdrawals for any reason other than 
PD. 
*10: Perform every 6 months (approximately) after discontinuation of protocol treatment. 
 
9.2 
Collection/test/observation items and procedures during the study 
The investigator will perform the following as scheduled in “9.1 Study calendar.” 
9.2.1 
Informed consent procedure 
The method for obtaining consent is described in "15.3 Written information and subject’s consent." 


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Consent should be obtained from each subject before initiation of study procedures. 
A unique subject ID code will be assigned to each subject when explanation is given to obtain consent. 
The subject ID code will be used throughout the study period. 
 
9.2.2 
Procedures for registration and allocation of drugs 
9.2.2.1 
Procedures for registration and initiation of protocol treatment 
The investigator will register subjects according to the following procedures. 
1) 
The investigator or study collaborator should record the necessary items in subject screening 
list for a subject who was selected to receive explanation for obtaining consent for study 
enrollment. 
2) 
The investigator or study collaborator should input the necessary items into the Web case 
registration system* for a subject who has given consent**. 
* : The case registration is temporarily processed on facsimiles using case registration forms 
until the Web case registration system release. The investigator, subinvestigator or study 
collaborator provides required descriptions in the case registration forms. The Case 
Registration Center determines the eligibility based on the provided case registration 
forms. The results are to be sent from the Case Registration Center to the investigator, 
subinvestigator or study collaborator by e-mail. 
** : The study collaborator may input into the Web case registration system by instruction of 
the investigator. 
3) 
Eligibility of a prospective subject is judged by the Web case registration system and a 
protocol study group will be assigned when the subject is eligible. 
4) 
The investigator and study collaborator will check the registration result and assigned protocol 
study group on the Web case registration system. The registration result and assigned protocol 
study group will be sent via e-mail from the Web case registration system to the investigator 
and study collaborator. 
5) 
The investigator should start the allocated protocol treatment within 15 days of formal 
registration (including the same day of week as the day of enrollment). 
6) 
The investigator or study collaborator should immediately contact the sponsor and input 
necessary items in the Web subject registration system when the study drug is not 
administered for reasons such as withdrawal of consent after allocation, or when a change 
related to allocation is made to the data of the registered subject. 
9.2.2.2 
Preparation of allocation and storage procedures 
The statistical analysis manager (or its designees) should prepare the allocation procedures and 
manage allocation information of subjects. Dynamic allocation by minimization will be applied to 
protocol treatment allocaion, using the following as stratification factors: study site, age at 
enrollment (≥ 20 and ≤ 69, or > 70), the number of metastasized organs (≤ 1, or ≥ 2) and response 
evaluated in accordance with the RECIST 1.1 criteria (CR, PR or SD). The allocation information 
should be accessible only by personnel with independent authorization from the statistical analysis 
manager or its designees. 
 


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9.2.3 
Subject demographics 
The following demographic data will be collected: date of birth and sex at the time of enrollment. 
The following data concerning the target disease of colorectal cancer will be collected. 
1) 
Tissue type 
The tissue type will be assessed based on the histological findings in the “Japanese Classification 
of Colorectal Carcinoma” and recorded in the CRF with the date and site of sampling for 
diagnosis. 
 
Date of initial diagnosis 
 
Date of diagnosis of Stage 4 (no need for CRF data entry when it is the day of the initial 
diagnosis) 
2) 
History of treatment 
 
History of surgery 
 
For subjects with a history of surgery, the date of surgery, surgery site 
(primary/metastatic lesion), and the number of lymph nodes resected. Endoscopic 
surgery, which is not considered a history of surgery, should not be entered into the 
CRF. 
 
History of radiotherapy 
 
For subjects with a history of radiotherapy, the final irradiated date. 
 
History of preoperative and/or postoperative adjuvant chemotherapy 
 
For subjects with a history of adjuvant chemotherapy, the type of preoperative and/or 
postoperative adjuvant chemotherapy, date of final treatment. 
3) 
Information on metastatic organ 
 
Number of metastatic organs (0, 1, 2 or more)* 
*: The primary lesion/regional lymph node is not included, and the distant lymph node is 
counted as “one organ” even if there is more than one. 
 
Metastatic organs (liver, lung, peritoneum, lymph node*, bone, adrenal gland, skin, other**) 
*: distant lymph node is counted as “one organ” even if there is more than one. 
**: The name of the organ will be recorded in the CRF. 
4) 
Information on primary organ 
 
Single/multiple 
 
Primary lesion site [ascending colon, transverse colon, descending colon, sigmoid colon, 
rectosigmoid or rectum (further information as follows will be required for the case of 
transverse colon: proximal two thirds or distal one third of the transverse colon, or 
unknown)] 
 
9.2.4 
Medical history 
A medical history is defined as any clinically problematic disease or symptom that has resolved within 
one year prior to initiation of protocol treatment. Any notable medical history will be recorded in the 
CRF. 
 


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9.2.5 
Current medical condition 
A current medical condition is defined as any symptom or disease present at initiation of protocol 
treatment. Any notable current medical condition will be recorded in the CRF. Clinically problematic 
laboratory test data, ECG findings, and abnormal physical examination findings observed immediately 
before initiation of protocol treatment should be handled as a current medical condition at the 
discretion of the investigator. 
 
9.2.6 
Clinical findings (physical examination) 
The following locations and parts of the body will be examined: 
(1) eyes, (2) ears, nose, and throat, (3) cardiovascular system, (4) respiratory system, (5) 
gastrointestinal system, (6) dermatologic system, (7) extremities, (8) musculoskeletal system, (9) 
nervous system, (10) lymph nodes, (11) other. 
In particular, subjects will be checked for the following symptoms at the physical examination: 
allergic reaction, fatigue, rash acneiform, dry skin, paronychia, infusion related reaction, 
palmar-plantar erythrodysaesthesia syndrome, anorexia, diarrhoea, nausea, vomiting, oral mucositis, 
febrile neutropenia, infection, hemorrhage, pain, peripheral motor neuropathy, peripheral sensory 
neuropathy, alopecia, thromboembolism, gastrointestinal perforation, pneumonitis, and pulmonary 
fibrosis. 
For diagnosis after initiation of protocol treatment, evaluate the clinically problematic abnormality 
compared with the result of diagnosis before initiation of protocol treatment. 
 
9.2.7 
Body weight and height 
Body weight and height will be measured at enrollment. Body weight (kg) will be measured to the 
first decimal place and rounded off to the first decimal place when the second decimal place is known. 
Height (cm) determined will be expressed in integer value (rounded off to integer). 
In principle, measurement is unnecessary during the treatment period. However, body weight should 
be measured for dose-change, although CRF recording is unnecessary. In the case of weight loss, 
which the investigator or subinvestigator considers as a clinical problem, should be classified as an AE 
and documented in the CRF. 
 
9.2.8 
Vital signs 
The following vital signs will be measured: body temperature, blood pressure at sitting position (after 
rest for 5 min or longer) and pulse rate (bpm). 
 
9.2.9 
ECOG-PS 
ECOG-PS will be assessed according to Table 9.c. 
Table 9.c  Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 
Grade 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 


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Grade 
Definition 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
9.2.10 Treatment compliance (Protocol Treatment [1] and [2] implementation 
status) 
The investigator should record the compliance with protocol treatment in the CRFs as follows: 
• 
When protocol treatment is administered: The dose and the date of treatment should be recorded. 
The reason for dose reduction should also be recorded when appropriate. 
• 
When any drug used in protocol treatment is suspended: The date of suspension should be 
recorded. 
• 
When any drug used in protocol treatment is discontinued: The date and reason for 
discontinuation should be recorded. 
 
9.2.11 Laboratory tests 
The laboratory tests performed at each time point during the study are shown in Table 9.d to Table 9.g. 
The laboratory tests will be performed at each study site. 
The investigator or subinvestigator should evaluate the reported laboratory test results. The standard 
values of laboratory tests are consistent to the "List of Common Reference Ranges" issued by the 
JCOG. 
Table 9.d  Laboratory tests performed at enrollment 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
CEA 
CA19-9 
 
Immunology 
HBs antigen 
Hepatitis tests including anti-HCV 
 


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Table 9.e  Laboratory tests performed before the initiationof each cycle(Protocol Treatment [1]) 
Hematology 
Serum chemistry 
Tumor marker 
WBC* 
Neutrophil count* 
Platelet count* 
Hemoglobin content* 
Total bilirubin* 
ALT* 
AST* 
Creatinine* 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA*, † 
CA19-9*, † 
*: The tests in Cycle 1 may be skipped when the tests at enrollment are performed within 2 
days before the treatment in Cycle 1. The tests in Cycle 1 should be performed before the 
treatment in Cycle 1 when the tests at enrollment are performed more than 3 days before the 
treatment in Cycle 1. 
†: Measure before the initiation of Cycle 1 only. 
 
Table 9.f  Laboratory tests performed before the initiation of each cycle(Protocol Treatment [2]) 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA* 
CA19-9* 
*: Perform every 8 weeks. 
 


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Table 9.g  Laboratory tests performed at the time of discontinuation 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA* 
CA19-9* 
*: Measure only when more than 56 days (8 weeks) have passed after the previous 
measurement. 
 
9.2.12 Imaging test (thoracoabdominal-pelvic CT/MRI) 
An imaging test at enrollment will be performed within 28 days prior to enrollment (including the 
same day of week as the day of enrollment). The results of imaging diagnosis/test performed before 
obtaining consent may be used if it is performed within 28 days prior to enrollment.  
During the period of Protocol Treatment [1], the imaging test will be performed before administration 
in Cycle 1 and Cycle 3. The results of imaging tests before administration in Cycle 1 will be handled 
as the image data for measurable lesion, and the test will be performed within 14 days prior to 
initiation of Protocol Treatment [1] (including the same day of week as the day of enrollment). If the 
imaging test before enrollment is performed within 14 days prior to initiation of Protocol Treatment 
[1], the imaging test can be omitted, but an imaging test should be preferably conducted immediately 
before administration in Cycle 1. 
The imaging test before administration in Cycle 3 will be performed 14 ± 3 days after 
administration in Cycle 2. 
The imaging test before initiation of Protocol Treatment [2] will be perfoemed within 2 weeks after 
administration in Cycle 6. It will be performed every 56 ± 14 days (8 ± 2 weeks) after initiation of 
Protocol Treatment [2], and at 9 months (252 ± 14 days, i.e., 36 ± 2 weeks) after randomization. 
Two years after the initiation of protocol treatment, the frequency of imaging test will be reduced to 
once every 112 ± 14 days (16 ± 2 weeks). (See "Table 9.b  Study calendar (Protocol Treatment 
[2])" for details.) 
Thoracoabdominal-pelvic CT (in principle, contrast CT with a slice width of 5 mm or less, but MRI is 
also acceptable) will be used for imaging test, and the modality and the date of imaging test will be 
recorded in the CRF. 
The same modality should be used during protocol treatment throughout the study period. 
The investigator should evaluate the test results according to the RECIST 1.1 criteria and record the 
evaluation results in the CRF. 
For subjects withdrawn from the study for any reason other than imaging findings such as clinical PD, 
the imaging test at discontinuation should be performed within 28 days (4 weeks) including the day of 
decision (including the same day of week as the day of decision). 
 


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The following data of subjects who shift into the Protocol Treatment [2] and are not associated with 
imaging evidence of PD shall be collected until death of the relevant subjects or the entire study 
termination by the Sponsor, even after the initiation of the next treatment course. 
 
• 
Date of clinical PD diagnosis (for cases without clinical PD diagnosis until discontinuation) 
 
Cases with imaging PD diagnosis before clinical PD diagnosis are out of the scope of data 
collection. 
• 
Date of imaging PD diagnosis 
 
The date of imaging PD diagnosis should be documented, regardless of presence/absence of 
clinical PD evidence. 
The date of last imaging test should be documented for cases without imaging PD diagnosis 
throughout the follow-up period. 
• 
Last confirmation date of PFS 
 
The last confirmation date of PFS should be documented for cases with neither clinical or 
imaging PD diagnosis throughout the follow-up period. 
• 
Imaging findings 
 
All the imaging findings during from the imaging test at discontinuation until imaging PD 
diagnosis should be documented. 
 
The last confirmation date of PFS should be documented if follow-up is unavailable, due to such as 
consent withdrawals and losses to follow-up. 
 
9.2.13 NRAS test 
9.2.13.1 Subjects 
The subjects will be the patients who agree to participate in the study before NRAS test comes to be 
covered by insurance, and the patients who agree to participate in the study after NRAS test comes 
to be covered by insurance but before the test becomes feasible at the study site and who give 
consents to the conduct of the test. 
9.2.13.2 Samples and submission 
For the patients who have given consent to the test, the tumor tissue samples which have been 
collected in surgery or biopsy performed prior to informed consent, and which are used for 
evaluation of KRAS will be used for the test. From paraffin-embedded samples, 5-μm slices will be 
obtained, and 5 pathological samples fixed on slide glasses will be submitted to 
 
. It is also acceptable to submit samples in the form of 
paraffin-embedded samples. When paraffin-embedded samples are submitted,
 will prepare a 
necessary number of slide glass samples, and will return the remaining sample to the study site. 
Investigators will use the materials prepared by 
 in advance at the beginning of the study and 
send the samples to 
. Details are described in the written procedure prepared separately. 
 
will send in advance the materials necessary for storing and sending samples to the study sites 
where enrollment of study subjects has become possible. 
Details regarding submission of tumor tissues will be described in the written procedure prepared 
separately. 


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9.2.13.3 Data 
Among the subjects specified in "9.2.13.1 Subjects", the investigators will enter the following 
issues regarding the submitted tumor tissues in the CRFs for the subjects for whom the samples 
required for the test have been submitted to 
. However, recording of the results of NRAS 
measurement in the CRFs will be unnecessary. 
1) 
Informed consent date 
2) 
Samples submission(Done/Not yet) 
3) 
Are the samples identical to the samples used for the KRAS test (KRAS exon 2)? (Yes/No) 
 
Table 9.h  EXON and codon verified on NRAS test 
KRAS 
EXON 
－ 
3 
4 
codon 
－ 
59, 61 
117, 146 
NRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
 
9.2.14 Surgery aimed at curative resection (complete resection: R0 resection) of 
colorectal cancer 
When surgery is performed for patients who are expected to tolerate curative resection of colorectal 
cancer during protocol treatment, the operative procedure, date of surgery, and postoperative 
assessment of residual tumor should be recorded in the CRF. The residual tumor is assessed according 
to the table shown below, and the histological results of resection specimens should be recorded in the 
CRF wherever possible. The date when surgery aimed at curative resection (complete resection: R0 
resection) of colorectal cancer is scheduled is considered as the date of discontinuation of protocol 
treatment 
When surgery aimed at curative resection is performed in more than one session, the number of 
sessions should be recorded in the CRF. As for the postoperative assessment of residual tumor, data 
obtained by the time of initiation of subsequent treatment should be recorded in the CRF. Data 
generated after initiation of subsequent treatment will be collected through monitoring and assessed by 
the steering committee for the validity.  
Table 9.i  Residual tumor after surgical treatment 
Classification 
Criteria 
RX 
The presence of residual tumor cannot be assessed. 
R0 
No residual tumor 
R1 
Resected, but tumor on the margins of a surgical resection specimen or the 
radial margin 
R2 
Macroscopic residual tumor 
 
9.2.15 Survival survey 
All subjects will be followed up after discontinuation of protocol treatment to confirm survival of 
subjects. Survival survey should be continued until a subject dies or the sponsor terminates the study. 


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• 
Date of death or date of last confirmation of survival 
 
9.2.16 Follow-up therapy 
When follow-up therapy is performed after discontinuation of Protocol Treatment [2], the following 
information on follow-up therapy should be collected until a subject dies or the sponsor terminates the 
study. 
• 
Name of regimen (name of drugs used) 
 
9.3 
Records of subjects who discontinued before enrollment 
For subjects withdrawn from the study before enrollment of protocol treatment, the main reason for 
discontinuation should be recorded in the CRF according to the following categories. 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria <specify 
the applicable inclusion/exclusion criteria> 
• 
Serious deviation from the protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation <specify the reason> 
• 
Discontinuation of the entire study 
• 
Other <specify the reason> 
The subject ID code of a subject withdrawn from the study before enrollment should not be reused. 
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
Adverse events are all untoward medical events encountered in a subject treated with a drug. They are 
not limited to the events with clear causal relationship with treatment with the concerned drug. 
In other words, adverse events are any unfavorable or unintended sign (including clinically 
problematic abnormalities of laboratory test data), symptoms or diseases that develop after 
administration of a drug irrespective of a causal relationship with the relevant drug. 
 
10.1.2 Items to be considered concerning adverse events 
Generally unfavorable findings are shown below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent event of 
the existing symptom is not considered an adverse event)  
• 
Requiring action or treatment 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation or change in the dose of protocol treatment (chemotherapy, 
panitumumab and bevacizumab) or concomitant drugs under use 
• 
Considered unfavorable by the investigator 
Diagnosis name and signs/symptoms: 
Adverse events should be recorded by a diagnosis name. Accompanying signs (including abnormal 
laboratory values, abnormal ECG findings) and symptoms should not be recorded as adverse events. 
Any adverse events that could not be expressed in medical terminology (name of diagnosis) should 
be recorded with signs or symptoms observed. 
Laboratory test findings: 
Abnormal laboratory values and ECG findings are recorded as adverse events when the investigator 
judges the course to be clinically problematic (in other words, when certain action or treatment is 
required, or the investigator judges the change to have exceeded the normal physiological variation 
range of the subject). 
Retest and continued monitoring of abnormality are not considered treatment. Also, repeated or 
additional conduct of non-invasive test for verification, evaluation and monitoring of abnormality 
are not considered treatment. 
However, when abnormal laboratory values and ECG findings are the accompanying symptoms of 
the disease diagnosed as an adverse event (e.g., increased creatinine due to renal dysfunction, etc.), 
the diagnosis name is handled as an adverse event. 
Existing symptoms (diseases and/or symptoms that have been present from before initiation of 
protocol treatment): 
Diseases and/or symptoms that have been present from before initiation of protocol treatment 
should be recorded as concurrent medical conditions and not as adverse events. When a concurrent 


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medical condition is aggravated, the aggravation is recorded as an adverse event and the 
investigator should record in the CRF that the adverse event as aggravation of the complication (e.g., 
“aggravation of hypertension”, etc.). 
When a subject has an existing symptom that is transient (e.g., asthma, epilepsy) and incidence of 
the symptom is increased, or the symptom becomes serious or severe, it should be recorded as an 
adverse event. When a subject has a chronic disease (e.g., cataract, rheumatoid arthritis) and the 
symptom is aggravated more than anticipated, it should be recorded as an adverse event. The 
investigator should record it so that a reported adverse event name is a change from the baseline 
(e.g., aggravation of XX). 
Previously planned surgery or treatment: 
Surgery or treatment planned before initiation of protocol treatment is not considered an adverse 
event. However, when the existing symptom is aggravated to require emergency surgery or 
treatment, the condition or the event is considered an adverse event. A complication which resulted 
from previously planned surgery is reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a subject 
(cosmetic surgery, etc.) is not considered an adverse event. Complications due to a non-urgent 
surgery should be reported as an adverse event. 
PD: 
PD should be considered lack of efficacy, not an adverse event. In addition, the single fact of PD 
does not necessarily constitute an SAE. However, clinical or imaging progression of the preexisting 
cancer (including new metastasis) is considered an SAE when the severity satisfies any of the 
criteria for seriousness specified in Section 10.1.3. 
Overdose of panitumumab: 
Overdose of panitumumab which does not accompany the occurrence of events will not be regarded 
as adverse events, but the overdose of panitumumab will be recorded in the page of overdose in the 
CRF. If any events have occurred, they will be recorded as adverse events in the page of adverse 
events in the CRF. 
 
10.1.3 Serious adverse events 
Of all the unfavorable medical events that developed by administration of drugs (irrespective of dose), 
an SAE is an event that: 
1. 
Results in death during protocol treatment and all deaths irrespective of a causal relationship with 
protocol treatment. 
2. 
Results in death after discontinuation of protocol treatment for which a causal relationship with 
protocol treatment cannot be denied. 
However, death obviously due to the underlying disease is not applicable. 
3. 
Is life-threatening 
The term “life-threatening” refers to an event in which the subject was at risk of death during 
onset of the adverse event; it does not refer to an event which hypothetically might have caused 
death if it were severer. 


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4. 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization described below is not considered an SAE: 
(1) Preplanned inpatient hospitalization or prolongation of existing hospitalization 
(2) Inpatient hospitalization or prolongation of existing hospitalization unrelated to an adverse 
event 
5. 
Results in persistent or significant disability/incapacity. 
6. 
Leads to a congenital anomaly/birth defect. 
7. 
Other medically significant condition: medically important event which causes a risk to a subject 
even if it is not immediately life-threatening, nor does it result in death or hospitalization, or 
requires an action or treatment to prevent the results shown in 1 to 6 above.. 
 
10.1.4 Noteworthy adverse events for the sponsor 
The events listed in "Takeda Medically Significant AE List" in Table 10.a will be handled as 
noteworthy adverse events by the sponsor irrespective of the severity determined by the principal 
investigator or investigator. Of the events listed in Table 10.a, the adverse event that the principal 
investigator or investigator determines to be serious should be handled as an SAE. 
Table 10.a  Takeda medically significant AE list 
Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion and 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of infection 
by a medicinal product 
Confirmed or suspected endotoxin shock 
 
10.1.5 Severity of adverse events 
The severity of adverse event is classified and defined as follows based on the CTCAE (Japanese 
edition JCOG version 4.03): 
Table 10.b  CTCAE Grade (Japanese edition JCOG version 4.03) 
Grade 1 
Mild; asymptomatic or slightly symptomatic; only clinical or test findings; or 
requiring no treatment 
Grade 2 
Moderate; requiring the least treatment or local or non-invasive treatment; or 
interfering with age-appropriate activities of daily living except for self-care 
activities* 


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Grade 3 
Severe or medically critical, but not immediately life-threatening; requiring 
hospitalization or prolongation of existing hospitalization; disabling/incapacitating; 
or interfering with self-care activities of daily living** 
Grade 4 
Life-threatening; or requiring emergent treatment 
Grade 5 
Death due to an adverse event 
*:  Activities of daily living except for self-care activities include meal preparation, shopping for daily 
necessities and clothings, phone call, and financial management. 
**: Self-care activities of daily living include bathing, dressing, eating, toilet, and oral drug intake, and 
indicate that a person is not confined to bed. 
 
10.1.6 Causality of adverse events 
Causal relationship between protocol treatment (OXA, 5-FU, or panitumumab) and adverse events is 
classified and defined as described below. Information on causal relationship with adverse event is not 
collected for any drugs other than protocol treatment. 
Related 
An adverse event with apparent temporal relation with treatment discontinuation 
(including clinical course after discontinuation). Possibly due to protocol treatment 
(chemotherapy or panitumumab) although other factors such as underlying disease, 
complications, concomitant drugs/treatment are also presumed. 
Not related 
An adverse event with no chronological correlationship with protocol treatment 
(chemotherapy or panitumumab). Very likely due to other factors such as 
underlying disease, complications, and concomitant drugs/treatment. 
 
10.1.7 Date of onset 
Judge the date of onset of adverse event according to the following criteria: 


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Adverse event, etc. 
Date of onset 
Signs, symptoms, diseases 
(diagnosis name) 
Record the date when the subject or the investigator noticed the 
first signs and symptoms of adverse event. 
Asymptomatic disease 
Record the date of obtaining a definite diagnosis after conducting 
a test for diagnosis.  
Record the date of obtaining a definite diagnosis even when the 
test findings show old findings or suggest approximate timing of 
onset.  
Aggravation of complications 
Record the date when the subject or the investigator noticed the 
signs and symptoms of adverse event for the first time. 
Abnormal laboratory findings 
after initiation of protocol 
treatment 
Record the date of test where abnormal laboratory values 
considered clinically problematic were observed.  
Abnormality was observed on 
the test at initiation of 
protocol treatment, and 
aggravation was shown on 
subsequent tests. 
Record the date of tests when values were medically judged to be 
obviously increased and decreased based on the changes in test 
values.  
 
10.1.8 Date of resolution 
The date when the adverse event resolved (or resolved with sequelae). Date of death when a subject 
died of the concerned adverse event. When recovery cannot be confirmed at study completion, it is 
considered ongoing. 
 
10.1.9 Incidence 
When the investigator considers the first occurrence up to the final remission of a series of adverse 
events which repeatedly appear to be resolved or recurred as one event (e.g., constipation, diarrhoea, 
vomiting, etc.), it is considered to be “intermittent”. Other events are considered “ongoing”. 
 
10.1.10 Action taken for protocol treatment 
The withdrawal of OXA, 5-FU, or panitumumab in protocol treatment should be documented in the 
CRF. The treatment discontinuation is defined as follows: 
Treatment discontinued 
Treatment with OXA, 5-FU, or panitumumab in protocol treatment 
was discontinued due to the adverse event. 
Not applicable 
Treatment with OXA, 5-FU, or panitumumab in protocol treatment 
had already been completed or discontinued by the time of the onset 
of the adverse event. 
 
10.1.11 Outcome 
Outcomes of adverse events are classified as follows: 


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Category 
Criteria for judgment 
Recovered 
• 
Disappearance or recovery of symptoms and findings 
• 
Laboratory values returned to normal or baseline 
Improved 
• 
Severity is improved by one or more grades 
• 
Symptoms or findings mostly disappeared 
Not recovered 
• 
No change in symptoms, findings, or laboratory data 
• 
The symptoms, findings, or laboratory data on the final day of observable 
period aggravated compared with the date of onset 
• 
Irreversible congenital anomaly 
• 
Death not directly caused by the adverse event (AE) but the AE remains 
unrecovered (no need for recording the date of death in this case) 
Recovered 
with sequelae 
• 
Disability which disturbs daily life 
Death 
• 
Direct relationship between death and the AE 
“Direct relationship” means that the AE is the cause of death, or death is 
clearly associated with the event. 
• 
The outcome of an AE which is not determined (considered or presumed) as a 
direct cause of death observed within the same subject is not considered as 
death. 
• 
The date of death should be documented when the outcome is death. 
Unknown 
• 
Losses to follow-up specified in the protocol after the date of onset, due to 
change of hospitals, relocation, etc. 
 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Period for collection of adverse events 
Adverse events should be continuously collected from initiation of protocol treatment up to four 
weeks after discontinuation of protocol treatment. 
10.2.1.2 Reporting of adverse events 
At each visit, the investigator should assess the onset of subjective symptoms are present. Onset of 
any adverse event that developed after the previous visit should be checked by asking a question 
such as “how has your condition been since the last visit?” to a subject. 
The investigator should follow up all subjects who developed adverse events irrespective of a 
causal relationship with protocol treatment until disappearance of symptoms or return of abnormal 
laboratory values to the value at initiation/dose reduction of protocol treatment, or until observed 
changes can be sufficiently explained for other events (persistent/irreversible adverse event, etc.). 
All adverse events should be recorded in the CRF. The name of an adverse event, date of onset, 
date of disappearance, frequency, severity, causal relationship with protocol treatment (unrelated or 
related), action taken for protocol treatment (chemotherapy and panitumumab), outcome, and 
seriousness should be recorded. 
Follow-up period of adverse events is until recovery of an adverse event, or the investigator judges 
that further follow-up would not be necessary. 


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When requested by the representative researcher, the investigator should check the additional 
necessary information and data and complete recording them in the CRF within the designated 
period. 
 
10.2.2 Collection and reporting of serious adverse events 
When an SAE develops during the period of collecting adverse events, it should be reported according 
to the following procedures. 
When the investigator judges that an SAE has occurred based on the reporting by a subject, etc. and 
the result of various tests, imaging findings or definitive diagnosis, a report should be submitted to the 
head of the study site and the representative researcher (see attached sheet for contact information) 
within one working day and a report should be made via the sponsor to the investigators of other sites 
jointly performing the clinical study. In addition, the investigator should submit a formal detailed 
report within 10 calendar days. 
The following items are the requisite for reporting within one working day, and other items should be 
reported as best as possible. 
• 
Study title 
• 
Subject ID code 
• 
Name of study site 
• 
Name of investigator 
• 
Name of the SAE, course (date of onset, reason for the judgment of “serious”, protocol 
treatment given, causal relationship with protocol treatment, course, and outcome) 
• 
Action taken for the SAE (suspension of new enrollment, revision of the written informed 
consent, newly obtaining consent from other subjects) 
 
10.2.3 Notification of unexpected serious adverse event to joint study sites 
Upon receiving a report of an unexpected SAE from the investigator, the head of the study site should 
ask for opinions from the IRB such as the ERC, add the following information to the report from the 
investigator, and notify the DMC and the joint study sites of the event-relevant information through 
the sponsor. 
• 
Date of review by the IRB such as the ERC, summary of review, results,  necessary actions, 
etc. 
 
10.3 
Follow-up of serious adverse events 
The investigator should follow-up each SAE, etc. until the recovery is confirmed, or the final outcome is 
determined. 
When a change such as alteration of an outcome was made to the report of an SAE, the investigator 
should submit a report specifying details of the change to the head of the study site and the sponsor. 
When requested by the sponsor or the IRB such as the ERC, related data owned by the study site (e.g., 
ECG, laboratory test values, discharge report summary, autopsy findings, etc.) should be provided. 
 


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10.4 
Reporting of additional information on adverse events 
When the sponsor requests the principal investigator or investigator to provide additional information on 
an adverse event for reporting to regulatory authorities and other agencies, the principal investigator or 
investigator, after verifying the required additional information, must enter it in an electronic CRF 
system or submit a written report within the period determined by the sponsor. 
 
10.5 
Notification of serious adverse events to IRB such as an ethics review 
committee and regulatory authorities 
Upon receiving a report of an SAE from the investigator, the head of the study site should ask for 
opinions from the IRB such as the ERC, and notify other joint study sites of the event-relevant 
information through the sponsor or theCRO. 
In the case of an unexpected SAE, the head of the study site shall prepare a written report of the 
unexpected SAE containing the information reported from the  investigator plus the following 
information, submit the report to the Minister of Health, Labour and Welfare, and notify other joint study 
sites of the event-relevant information. (The head of the study site may, through the sponsor, make the 
report to the Minister of Health, Labour and Welfare and the notification to other joint study sites.) 
• 
Actions taken for the SAE 
(e.g., any interruption of enrollment of new subjects, revision of the informed consent form 
and re-consent from other subjects currently in the study) 
• 
Date reviewed by the IRB such as the ERC, review summary, review results, and necessary 
actions to be taken, etc. 
• 
Notification to other joint study sites 
The sponsor must report unexpected serious side effects and other SAEs applicable to expedited 
reporting to regulatory authorities, the investigators, and the heads of the study sites, according to the 
regulations. 
The sponsor or the CRO outsourced by the sponsor must submit the expedited report of the unexpected 
or expected serious side effect to regulatory authorities in compliance with the reporting time frames 
determined by the regulations after first knowledge of the event or acquisition of the additional 
information. In addition, the sponsor must submit the expedited report of other important safety 
information which is expected to greatly affect the risk-benefit of the study drug, continuation of the 
treatment with the study drug, or continuation of the clinical study, in the same way. The study site will 
submit the copy of the document of expedited report to the IRB such as the ERC. 


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11.0 
COMMIITTEES ESTABLISHED FOR ADMINISTRATIVE STRUCTURE 
AND THIS STUDY 
11.1 
Research steering committee 
The research steering committee will be established to effectively promote this study. The research 
steering committee will consist of steering committee members and biostatistician, and the sponsor or the 
person designated by the sponsor will act as the secretariat. 
See the supplement for the research steering committee members. 
The research steering committee will not be informed of the treatment allocation throughout the study 
period. 
Details of the research steering committee will be specified in a separately prepared SOP. 
 
11.2 
Data Monitoring Committee 
The Data Monitoring Committee (DMC) will be established according to the ICH E6 (1.25), and the 
person designated by the sponsor will act as the secretariat. See the supplement for the DMC member. 
The DMC will notify a DMC advisory report on continuation/discontinuation of the study and change of 
the study plan according to the safety analysis results for evaluation to the sponsor. The sponsor will 
determine whether to continue, discontinue, or change the study based on the results. 
The sponsor will prepare the DMC procedures (DMC charter) specifying the details such as the objective, 
roles, and responsibilities of the DMC, and management procedure. 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Detailed procedures concerning data management will be specified in the data management plan. Adverse 
events, medical history, and concurrent conditions should be substituted with the MedDRA terms. 
12.1 
Case report form 
The investigator should prepare CRFs for all subjects who have provided informed consent. 
The sponsor or its designee should provide study sites with access authorization to the electronic data 
capture (EDC). The sponsor should provide the investigator and study collaborators with training for 
utilization of EDC. The CRF will be used to report the information collected during the study period to 
the sponsor. The CRFs will be prepared in Japanese. Data will be directly entered into the CRFs. 
A change or correction of the CRF will be recorded as an audit trail that records the information before 
and after the change or correction, a person who made the change or correction, date of change or 
correction, and the reason. 
The investigator should ensure the accuracy and completeness of the CRFs, and provide an electronic 
signature on the relevant page of the CRFs. The investigator assumes full responsibility for the accuracy 
and reliability of all the data entered into the CRFs. 
The data below will be directly recorded into the CRFs. 
• 
Severity and causal relationship of adverse event with “OXA”, “5-FU”, or “panitumumab” in 
protocol treatment 
When the investigator makes a change or correction in the data entered into a CRF after clinical database 
lock, a record of change or correction in the CRF provided by the sponsor (Data Clarification Form) 
should be used. The investigator should confirm that the record of change or correction in the CRF is 
accurate and complete, and sign or write name/affix a seal, and date it. 
The sponsor or its designee should confirm the accuracy and completeness of the CRF during a visit to a 
study site. The sponsor or its designee should access to the medical records of study subjects and 
in-house records to ensure the accuracy of the CRFs. The completed CRFs are the property of the 
sponsor, and the investigator should not divulge the information to a third party other than the regulatory 
authority without a written permission of the sponsor. 
 
12.2 
Time limit for data input into the EDC 
It is recommended that data obtained after informed consent be entered into the EDC within the time 
frame described below, in principle. A failure to enter the data within the time frame does not constitute 
a deviation, but efforts shall be made to adhere to the time frame. 
1) 
At enrollment: within two weeks after enrollment 
2) 
During protocol treatment: within two weeks after discontinuation of each cycle of protocol 
treatment 
3) 
At discontinuation of protocol treatment: within four weeks after discontinuation of protocol 
treatment 
4) 
Imaging findings: within two weeks after evaluation of efficacy 
5) 
Follow-up period: within two weeks after request for follow-up 
6) 
Inquiries about data to be input into the EDC: within two weeks after inquiry 
 


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12.3 
Storage of records 
The investigator or the head of the study site should store the following materials including those 
specified in Section 12.1 and study specific documents for use by the investigation or audit by the 
regulatory authority and the sponsor or their designee. The materials include a list of subject screening, 
medical records, signed and dated original consent form, and a record of change and correction of the 
CRF (copy)/electronic copy of electronic CRF containing audit trail. The investigator and the head of the 
study site should store the essential documents to be stored until five years after discontinuation or 
completion of the study. However, when the sponsor requires a longer storage period, the head of the 
study site will discuss the period and methods of storage with the sponsor. 
The investigator and the head of the study site will store the essential documents to be stored until the 
sponsor notifies that storage is no longer necessary. 


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13.0 
STATISTICAL ANALYSIS METHODS 
The statistical analysis manager and its designees (personnel who belong to a CRO independent from the 
sponsor; hereinafter refeered to as "statisticians") perform the analyses. The sponsor should not be involved 
in the analyses. 
 
13.1 
Statistical and analytical plans 
The statistical analysis manager and statisticians should prepare and finalize the statistical analysis plan 
(SAP) before data lock. Detailed definition of endpoints and analysis methods should be specified in the 
SAP to cover all purposes of the study. 
Data review should be performed before data lock. Data review is performed to evaluate the accuracy 
and completeness of the study data, subject evaluability, and appropriateness of the planned analysis 
methods. 
13.1.1 Analysis set 
Two analysis sets, "full analysis set" and "safety population," are used in this study. "Full analysis set" 
is defined as "randomized subjects," and the "safety population" is defined as "the subjects who 
received at least one dose of protocol treatment after randomization." 
The sponsor should confirm the definition of analysis sets and appropriateness of analytical handling 
rules of the subject data in the analysis sets before data lock, add handling of problematic issues which 
have not been prescribed in the planning stage, and finalize the SAP.  
 
13.1.2 Analysis of demographic and other baseline characteristics 
The following analysis should be conducted in "full analysis set." 
Concerning major subject background factors, frequency analysis should be conducted for numerical 
data and summary statistics should be calculated for quantitative data for each treatment group and 
collectively for all treatment groups. 
 
13.1.3 Efficacy analysis 
13.1.3.1 Primary endpoint and analysis method 
[Primary endpoint] 
PFS rate at 9 months after randomization 
The PFS rate at 9 months after randomization serves as a primary endpoint and is defined as the 
gross proportion of subjects who survive with no evidence of progression during from the day of 
randomization (Day 0) until at 9 months after the Day 0. The presence/absence of PD will be 
determined based on imaging, consideration as clinical PD or survival research results at 9 months 
after randomization. The absence of progression includes a case unassociated with image data at 9 
months after randomization, as far as the absence of progression is diagnosed by imaging at the 
latest time point and PFS is subsequently confirmed by imaging at the time point exceeding 9 
months. 
A subject who does not remain in the study for 9 months after randomization, and then withdraws 
his/her consent or becomes lost to follow-up will be excluded from the population without 
progression, although the denominator will include such subject. A diagnosis of progression will 
comply with the criteria described in "13.1.3.2 Secondary endpoints and analysis method." 


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[Main analysis] 
Perform the following analysis for the “full analysis set.” 
For each treatment group, a binomial test will be performed for the null hypothesis that the PFS 
rate to determine invalidity will be equal to or less than 30%, based on the PFS rate observed at 9 
months after randomization. The main analysis will be at the one-sided 10% significance level. A 
two-sided 95% confidence interval using Agresti-Coull Method will be applied to the interval 
estimation. 
13.1.3.2 Secondary endpoints and analysis method 
[Secondary endpoints] 
• 
PFS duration 
The PFS duration is defined as the time from the day of randomization (Day 0) until the first 
evidence of progression, or until death from any cause, whichever comes earlier. 
Progression includes both PD based on diagnostic imaging according to RECIST 1.1 and 
progression of the underlying disease which cannot be confirmed on diagnostic imaging (clinical 
progression). If progression is diagnosed on the basis of diagnostic imaging, the date of the 
imaging test will be regarded as the date of progression, and the date of clinical judgment will be 
regarded as the date of progression in the case of clinical progression. Even when a condition is 
regarded as PD according to the criteria for efficacy evaluation, such as in the cases of extreme 
shrinkage of the tumor size, but "progression is obviously ruled out" from a clinical point of view, 
PD according to the efficacy evaluation criteria will be given priority and the condition will be 
regarded as progression (in this case, clinical judgment will be prioritized with respect to whether 
or not protocol treatment should be continued). When the condition is not regarded as PD 
according to the efficacy evaluation criteria but it is obviously deemed as progression from a 
clinical point of view, the clinical judgment will be prioritized and the condition will be regarded as 
progression. The study will be cut off for the surviving patients without a diagnosis of progression 
on the last day of clinical confirmation of the absence of progression (date of last confirmation of 
progression-free survival; Confirmation of the absence of progression on imaging test and sample 
test is not essential. Clinical confirmation of the absence of progression at outpatient clinic will 
suffice. Reporting by telephone only will not be accepted). Even in the cases of protocol treatment 
discontinuation for such reasons as toxicity and patients' withdrawal in which other treatment has 
been given in the after-care, events and cutoff will be handled in the same manner. In other words, 
the timing of discontinuation of treatment or the date of the start of after care will not be regarded 
as the cut-off dates. 
[Analysis method] 
In the "full analysis set," the PFS duration will be illustrated with Kaplan-Meier curves, and the quartile 
of PFS and its 95% confidence interval (two-sided) will be culculated. The 95% confidence interval of 
the quartile of PFS will be calculated using log-log transformation in accordance with Brookmeyer and 
Crowley method25). At the same time, for the sake of reference, the hazard ratio of Group B versus 
Group A and its 95% confidence interval (two-sided) will be calculated on the basis of the stratified Cox 
regression model, and a log-rank test will be performed. 
• 
OS 
OS is defined as the time from the day of randomization (Day 0) until death by all causes. 
[Analysis method] 
The same analysis as that for the PFS duration will be performed for OS in the "full analysis set." 
• 
RR 


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RR is defined as the percentage of subjects who have shown CR or PR as the best overall response 
in accordance with the RECIST 1.1 criteria after randomization. The best overall response will be 
CR, followed by PR, SD, progression, and nonevaluable. 
[Analysis method] 
In the "full analysis set," RR and two-sided 95% confidence interval will be calculated for each 
group. At the same time, for the sake of reference, the difference of RR between the groups (Group 
B - Group A) and the two-sided 95% confidence interval will be calculated. Agresti-Coull and 
Agresti-Caffo26) methods will be applied to the confidence interval calculations for RR and the 
difference of RR between the groups, respectively. 
• 
TTF 
TTF is defined as the time from the day of randomization (Day 0) until the day of protocol 
treatment discontinuation determination, the day of PD diagnosis during protocol treatment or 
death from any cause, whichever comes the earliest. 
[Analysis method] 
The same analysis as that for the PFS duration will be performed for TTF in the "full analysis set." 
13.1.3.3 Other efficacy endpoints 
• 
DPSM 
DPSM is defined as the time from the day of randomization (Day 0) until the first evidence of 
aggravation by 1 or more points in accordance with the PS scale, the day of protocol treatment 
discontinuation determination or death from any cause, whichever comes the earliest. 
[Analysis method] 
The same analysis as that for the PFS duration will be performed in the "full analysis set." 
• 
Duration of OXA continuation in mFOLFOX6 + panitumumab group (Group A) 
Duration of OXA continuation is defined as the time from the day of randomization (Day 0) until 
the day of OXA discontinuation determination in the Group A protocol treatment, the day of PD 
diagnosis or death from any cause, whichever comes the earliest. 
[Analysis method] 
The same analysis as that for the PFS duration (other than group comparisons) will be performed 
in the "full analysis set." 
• 
Duration of panitumumab continuation in both groups 
Duration of panitumumab continuation is defined as the time from the day of randomization (Day 
0) until the day of panitumumab discontinuation determination in the protocol treatment, the day of 
PD diagnosis or death from any cause, whichever comes the earliest. 
[Analysis method] 
The same analysis as that for the PFS duration will be performed in the "full analysis set." 
 
13.1.3.4 Data conversion method and handling of missing data 
The subjects who without any event experienceat the end of entire study will be classified as 
cencored cases in the analyses of PFS, OS and TTF. 


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The cencored day will be the last confirmation day of PFS in the PFS duration analysis, the last 
confirmation day of survival in the OS analysis, and the initiation day of the last protocol treatment. 
In DPSM analysis, the cencored day will be the last PS evaluation day for cases without PS 
aggravation. 
Details about the method of conversion of other data and handling of missing data will be specified 
separately in the SAP. 
13.1.3.5 Level of significance, confidence coefficient 
• 
Level of significance: 5% 
• 
Confidence coefficient: 95% (two-sided estimation) 
 
13.1.4 Safety analysis 
Perform the following analyses in the “safety population.” 
13.1.4.1 Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are the adverse events which developed after 
initiation of protocol treatment after randomization. 
For TEAEs, perform the following analyses for each treatment group. TEAEs should be substituted 
withthe MedDRA terms to summarize them by Preferred Term (PT) and System Organ Class 
(SOC). 
• 
Frequency tabulation of all TEAE 
• 
Frequency tabulation of TEAE for which the causal relationship with any of the protocol 
treatments was judged as “related” 
• 
Frequency tabulation of all TEAE by severity 
• 
Frequency tabulation of TEAE by severity for which the causal relationship with any of 
protocol treatment was judged as “related” 
• 
Table of TEAE by frequency with the action taken for any of protocol treatment was handled 
as “discontinuation” 
• 
Frequency tabulation of serious TEAE 
• 
Frequency tabulation of TEAE of peripheral nerve disorders (secondary endpoint) 
Peripheral nerve disorders will be defined as the events classified with the preferred term of 
"peripheral neuropathy" according to the Standardised MedDRA Queries, and skin disorders will 
be defined as the events classified with the System Organ Class of "Skin and subcutaneous tissue 
disorders" or the events classified as with the Preferred Term of "paronychia." The interstitial 
pneumonia will be the events of the Preferred Terms of the MedDRA Standard Search Formula. 
 
13.1.5 Predetermined subgroup analysis 
In this study, the following subgroup analysis will be conducted. 
• 
Subgroup analysis based on NRAS test 


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• 
Subgroup analyses based on the following stratification factors other than study sites: age at 
enrollment (≥ 20 and ≤ 69, or > 70), the number of metastasized organs (≤ 1, or ≥ 2) and 
response evaluated in accordance with the RECIST 1.1 criteria (CR/PR/SD). 
 
13.2 
Criteria for interim analysis and premature discontinuation 
Interim analysis will not be conducted. 
 
13.3 
Determination of the planned number of subjects 
This study will be designed as a phase II randomized screening comparison study which does not use 
direct comparison for primary analysis22). 
In the phase III study (PRIME Study) in which FOLFOX4 therapy was combined with bi-weekly 
administration of panitumumab 6 mg/kg as a first-line therapy, the median PFS in the patients of KRAS 
wild-type as the primary endpoint was reported as 9.6 months12). Moreover, in PEAK study23) in which 
panitumumab and bevacizumab were compared as the drugs to be administered in combination with 
mFOLFOX6 therapy, the median PFS in the mFOLFOX6 therapy + panitumumab group was reported as 
10.9 months. The percentage of the cases in which any events occurred or the study was cut off within 3 
months in PRIME Study and PEAK Study was approximately 10% of all cases. 
The subjects of this study will be the patients who receive mFOLFOX6 + panitumumab combination 
therapy for 3 months, and can continue OXA administration. Since the PFS 40% point in PRIME Study 
and PEAK Study was approximately 13 months, the median PFS in Group A in this study is expected to 
be approximately 10 months, which is obtained by subtracting 3 months from the 40% point. The median 
PFS in Group B is assumed to be comparable to that in Group A. 
In the primary analysis, a test based on the method of Brookmeyer-Crowley24) will be conducted for the 
null hypothesis, "true median PFS will be lower than the threshold median PFS for judgment as 
ineffective", separately in Group A and Group B on the basis of the observed median PFS. When the 
threshold median PFS is regarded as 6 months, true median PFS as 10 months, enrollment period as 12 
months, follow-up period as 12 months, one-sided significance level as 5%, and power of test as 80%, 
the number of subjects required in Group A and Group B will become 54 subjects each. Considering the 
cases of discontinuation, the target number of subjects to be randomised was set at 60 patients for each 
group (120 patients in total).  


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of study sites 
The sponsor or its designee will perform periodic monitoring of study sites during the study to confirm 
that the study is carried out in accordance with all specifications in the protocol. Central monitoring and 
site visit monitoring, when necessary, will be performed in this study. During site visit monitoring, the 
data recorded in EDC are checked against source documents. Source documents are the original 
documents, data and records. The investigator and the head of study site will ensure that the sponsor or 
its designee and the IRB such as the ERC have access to the source documents. 
The sponsor or its designee will access the records including the subject code list, medical records, 
signed and dated original consent forms to confirm that the study is appropriately conducted in 
compliance with the protocol. The investigator and other persons involved in the study will spare 
sufficient time to facilitate monitoring procedures during visits to the study site. 
14.1.1 Central monitoring 
Central monitoring will be performed to check that the study is safely conducted in accordance with 
the protocol and that data are accurately collected, based on the data collected by EDC. Central 
monitoring will be conducted twice a year in principle, and periodic monitoring report will be 
prepared. Periodic monitoring report will be evaluated by research steering committee and feedback 
will be given to study sites when necessary. 
Detailed procedures for central monitoring will be determined in the separately prepared procedures. 
 
14.1.2 Site visit monitoring 
Site visit monitoring is conducted to confirm that the study is carried out safely and in compliance 
with the protocol and the data are accurately collected by checking the data entered into the EDC 
against source documents. 
Prior to site visit monitoring, sites are randomly selected to perform Source Documents Verification 
(SDV) for the enrolled subjects. 
See separately prepared monitoring plan for the frequency and procedures of site visit monitoring. 
 
14.2 
Protocol deviations 
The investigator should record all deviations from the protocol. When a deviation is disclosed, the 
investigator will immediately notify the head of study site and the sponsor in writing. Revision of the 
protocol should be discussed with the sponsor when necessary, and when the protocol is revised, the 
revised protocol should be submitted to the head of study site and approved by the IRB such as the ERC. 
 
14.3 
Quality assurance and regulatory agency inspections 
The sponsor or its designee will perform audit at the study site when necessary. In such a case, the 
auditor designated by the sponsor should contact the study site in advance to determine the date of audit. 
The auditor may request a visit to the site of collecting laboratory test samples and other sites to be used 
during the study. This study may also be audited by overseas regulatory authorities (e.g., Food and Drug 
Administration [FDA], Medicines and Healthcare Products Regulatory Agency [MHRA]). The study site 
will immediately notify the sponsor when the study site is contacted by the regulatory authority 
concerning an audit. The investigator and the head of study site should ensure that the auditor has access 
to all the source documents listed in Section 14.1. 


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15.0 
ETHICAL CONDUCT OF A STUDY 
This study will be conducted in compliance with the protocol, ethical principles based on the Declaration of 
Helsinki, ICH-GCP and "Ethical Guidelines for Clinical Research" to preserve the interest of study 
participants (subjects). Each investigator should conduct a study based on the regulatory requirements and 
in compliance with the “Responsibilities of the investigator” in Attachment A. 
15.1 
Conflict of interests 
Prior to the study, the investigator should obtain the review/approval by the IRB such as the COI 
committee that this study has no conflict of interests (COI)25)-29). 
The study site should comply with all the requirements specified by the IRB such as the ERC. The 
requirements include the COI self-declaration, protocol, and informed consent form. 
 
15.2 
Approval by the institutional review board including the ERC 
The IRB including the ERC is constituted according to local regulations applicable to the study site. The 
sponsor or its designee should obtain the document listing the name and title of each IRB member. When 
the IRB members are directly participating in this study, a document should be obtained that they are not 
taking part in deliberation and voting. 
The sponsor or its designee should provide related documents to the IRB such as the ERC for review and 
approval of the protocol. In addition to the protocol, a copy of informed consent form, written materials 
related to subject recruitment, advertisement, and other documents required by regulation, when 
necessary, should be submitted to the central IRB or the IRB of each study site such as the ERC to obtain 
approval. The sponsor or its designee should obtain written approval of the protocol and the informed 
consent form from the IRB such as the ERC prior to initiation of protocol treatment. The IRB’s approval 
document should contain the study title, protocol number, and date of preparation/revision of the 
concerned study, as well as version numbers and approval dates of other reviewed documents (e.g., 
informed consent form). The sponsor should notify the study site and the investigator after confirming 
the appropriateness of the regulatory documents of the study site. Protocol procedures such as obtaining 
consent should not be started until the study site and the investigator receive the notification. 
The study site should comply with all the requirements specified by the IRB such as the ERC. The 
requirements include notifications to the IRB such as the ERC, for instance, revision of the protocol, 
revision of the informed consent form, revision of materials related to subject recruitment, report on 
safety in accordance with the regulatory requirement, report on study implementation state at intervals 
determined by the IRB such as the ERC, and study completion report. The sponsor or its designee should 
obtain written approval of the abovementioned items and all related materials from the IRB such as the 
ERC. 
 
15.3 
Written information and subject’s consent 
The informed consent from contains specific requirements of the Declaration of Helsinki and all 
applicable laws and regulations. The informed consent from specifies the use of personal information 
and medical information of subjects in this study (both in and outside Japan: supply to a third party), and 
disclosure. Written explanation explains in detail the general idea and purpose of the study, and its 
possible risks and benefits. The informed consent from also clarifies the conditions for study 
participation and states the fact that subjects can discontinue study participation at any time without 
giving reasons and without loss of benefits in treatment. 
The investigator is responsible for preparation, content, and IRB approval of the informed consent form. 
The informed consent form should be approved by IRB before use. 


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The informed consent from should be written in a language easily understood by subjects. The 
investigator is responsible for providing detailed explanation of the informed consent from to subjects. 
Information should be provided orally and in writing as best as possible by the method deemed 
appropriate by the IRB. 
The investigator should ensure that the subjects have (1) an opportunity to inquire about the study and 
(2) sufficient time to determine study participation. When a subject decides to participate in the study, 
the subject should sign or write name/affix seal, and date the consent form prior to study participation. 
The investigator should request the subject to sign or write name/affix seal using a legal name and not a 
popular name with black or blue ballpoint pen. The investigator should also sign or write name/affix seal, 
and date the consent form prior to subject participation. 
The investigator should store the original consent form which was signed or contains name/affixed seal. 
The investigator should document in the subject’s medical record the date when the subject signed or 
wrote name/affixed seal on the consent form. A copy of the consent form with signature or name typed 
with name seal affixed should be provided to the subject. 
The investigator should take the same procedures as those for obtaining the initial consent to newly 
obtain consent from the concerned subject when the informed consent from is revised. The date of 
obtaining new consent should be recorded in the subject’s medical record, and a copy of the revised 
consent form should be provided to the subject. 
 
15.4 
Subject confidentiality 
The sponsor and its designee should comply with the principles of protection of the subject’s right 
against invasion of privacy. The subject ID code in this study is used to connect the clinical study 
database and related study documents of the sponsor with the source data of subjects. The limited 
information of subjects such as sex, age, and date of birth may be used within the scope of all applicable 
laws and regulations for identification of subjects and confirmation of accuracy of subject ID code. 
To confirm that this study is performed in compliance with the protocol, the sponsor should request the 
investigator for the access to the original laboratory test data, ECG, record of hospitalization/discharge 
during study period, and the original medical records such as autopsy report (source data or materials) by 
a monitor or the person designated by the sponsor, representative regulatory authority, auditor designated 
by the sponsor, and the IRB. The investigator should obtain approval of subjects concerning access to the 
original medical records by a monitor and the representative regulatory authority, etc. when obtaining 
consent from a subject (see Section 15.3). 
When providing a copy of source documents to the sponsor, the investigator should delete the 
information leading to identification of an individual (name and address of subject, other personal 
information not recorded in EDC of subject). 
 
15.5 
Advantages and disadvantages to subjects 
15.5.1 Advantage to subjects 
This study is performed as part of routine clinical practice, and no advantage is expected by 
participation in this study. 
 
15.5.2 Disadvantage to subjects 
This study is performed in the scope of ordinary medical examination, and no disadvantage is 
expected by participation in this study. 
 


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15.6 
Publication, disclosure, and clinical trial registration policy 
15.6.1 Publication and disclosure 
The investigator should provide the sponsor with all the results and data obtained from the study. Only 
the sponsor may disclose the study information to other investigators or regulatory authorities during 
the study period except for a case required by laws and regulations. The sponsor will be responsible 
for publication of the protocol and study-related results (including the public web site) except for other 
cases permitted in the study contract. 
The sponsor may make public the data and information obtained from the study (including the data 
and information provided by the investigator) based on the agreement with the representative 
researcher. 
The investigator should obtain the prior written consent of the sponsor when making public the 
information obtained in this study at a specialized academic meeting, etc. 
 
15.6.2 Clinical trial registration 
Takeda Pharmaceutical Company Limited. will ensure timely publication of the information of a 
clinical study and registration of all clinical researches in patients under way all over the world at least 
to the Clinical Trials.gov and public web site (UMIN-CTR) to comply with the applicable 
laws/regulations and guidelines. The city and country where a study is performed, and the subject 
recruitment state should be registered as well as the contact information of Takeda Pharmaceutical 
Company Limited. to enable general access. 
 
15.6.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited. will post the results of a clinical study at the Clinical 
Trials.gov and public web site (UMIN-CTR) as specified by the applicable laws and regulations 
irrespective of results. 
 
15.7 
Attribution of study results and intellectual property rights 
The study results generated in this study belong to Takeda Pharmaceutical Company Limited. The 
intellectual property rights regarding the pharmaceutical products manufactured and/or distributed by 
Takeda Pharmaceutical Company Limited. also belong to Takeda Pharmaceutical Company Limited. 
Data generated from this study may be made available for secondary use (e.g., meta-analysis) without 
any link to personally identifying information only with permission from the representative researcher 
and the research steering committee. 
 
15.8 Insurance and compensation for injury 
The subjects participating in this study will be compensated for any injury resulting from participation in 
the study according to local regulations applicable to the study site. It should be noted that any treatment 
provided will be covered by health insurance, and no monetary compensation will be provided. 


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16.0 
REFERENCES 
1 
The Editorial Board of Cancer Statistics in Japan. Cancer Statistics in Japan 2013. Foundation for 
Promotion of Cancer Research: 2013. 
2 
Japanese Society for Cancer of the Colon and Rectum (JSCCR). JSCCR Guidelines 2014 for the 
Treatment of Colorectal Cancer. 
3 
Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med. 1994;330(16):1136-42. 
4 
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil 
and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 
2000;343(13):905-14. 
5 
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined 
with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal 
cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041-7. 
6 
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and 
fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin 
Oncol. 2000;18(16):2938-47. 
7 
Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, et al. Superiority of 
oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with 
progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III 
trial. J Clin Oncol. 2003;21(11):2059-69. 
8 
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A 
randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in 
patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23-30. 
9 
Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by 
FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J 
Clin Oncol. 2004;22(2):229-37. 
10 National Comprehensive CancerNetwork. Clinical Practice Guidelines in Oncology. Colon Cancer 
verslon 3, 2013 
11 Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial 
of panitumumab plus best supportive care compared with best supportive care alone in patients with 
chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658-64. 
12 Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial 
of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus 
FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal 
cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697-705. 
13 Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III 
study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with 
FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 
2010;28(31):4706-13. 
14 Muro K, Yoshino T, Doi T, Shirao K, Takiuchi H, Hamamoto Y, et al. A phase 2 clinical trial of 
panitumumab monotherapy in Japanese patients with metastatic colorectal cancer. Jpn J Clin Oncol. 
2009;39(5):321-6. 
15 Boku N, Sugihara K, Kitagawa Y, Hatake K, Gemma A, Yamazaki N, et al. Panitumumab in Japanese 
Patients with Unresectable Colorectal Cancer: A Post-marketing Surveillance Study of 3085 Patients. 
Jpn J Clin Oncol. 2014;44(3):214-223. 


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16 Hochster HS, Hart LL, Ramanathan RK, Hainsworth JD, Hedrick EE, Childs BH. Safety and efficacy 
of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of 
metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study. J Clin Oncol 2006;24(18S) 
3510. 
17 Summary of product characteristics, December 2003: Sanofi-Synthelabo. 
18 Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1:A Randomized 
Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal 
Cancer—A GERCOR Study. J Clin Oncol 2006;24(3):394-400. 
19 Maindrault-Goebel F, et al. Final results of OPTIMOX2, a large randomized phaseⅡ study of 
maintenance herapy or chemotherapy–free intervals(CFI) after FOLFOX in patients with metastatic 
colorectal cancer(MRC) : A GERCOR study. ASCO Meeting Abstructs, Jun 2007;25:4013. 
20 Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Therapeutics and 
Clinical Risk Management 2005;1(4):249–258. 
21 Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in 
combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated 
metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J 
Clin Oncol. 2007;25(12):1539-44. 
22 Buyse M. Randomized designs for early trials of new cancer treatments - an overview. Drug Inf J 
2000; 34: 387-396. 
23 Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: A Randomized, 
Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil, Leucovorin, and Oxaliplatin 
(mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With Previously Untreated, Unresectable, 
Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer. J Clin Oncol. 2014. 
24 Brookmeyer R and Crowley, JJ. A confidence interval for the median survival time. Biometrics 1982; 
38: 29-41. 
25 Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, Science 
and Technology dated November 1, 2002) 
26 Guidelines for determining the conflict of interest polity for clinical researches (Review group for 
ethical aspects of clinical researches and conflict of interest, March 2006) 
27 Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences Research 
(March 31, 2008) 
28 Guidelines for management of COI in medical reserach (COI Committee of Japan Association of 
Medical Sciences, February 2011) 
29 Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of Internal 
Medicine, Japan Society of Hepatology, Japanese Circulation Society, Japan Endocrine Society, Japan 
Diabetes Society, Japanese Respiratory Society, Japanese Society of Hematology, Japanese Society of 
Allergology, Japanese Association for Infectious Diseases, August 2011) 
 


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Appendix A 
Responsibilities of the investigator 
1 
To appropriately conduct the clinical study in compliance with the protocol and in consideration of 
the human rights, safety and welfare of subjects. 
2 
To request COI committee of each study site to review and approve that there is no COI issues with 
this study. 
3 
When assigning a part of important duties related to this study to subinvestigators or study 
collaborators, prepare a list of assigned duties and persons, submit it in advance to the head of study 
site, and to obtain approval. 
4 
To prepare the informed consent form and revise it as necessary. 
5 
To check the contents of the study contract. 
6 
To provide sufficient information on the protocol, drug and duties of each person to 
subinvestigators and study collaborators, and to provide them with guidance and supervision. 
7 
To select subjects who satisfy the protocol, give explanation using written information, and obtain 
consent in writing. 
8 
To be responsible for all medical judgments related to the study. 
9 
To ensure together with the head of study site that sufficient medical care is provided to subjects for 
all study-related clinically problematic adverse events throughout the period of subject’s study 
participation and thereafter. 
10 When a subject is treated at another medical institution or department, inform a physician of the 
medical institution or department in writing of the subject’s study participation and study 
completion/discontinuation after obtaining the subject’s consent, and then prepare the record. 
11 When an emergency report of SAEs, etc. is required, immediately report it in writing to the head of 
the study site and the sponsor. 
12 To prepare accurate and complete EDC and submit it to the sponsor with an electronic signature. 
13 To inspect and check the contents of EDC prepared by subinvestigators, or transcribed by study 
collaborators from the source data, and submit it to the sponsor with an electronic signature. 
14 To discuss a revision of the protocol, etc. when proposed by the sponsor. 
15 To report the study completion in writing to the head of study site. 
 
 


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SAPPHIRE study 
(A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + 
panitumumab combination therapy and 5-FU/LV + panitumumab combination therapy in 
the patients with chemotherapy-naïve unresectable advanced recurrent colorectal 
carcinoma of KRAS wild-type after 6 cycles of combination therapy with mFOLFOX6 + 
panitumumab.) 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
183/NRP-005 
Product name 
Panitumumab 
Creation date 
March 19, 2015 
 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Takeda.  


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1.0 
STUDY ADMINISTRATIVE STRUCTURE AND PRINCIPLES 
1.1 Study Administrative Structure 
See Appendix for the contacts and study-related responsibilities. 
1.2 Principles of the study 
This study will be conducted with the highest respect for the individual participants in accordance with 
the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference on Harmonisation E6 Good Clinical Practice (hereinafter referred to as 
“GCP”). 
• 
All applicable laws and regulations, including, without limitation, data privacy laws, conflict of 
interest guidelines, Ethical Guideline for Clinical Research (the Ministry of Health, Labour and 
Welfare, revised in 2008). 


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TABLE OF CONTENTS 
1.0 
STUDY ADMINISTRATIVE STRUCTURE AND PRINCIPLES .......................................... 2 
1.1 
Study Administrative Structure .......................................................................................... 2 
1.2 
Principles of the study......................................................................................................... 2 
2.0 
STUDY SUMMARY ................................................................................................................ 9 
3.0 
LIST OF ABBREVIATIONS ................................................................................................. 14 
4.0 
INTRODUCTION ................................................................................................................... 16 
4.1 
Background ....................................................................................................................... 16 
4.1.1 
Etiology of target disease ........................................................................................... 16 
4.1.2 
Standard treatment for target disease ......................................................................... 16 
4.1.3 
Efficacy and safety of mFOLFOX6 in patients with unresectable, advanced or recurrent 
colorectal cancer ........................................................................................................ 17 
4.1.4 
Efficacy and safety of panitumumab in patients with unresectable, advanced or 
recurrent colorectal cancer ......................................................................................... 17 
4.1.5 
Adverse reactions to OXA ......................................................................................... 20 
4.1.6 
Examination of the method of administration of OXA in first-line therapy .............. 21 
4.2 
Rationale for the proposed study ...................................................................................... 21 
5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY .............................................................. 22 
5.1 
Objective ........................................................................................................................... 22 
5.2 
Endpoints .......................................................................................................................... 22 
5.2.1 
Primary endpoint ........................................................................................................ 22 
5.2.2 
Secondary endpoints .................................................................................................. 22 
5.2.3 
Additional endpoint ................................................................................................... 22 
5.3 
Rationale for the endpoints ............................................................................................... 23 
5.3.1 
Primary endpoint ........................................................................................................ 23 
5.3.2 
Secondary endpoints .................................................................................................. 23 
6.0 
STUDY DESIGN .................................................................................................................... 24 
6.1 
Study design...................................................................................................................... 24 
6.2 
Rationale for study design, dose and endpoints ................................................................ 25 
6.2.1 
Study population ........................................................................................................ 25 
6.2.2 
Treatment regimens and planned number of subjects ................................................ 25 
6.3 
Discontinuation of entire study or discontinuation at a study site .................................... 25 
6.3.1 
Criteria for discontinuation of entire study ................................................................ 25 


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6.3.2 
Procedures of study suspension and discontinuation of entire study or study at a study 
site 26 
6.4 
Procedures for revision of the protocol ............................................................................. 26 
7.0 
SELECTION OF STUDY SUBJECTS ................................................................................... 27 
7.1 
Inclusion criteria ............................................................................................................... 27 
7.1.1 
Inclusion criteria for enrollment ................................................................................ 27 
7.1.2 
Inclusion criteria for randomization ........................................................................... 27 
7.2 
Exclusion criteria .............................................................................................................. 28 
7.2.1 
Exclusion criteria for enrollment ............................................................................... 28 
7.2.2 
Exclusion criteria for randomization .......................................................................... 28 
8.0 
TREATMENT ......................................................................................................................... 29 
8.1 
Protocol treatment ............................................................................................................. 29 
8.1.1 
Protocol Treatment [1] ............................................................................................... 29 
8.1.2 
Protocol Treatment [2] ............................................................................................... 29 
8.2 
Treatment regimen ............................................................................................................ 29 
8.2.1 
Protocol Treatment [1] ............................................................................................... 29 
8.2.2 
Protocol Treatment [2] ............................................................................................... 30 
8.3 
Recommended dose of protocol treatment ....................................................................... 31 
8.4 
Criteria for initiation of protocol treatment (common for Protocol Treatment [1] and [2])
 31 
8.5 
Criteria for dose change .................................................................................................... 32 
8.5.1 
Protocol Treatment [1] ............................................................................................... 32 
8.5.2 
Protocol Treatment [2] ............................................................................................... 34 
8.6 
Criteria for dose increase of protocol treatment................................................................ 35 
8.7 
Overdose of panitumumab ................................................................................................ 35 
8.8 
Criteria for discontinuation of protocol treatment ............................................................ 35 
8.9 
Contraindicated drugs/therapies........................................................................................ 36 
8.10 
Allowed supportive care and combination medications ................................................... 37 
8.11 
Handling of surgery aimed at curative resection (complete resection: R0 resection) of 
colorectal cancer ............................................................................................................... 38 
8.12 
Recommended follow-up therapy ..................................................................................... 38 
8.12.1 Recommended second-line treatment ........................................................................ 38 
8.12.2 Recommended third-line or subsequent treatment ..................................................... 38 


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9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR OBSERVATIONS ....... 39 
9.1 
Study calendar .................................................................................................................. 39 
9.2 
Collection/test/observation items and procedures during the study .................................. 40 
9.2.1 
Informed consent procedure ....................................................................................... 40 
9.2.2 
Procedures for registration and allocation of drugs ................................................... 41 
9.2.3 
Subject demographics ................................................................................................ 41 
9.2.4 
Medical history .......................................................................................................... 42 
9.2.5 
Current medical condition .......................................................................................... 42 
9.2.6 
Clinical findings (physical examination) ................................................................... 42 
9.2.7 
Body weight and height ............................................................................................. 43 
9.2.8 
Vital signs .................................................................................................................. 43 
9.2.9 
ECOG P.S. ................................................................................................................. 43 
9.2.10 Treatment compliance (Protocol Treatment [1] and [2] implementation status) ....... 43 
9.2.11 Laboratory tests .......................................................................................................... 44 
9.2.12 Imaging test (thoracoabdominal-pelvic CT/MRI)...................................................... 45 
9.2.13 NRAS test ................................................................................................................... 46 
9.2.14 Surgery aimed at curative resection (complete resection: R0 resection) of colorectal 
cancer ......................................................................................................................... 47 
9.2.15 Survival survey .......................................................................................................... 47 
9.2.16 Follow-up therapy ...................................................................................................... 47 
9.3 
Records of subjects who discontinued before enrollment ................................................ 48 
10.0 
ADVERSE EVENTS .............................................................................................................. 49 
10.1 
Definitions ........................................................................................................................ 49 
10.1.1 Adverse events ........................................................................................................... 49 
10.1.2 Items to be considered concerning adverse events..................................................... 49 
10.1.3 Serious adverse events ............................................................................................... 50 
10.1.4 Noteworthy adverse events for the sponsor ............................................................... 51 
10.1.5 Severity of adverse events.......................................................................................... 51 
10.1.6 Causality of adverse events ........................................................................................ 52 
10.1.7 Date of onset .............................................................................................................. 52 
10.1.8 Date of resolution ....................................................................................................... 53 
10.1.9 Incidence .................................................................................................................... 53 


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10.1.10 Action taken for protocol treatment ........................................................................... 53 
10.1.11 Outcome ..................................................................................................................... 53 
10.2 
Procedures......................................................................................................................... 54 
10.2.1 Collection and reporting of adverse events ................................................................ 54 
10.2.2 Collection and reporting of serious adverse events .................................................... 55 
10.2.3 Dissemination of a serious adverse event to study sites jointly performing the clinical 
study ........................................................................................................................... 55 
10.3 
Follow-up of serious adverse events ................................................................................. 55 
10.4 
Reporting of additional information on adverse events .................................................... 56 
10.5 
10.5 Notification of serious adverse events to IRB such as an ethics review committee and 
regulatory authorities ........................................................................................................ 56 
11.0 
COMMIITTEES ESTABLISHED FOR ADMINISTRATIVE STRUCTURE AND THIS 
STUDY .................................................................................................................................... 57 
11.1 
Research steering committee ............................................................................................ 57 
11.2 
Data monitoring committee .............................................................................................. 57 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS .................................................. 58 
12.1 
Case report form ............................................................................................................... 58 
12.2 
Time limit for data input into the EDC ............................................................................. 58 
12.3 
Storage of records ............................................................................................................. 59 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................................... 60 
13.1 
Statistical and analytical plans .......................................................................................... 60 
13.1.1 Analysis set ................................................................................................................ 60 
13.1.2 Analysis of demographic and other baseline characteristics ...................................... 60 
13.1.3 Efficacy analysis ........................................................................................................ 60 
13.1.4 Safety analysis ........................................................................................................... 62 
13.1.5 Predetermined subgroup analysis ............................................................................... 62 
13.2 
Criteria for interim analysis and premature discontinuation ............................................. 63 
13.3 
Determination of the planned number of subjects ............................................................ 63 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................................... 64 
14.1 
Monitoring of study sites .................................................................................................. 64 
14.1.1 Central monitoring ..................................................................................................... 64 
14.1.2 Site visit monitoring ................................................................................................... 64 
14.2 
Protocol deviations ........................................................................................................... 64 


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14.3 
Quality assurance and regulatory agency inspections ....................................................... 65 
15.0 
ETHICAL CONDUCT OF A STUDY .................................................................................... 66 
15.1 
Conflict of interests ........................................................................................................... 66 
15.2 
Approval by the institutional review board including the ethics review committee ......... 66 
15.3 
Written information and subject’s consent ....................................................................... 66 
15.4 
Subject confidentiality ...................................................................................................... 67 
15.5 
Advantages and disadvantages to subjects ....................................................................... 67 
15.5.1 Advantage to subjects ................................................................................................ 67 
15.5.2 Disadvantage to subjects ............................................................................................ 68 
15.6 
Publication, disclosure, and clinical trial registration policy ............................................ 68 
15.6.1 Publication and disclosure ......................................................................................... 68 
15.6.2 Clinical trial registration ............................................................................................ 68 
15.6.3 Clinical trial results disclosure ................................................................................... 68 
15.7 
Attribution of study results and intellectual property rights ............................................. 68 
15.8 
Insurance and compensation for injury ............................................................................. 68 
16.0 
REFERENCES ........................................................................................................................ 69 
 
Figures and Tables List 
Figure 8.a  mFOLFOX6 + panitumumab combination therapy ........................................................... 30 
Figure 8.b  5-FU/LV + panitumumab combination therapy ................................................................ 31 
 
Table 4.a  Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study ......... 18 
Table 4.b  Adverse Drug Reactions (ADRs) of special interest on Post-marketing survey in Japan ... 20 
Table 8.a  Treatment regimen of mFOLFOX6 + panitumumab combination therapy ......................... 29 
Table 8.b  Treatment regimen of 5-FU/LV + panitumumab combination therapy .............................. 30 
Table 8.c  Criteria for initiation of treatment cycle .............................................................................. 32 
Table 8.d  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [1]) ............................ 32 
Table 8.e  Doses of OXA and 5-FU (Protocol Treatment [1]) ............................................................. 33 
Table 8.f  Criteria for dose reduction of panitumumab ........................................................................ 33 
Table 8.g  Dose of panitumumab ......................................................................................................... 34 
Table 8.h  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [2]) ............................ 34 
Table 8.i  Doses of OXA and 5-FU (Protocol Treatment [2]) ............................................................. 35 


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Table 9.a  Study calendar (Protocol Treatment [1]) ............................................................................. 39 
Table 9.b  Study calendar (Protocol Treatment [2]) ............................................................................. 40 
Table 9.c  Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) ........................... 43 
Table 9.d  Laboratory tests performed at the time of enrollment ......................................................... 44 
Table 9.e  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment 
[1]) ............................................................................................................................. 44 
Table 9.f  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment 
[2]) ............................................................................................................................. 45 
Table 9.g  Laboratory tests performed at the time of discontinuation.................................................. 45 
Table 9.h  EXON and codon verified on NRAS test ............................................................................. 47 
Table 9.i  Residual tumor after surgical treatment ............................................................................... 47 
 


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2.0 
STUDY SUMMARY 
Sponsor: Takeda Pharmaceutical Company Limited 
Test product: Panitumumab 
Study title: 
SAPPHIRE study（A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + 
panitumumab combination therapy and 5-FU/LV + panitumumab combination therapy in the patients with 
chemotherapy-naïve unresectable advanced recurrent colorectal carcinoma of KRAS wild-type after 6 cycles of 
combination therapy with mFOLFOX6 + panitumumab） 
Protocol number: 183/NRP-005 
Study type: Exploratory study 
Study design: 
 
Objective: 
To exploratorily examine efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type who have been treated with 6 cycles of first-line 
mFOLFOX6 + panitumumab combination therapy and then assigned to two groups, i.e., a group receiving 
5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + panitumumab combination 
therapy. 
Study population: 
The patients with chemotherapy-naïve unresectable, advanced/recurrent colorectal carcinoma of KRAS wild-type 
Planned number of subjects: 
mFOLFOX6 + panitumumab arm (Group A): 50 
5-FU/LV + panitumumab arm (Group B): 
50 


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Number of study sites: 40 
Method of administration: 
In both Protocol Treatment [1] and Protocol Treatment [2] (Group A and Group B), one cycle consists of two 
weeks, and the drugs will be administered at the following doses according to the following schedule. 
Protocol Treatment [1] 
mFOLFOX6 + panitumumab combination therapy, once every two weeks, 6 cycles 
OXA: 85 mg/m2/day 1 
l-LV: 200 mg/m2/day 1 
bolus 5-FU: 400 mg/m2/day 1 
infusional 5-FU: 2400 mg/m2/day 1-3 
panitumumab: 6 mg/kg 
Protocol Treatment [2] 
Group A: mFOLFOX6 + panitumumab combination 
therapy, once every two weeks 
OXA: 85 mg/m2/day 1 
l-LV: 200 mg/m2/day 1 
bolus 5-FU: 400 mg/m2/day 1 
infusional 5-FU: 2400 mg/m2/day 1-3 
panitumumab: 6 mg/kg 
Group B: 5-FU/LV + panitumumab combination 
therapy, once every two weeks 
l-LV: 200 mg/m2/day 1 
bolus 5-FU: 400 mg/m2/day 1 
infusional 5-FU: 2400 mg/m2/day 1-3 
panitumumab: 6 mg/kg 
Duration of treatment (approximately): 12 months (Period from the day of first administration in Protocol 
Treatment [1] to PD or intolerance) 
Inclusion criteria 
Inclusion criteria for enrollment: 
(1) Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the 
appendix and anal canal cancer) 
(2) Patients with measurable lesion(s) according to the RECIST ver. 1.1 
(3) Patients who have not received chemotherapy for colorectal cancer. Patients who experience relapse more 
than 6 months after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents 
may be enrolled. 
(4) Aged ≥20 years at the time of informed consent 
(5) Patients classified as KRAS wild-type*. However, the criteria will be changed to all patients who are 
verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be covered by 
National Health Insurance, and the tests become feasible at medical institutions. 
*: 
Patients with no mutation in any of the codons shown below are considered wild type. 
KRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
NRAS** 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
**: To be considered when the test comes to be covered by insurance and becomes feasible at medical 
institutions. 
(6) Patients who satisfy the following criteria for the major organ function in tests performed within 14 days 
prior to enrollment 
1) 
Neutrophil count ≥ 1,500/mm3 
2) 
White blood cell count ≥ 3,000/mm3 
3) 
Platelet count ≥ 10.0 × 104/mm3 
4) 
Hemoglobin ≥ 9.0 g/dL 


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5) 
Total bilirubin ≤ 2.0 mg/dL 
6) 
AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
7) 
ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
8) 
Serum creatinine ≤ 1.5 mg/dL 
(7) ECOG performance status (PS) of 0 or 1 
(8) Life expectancy of ≥ 6 months after enrollment 
(9) Patients who have given written consent to take part in the study after detailed explanation of the study 
prior to enrollment 
Inclusion criteria for randomization: 
(1) Patients who have received 6 cycles＊ (Protocol Treatment [1]) of mFOLFOX6 + panitumumab 
combination therapy 
*: Protocol Treatment [1] without discontinuation in all cycles (6 cycles) of Protocol Treatment [1]. 
However, bolus 5-FU and panitumumab are an exception. 
(2) ECOG performance status (PS) of 0-1 before administration of the 7th cycle. 
(3) Patients for whom PD or not evaluable has been denied on the Response Evaluation Criteria in Solid 
Tumors (RECIST) based on imaging tests conducted after administration of 6 cycles. 
Exclusion criteria 
Exclusion criteria for enrollment: 
(1) Radiotherapy received for a measurable lesion(s) 
(2) Radiotherapy received within 4 weeks prior to enrollment except measurable lesion(s). However, the 
treatment to relieve the pain of metastatic bone tumor is allowed 
(3) Known brain metastasis or strongly suspected of brain metastasis 
(4) Synchronous cancers or metachronous cancers with a disease-free period of ≤ 5 years (excluding colorectal 
cancer) excluding mucosal cancers cured or be possibly cured by regional resection (esophageal, stomach, 
and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.). 
(5) Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) 
(6) Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant or 
breast-feeding, or test positive for pregnancy 
(7) Active hemorrhage requiring blood transfusion 
(8) Disease requiring systemic steroids for treatment (excluding topical steroids) 
(9) Intestinal resection and colostomy within 2 weeks prior to enrollment 
(10) History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, 
pulmonary fibrosis, etc.) 
(11) Serious drug hypersensitivity 
(12) Local or systemic active infection requiring treatment, or fever indicating infection 
(13) Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating symptoms 
despite adequate treatment) 
(14) Active hepatitis B and/or C 
(15) Known HIV infection 
(16) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study 
Exclusion criteria for randomization: 
(1) Patients in whom interstitial pneumonia has been newly diagnosed during the period from registration to 
randomization 
(2) Patients who have received radiotherapy during the period from registration to randomization. However, 


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the treatment to relieve the pain of metastatic bone tumor is allowed 
(3) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study 
Endpoints: 
[Primary endpoint] 
 Efficacy 
Progression-Free Survival (PFS) at 9 months after the day of randomization 
[Secondary endpoints] 
 Efficacy 
 Progression-Free Survival (PFS) 
 Overall survival (OS) 
 Response rate (RR) 
 Time to treatment failure (TTF) 
 Safety 
 Incidence rate of adverse events and severity by incidence rate 
 Incidence rate of peripheral nerve disorders 
 Incidence rate of skin disorders 
 Additional endpoint 
 Percentage of maintenance of Performance Status (PS) 
 Percentage of continuation of OXA in mFOLFOX6 + panitumumab group (Group A) 
 Percentage of continuation of panitumumab in both groups 
Statistical method: 
The purpose of this study is to explorethe the analysis of PFS compared mFOLFOX6 + panitumumab arm with 
5-FU/LV + panitumumab arm.  
The PFS is the period from the day of randomization (Day 0) until the day of judgment of exacerbation from the 
day of randomization, or until death by all causes, whichever comes earlier. 
For each treatment group, calculate the progression-free survival rate at a given time point and its 95% 
confidence interval (two-sided) by Kaplan-Meier method, and calculate the quartile of PFS and its 95% 
confidence interval (two-sided). At the same time, draw a Kaplan-Meier chart for the progression-free survival 
rate. If the median value of observed PFS is 9 months or more in each group, the treatment regimen concerned 
will be regarded as being of worth of further investigation. 
Moreover, for the sake of reference, calculate the hazard ratio of Group B to Group A and its 95% confidence 
interval (two-sided) on the basis of the stratified Cox regression model and apply the log-rank test. 
Rationale for planned number of subjects: 
This study will be designed as a phase II randomized screening comparison study which does not use direct 
comparison for primary analysis. 
In the phase III study (PRIME Study) in which FOLFOX4 therapy was combined with bi-weekly administration 
of panitumumab 6 mg/kg as a first-line therapy, the median PFS in the patients of KRAS wild-type as the 
primary endpoint was reported as 9.6 months12). Moreover, in PEAK study in which panitumumab and 
bevacizumab were compared as the drugs to be administered in combination with mFOLFOX6 therapy, the 
median PFS in the mFOLFOX6 therapy + panitumumab group was reported as 10.9 months. The percentage of 
the cases in which any events occurred or the study was cut off within 3 months in PRIME Study and PEAK 
Study was approximately 10% of all cases. 
The subjects of this study will be the patients who receive mFOLFOX6 + panitumumab combination therapy for 
3 months, and can continue OXA administration. Since the PFS 40% point in PRIME Study and PEAK Study 


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was approximately 13 months, the median PFS in Group A in this study is expected to be approximately 10 
months, which is obtained by subtracting 3 months from the 40% point. The median PFS in Group B is assumed 
to be comparable to that in Group A. 
In the primary analysis, a test based on the method of Brookmeyer-Crowley will be conducted for the null 
hypothesis, "true median PFS will be lower than the threshold median PFS for judgment as ineffective", 
separately in Group A and Group B on the basis of the observed median PFS. When the threshold median PFS is 
regarded as 6 months, true median PFS as 10 months, enrollment period as 12 months, follow-up period as 12 
months, one-sided significance level as 5%, and power of test as 80%, the number of subjects required in Group 
A and Group B will become 54 subjects each. Considering the cases of discontinuation, the target number of 
subjects to be randomised was set at 60 patients for each group (120 patients in total). 


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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Unabbreviated expression 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ALP 
alkaline phosphatase 
ASCO 
American society of clinical oncology 
BRAF 
v–raf murine sarcoma viral oncogene homolog B1 
BSC 
best supportive care 
CEA 
carcinoembryonic antigen 
COI 
conflict of interest 
CR 
complete response 
CRO 
contract research organization 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
deepness of response 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EGF 
epidermal growth factor 
EGFR 
epidermal growth factor receptor 
ETS 
early tumor shrinkage 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FFPE 
Formalin-Fixed Paraffin-Embedded 
G-CSF 
granulocyte colony stimulating factor 
γ-GTP 
γ-glutamyl transpeptidase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
IRB 
institutional review board 
JCOG 
Japan Clinical Oncology Group 
KRAS 
Kirsten rat Sarcoma-2 virus 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
l-LV 
Leucovorin 
mCRC 
metastatic colorectal cancer 


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Abbreviation 
Unabbreviated expression 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NE 
Not Evaluable 
NRAS 
 
OS 
Overall survival 
OXA 
Oxaliplatin 
PD 
progressive disease 
PFS 
Progression free survival 
PPS 
per-protocol analysis set 
PR 
partial response 
P.S. 
performance status 
PT 
Preferred Term 
PI3K 
Phosphoinositide 3-kinase 
RAS 
rat sarcoma 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TTF 
Time to Treatment Failure 
ULN 
upper limit of normal 
UMIN-CTR 
University Hospital Medical Information Network - Clinical Trials 
Registry 
UPC 
urine protein creatinine 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell 
WT 
wild type 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 
Etiology of target disease 
According to “Cancer Statistics 2013,”1) and “Site-specific Cancer Prevalence” in 2008 in Japan, 
colon cancer was the third most prevalent cancer in men (15.0%) and the second in women (15.1%). 
According to “Site-specific Cancer Deaths (2012),” in men, lung cancer was the leading cause of 
cancer death (accounting for 23.9% of cancer deaths), followed by gastric cancer (15.0%) and hepatic 
cancer (9.3%); colorectal cancer (colon cancer and rectal cancer combined) accounted for 11.9% of 
cancer deaths which exceeded the death rate of hepatic cancer, representing that colorectal cancer is 
the third leading cause of cancer death. In women, lung cancer (13.8%) was also the leading cause of 
cancer death, followed by gastric cancer (11.6%) and pancreatic cancer (9.9%); deaths from colorectal 
cancer (colon cancer and rectal cancer combined) accounted for 14.9% of cancer deaths, representing 
that colorectal cancer is the first leading cause of cancer death. 
4.1.2 
Standard treatment for target disease 
The “Guidelines for Treatment of Colorectal Cancer (2014)”2) classify the standard treatment of 
colorectal cancer according to staging as follows: endoscopic resection for Stage 0, in which the lesion 
is limited in the mucosa; surgical resection for Stage I to III with postoperative adjuvant chemotherapy 
for Stage III involving lymph nodes; and surgical resection for Stage IV and recurrent disease if liver 
or lung metastasis is resectable, and systemic chemotherapy if not.  
The first-line chemotherapy regimens for the patients with unresectable, advanced/recurrent colorectal 
carcinoma necessitating powerful treatment that have been demonstrated to be useful in clinical 
studies and are currently covered by national health insurance in Japan are presented below. There is a 
consensus that cetuximab and panitumumab should be used only for KRAS wild-type (WT) colorectal 
cancer. 
(1) FOLFOX therapy or CapeOX therapy +bevacizumab*1 
FOLFOX therapy: combination chemotherapy with fluorouracil (hereinafter referred to as 
5-FU), Isovorin (hereinafter referred to as l-LV), and oxaliplatin (hereinafter referred to as 
OXA) 
CapeOX therapy: combination chemotherapy with capecitabine and OXA 
(2) FOLFIRI therapy + bevacizumab*1 
FOLFIRI therapy: combination chemotherapy with irinotecan (hereinafter referred to as IRI), 
5-FU, and l-LV 
(3) FOLFOX therapy + cetuximab*1, 2 or panitumumab*1, 2 
(4) FOLFIRI therapy + cetuximab*1, 2 or panitumumab*1, 2 
(5) FOLFOXIRI therapy  
FOLFOXIRI therapy: combination chemotherapy with OXA, IRI, 5-FU and l-LV 
(6) FL*3, CapeOX + bevacizumab*1 or UFT + LV 
UFT: combination preparation of tegafur and uracil 
*1: Combination with molecular-targeted drugs such as bevacizumab and epidermal 
growth factor receptor (EGFR) antibody is recommended, but if this cannot be 
indicated, chemotherapy alone will be provided. 
*2:  Indicated only for KRAS wild-type. 
*3: infusional 5-FU + l-LV 


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FOLFOX-based therapy is more frequently selected as first-line chemotherapy than FOLFIRI-based 
therapy, and bevacizumab is widely used for KRAS wild-type colorectal cancer as well. As a result, 
FOLFOX + bevacizumab combination therapy is the most common first-line treatment in Japan 
(in-house document).  
It is recommended that in principle, a regimen not used in first-line treatment should be used for 
second-line treatment. More specifically, IRI-based regimens are recommended as a second-line 
treatment of patients who have received an OXA-based regimen as a first-line treatment, while 
OXA-based regimens are recommended for patients who have received an IRI-based regimen. 
This principle also applies to molecular-targeted drugs concomitantly used for second-line treatment. 
For KRAS wild-type colorectal cancer, bevacizumab is recommended as a second-line treatment of 
patients who have received an anti-EGFR antibody as a first-line treatment, while switching to an 
anti-EGFR antibody or continued use of bevacizumab is an option as a second-line treatment of 
patients who have received bevacizumab as a first-line treatment. 
For third-line treatment, regorafenib or symptomatic therapy is currently recommended. 
4.1.3 
Efficacy and safety of mFOLFOX6 in patients with unresectable, advanced 
or recurrent colorectal cancer 
As therapy for unresectable, advanced/recurrent colorectal cancer, regimens mainly based on 
fluoropyrimidine anticancer agents are considered to be the standard for a long term3). Based on the 
evidence showing that 5-FU combined with l-LV is superior to 5-FU monotherapy, the combination 
therapy with 5-FU and l-LV (hereinafter referred to as 5-FU/LV therapy) had been considered as 
standard chemotherapy for colorectal cancer for a long time. The type I topoisomerase inhibitor IRI 
and the third generation of platinum-based anticancer drug OXA were then developed, and have been 
shown to improve treatment outcome in a number of large scale controlled trials4) to 9). At present, 
continuous infusion of 5-FU/LV in combination with OXA (FOLFOX therapy) or in combination with 
IRI (FOLFIRI therapy) is the standard chemotherapy regimen for advanced/recurrent colorectal 
cancer3), 10). FOLFOX and FOLFIRI therapies were compared in the GERCOR V308 study9,) in which 
the median final overall survival (hereinafter referred to as OS) was similar between the precedent 
FOLFIRI and the precedent FOLFOX arms (21.5 months vs. 20.6 months), and thereby both of the 
therapies are used as the standard for unresectable colorectal cancer. The development of these 
therapies provided improvement of the median survival time of unresectable advanced colorectal 
cancer from 12 months with 5-FU/LV therapy to 20 months or more with 5-FU/LV therapy in 
combination with IRI or OXA. 
Among several FOLFOX regimens, FOLFOX4 therapy and modified FOLFOX6 (hereinafter referred 
to as mFOLOFX6) therapy, which include OXA at the approved dosage (85 mg/m2) in Japan, are 
covered by national health insurance, and simpler and easier mFOLFOX6 therapy is more frequently 
used. 
4.1.4 
Efficacy and safety of panitumumab in patients with unresectable, advanced 
or recurrent colorectal cancer 
4.1.4.1 
Panitumumab 
EGFR, a member of the ErbB family of transmembrane receptor tyrosine kinases constantly 
expressed in epithelial-derived tissues, has been shown to be overexpressed in various types of 
solid tumors. Colorectal cancer is characterized by high EGFR expression, and the EGFR signaling 
pathway has been shown to play in the pathogenesis and progression of tumors. Binding of 
epidermal growth factor (EGF), the major ligand of EGFR, to EGFR is considered to induce 
auto-phosphorylation of EGFR and activation of various signaling pathways, resulting in induction 
of cellular proliferation, inhibition of apoptosis, and increased production of inflammatory 
cytokines and angiogenesis factors. Panitumumab is a human IgG2 monoclonal antibody that binds 


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to EGFR with specificity and high affinity, and inhibits the proliferation of tumor cells by 
competitively inhibiting the binding of the ligand to EGFR. 
4.1.4.2 
Clinical study results for panitumumab in the U.S. and Europe 
As a clinical trial of panitumumab monotherapy for colorectal cancer, a phase III study was 
conducted to compare best supportive care (hereinafter referred to as BSC) vs. BSC + 
panitumumab therapy in patients with unresectable, recurrent or advanced, EGFR-positive 
colorectal cancer that became resistant to fluoropyrimidine agents, OXA, and IRI (BSC arm, 232 
patients; BSC + panitumumab arm, 231 patients) 11). The primary endpoint of median progression 
free survival (hereinafter referred to as PFS) was 8 weeks and significantly longer in the BSC + 
panitumumab therapy, showing the efficacy of panitumumab therapy as compared with 7.3 weeks 
in the BSC alone arm (hazard ratio [HR], 0.54; two-sided 95% confidence interval [CI], 0.44 to 
0.66; p<0.0001). The secondary endpoint of OS was not significantly different between the two 
arms (HR, 1.00; two-sided 95% CI, 0.82 to 1.22; p = 0.81); however, this may be primarily due to 
the fact that 173 subjects (75%) in the BSC arm received follow-up therapy with panitumumab. 
With regard to combination of chemotherapy and panitumumab, a phase III clinical study (PRIME 
Study) has been reported, in which FOLFOX4 monotherapy vs. FOLFOX4 therapy + panitumumab 
(given at a dose of 6 mg/kg every 2 weeks) as a first-line treatment was compared in a total of 
1,180 patients (590 in each arm)12). The primary endpoint of median PFS in KRAS wild-type 
patients was 9.6 months and significantly longer in the FOLFOX4 + panitumumab arm as 
compared with 8.0 months in the FOLFOX4 alone arm (HR, 0.80; two-sided 95% CI, 0.66 to 0.97; 
p = 0.02). Of Grade 3/4 adverse events, panitumumab-related adverse events such as dermatologic 
toxicities, diarrhoea, and hypomagnesaemia occurred more frequently in the FOLFOX4 + 
panitumumab arm, but there were no major differences in the incidence of other adverse events 
between the two arms. Grade 3 infusion reaction occurred in 2 patients (Table 4.a). 
Table 4.a  Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study 
Adverse event 
FOLFOX4 + panitumumab 
(n = 322) 
FOLFOX4 alone 
(n = 327) 
n 
(%) 
N 
(%) 
Any adverse drug reaction 
270 
84 
227 
69 
Leukopenia 
136 
42 
134 
41 
Skin disorder 
116 
36 
7 
2 
Diarrhoea 
59 
18 
29 
9 
Nerve disorder 
52 
16 
51 
16 
Hypokalaemia 
32 
10 
15 
5 
Malaise 
30 
9 
10 
3 
Stomatitis 
28 
9 
2 
<1 
Hypomagnesaemia 
20 
8 
1 
<1 
Paronychia 
11 
3 
0 
0 
Pulmonary embolism 
9 
3 
5 
2 
Febrile neutropenia 
8 
2 
7 
2 
Infusion reaction 
2 
<1 
- 
- 
With regard to second-line treatment, a phase III clinical study (Study 20050181) has been 
conducted, in which FOLFIRI monotherapy vs. FOLFIRI therapy + panitumumab (given at a dose 
of 6 mg/kg every 2 weeks) was compared. 13) The primary endpoints were PFS and OS in KRAS 
wild-type patients. In KRAS wild-type patients, the median PFS was 5.9 months and significantly 
longer in the FOLFIRI + panitumumab arm than 3.9 months in the FOLFIRI alone arm (HR, 0.73; 
two-sided 95% CI, 0.59 to 0.90; p = 0.004). On the other hand, OS was 14.5 months in the 
FOLFIRI + panitumumab arm and 12.5 months in the FOLFIRI alone arm, with no statistically 
significant difference between the two arms (HR, 0.85; two-sided 95% CI, 0.70 to 1.04; p = 0.12). 
The response rate (hereinafter referred to as RR) was 35% and higher in the FOLFIRI + 


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panitumumab arm as compared with 10% in the FOLFIRI alone arm. Of Grade 3/4 adverse events, 
the incidence of dermatologic toxicities was higher and the incidences of diarrhoea and 
hypomagnesaemia tended to be higher in the FOLFIRI + panitumumab arm; however, there were 
no major differences in the incidence of toxicities including hematologic toxicities between the two 
arms, and the incidence of infusion reaction was not more than 1%. 
Both the PRIME Study12) and Study 2005018113) described above, in which KRAS mutation status 
was prospectively studied, showed that combination therapy containing panitumumab was not 
effective in KRAS-mutant patients, suggesting that KRAS mutation is predictive of poor response to 
anti-EGFR antibody therapy. 
4.1.4.3 
Clinical study results for panitumumab in Japan 
In a Japanese phase I clinical study of panitumumab, panitumumab was administered at the same 
dosing regimens with which the drug was confirmed to be safe and effective in overseas studies; 
i.e., a dose of 2.5 mg/kg once weekly, 6 mg/kg once every 2 weeks, and 9 mg/kg once every 3 
weeks. Each of these dosing regimens was evaluated in 6 patients. Again, in this study, 
panitumumab showed a good tolerability profile. 
In a Japanese phase II clinical study of panitumumab monotherapy14), 52 patients with previously 
treated, unresectable colorectal cancer were enrolled. In this study, the 6-mg/kg biweekly regimen 
of panitumumab, which was the recommended dosing regimen in the overseas phase III clinical 
study, was well tolerated, and the incidence of adverse events was similar to that observed in the 
U.S. and Europe (Table 4.b). In addition, 7 patients (13.5%) had partial response (hereinafter 
referred to as PR), and this Japanese study yielded an RR of 13.5% (two-sided 95% CI: 5.6 to 
25.8),a time to treatment failure of 11.4 weeks (two-sided 95% CI: 8.4 to 15.0), a median PFS of 
8.0 weeks (two-sided 95% CI: 7.4 to 11.4), and a median OS of 9.3 months (two-sided 95% CI: 7.1 
to 12.8), similar to those observed in clinical studies in the U.S and Europe. 
On the basis of the above results, panitumumab was approved in April 2010 for the treatment of 
incurable/unresectable, advanced/recurrent colorectal cancer in Japan as well. 
Table 4.b  Common adverse events (≥ 20%) noted in a Japanese phase II clinical study of 
Panitumumab monotherapy 
Adverse Events 
Panitumumab Monotherapy (n = 52) 
All 
≥ Grade 3 
n 
% 
N 
% 
Any adverse drug reaction  
51 
98 
6 
12 
Skin disorder 
51 
98 
3 
6 
Acne 
42 
81 
1 
2 
Dry skin 
32 
62 
0 
 
Skin rash 
24 
46 
1 
2 
Pruritus 
17 
33 
0 
 
Paronychia 
17 
33 
1 
2 
Hypomagnesaemia 
17 
33 
0 
 
Malaise 
13 
25 
0 
 
Stomatitis 
12 
23 
0 
 
Anorexia 
11 
21 
1 
2 
 
4.1.4.4 Result of the post-marketing Surveillance (overall survey) in Japan 
In a study conducted during a certain post-marketing period by enrolling all patients15), the median 
treatment duration (first day of administration to last day of administration) in 3,085 patients 
included in safety evaluation was 113 days (range: 1-559 days), and the incidence rate of adverse 


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drug reactions was 84.1% (≥Grade 3, 25.8%). The incidence rate in 1,254 patients in the group 
treated with panitumumab monotherapy was 80.1% (≥Grade 3, 19.7%) and that in 1,831 patients in 
the group treated with panitumumab + chemotherapy was 86.9% (≥Grade 3, 30.0%). The status of 
occurrence of adverse drug reactions of special interest is shown in Table 4.b.  
Table 4.b  Adverse Drug Reactions (ADRs) of special interest on Post-marketing survey in Japan 
Overall incidence of 
Post-marketing survey 
Panitumumab Monotherapy 
(n=1,254) 
Combination therapy (n=1,831) 
All 
≥ Grade 3 
All 
≥ Grade 3 
ADRs of special interest 
n 
% 
n 
% 
n 
% 
N 
% 
Skin and subcutaneous 
tissue disorders (SOC) 
918 
73.2 
118 
9.4 
1446 
79.0 
274 
15.0 
Paronychia 
272 
21.7 
33 
2.6 
459 
25.1 
99 
5.4 
Interstitial lung disease* 
16 
1.3 
- 
- 
23 
1.3 
- 
- 
Infusion reaction 
17 
1.4 
1 
0.1 
30 
1.6 
5 
0.3 
Hypomagnesemia 
257 
20.5 
61 
4.9 
263 
14.4 
62 
3.4 
Hypocalcemia 
59 
4.7 
16 
1.3 
77 
4.2 
26 
1.4 
Cardiac disorders（SOC) 
2 
0.2 
0 
0.0 
5 
0.3 
1 
0.1 
*：Based on the evaluation of the ILD 
 
4.1.5 
Adverse reactions to OXA 
Major dose-limiting toxicities of OXA are neurological manifestations, which are peripheral sensory 
nerve disorders characterized by dysaesthesia or paraesthesia in four limbs. They may accompany 
convulsion and are induced by exposure to coldness. Hochster et al.16) reported that these symptoms 
appeared in 85% to 95% of the patients who received FOLFOX therapy in combination with 
bevacizumab, that the duration became longer as the administration cycles increased, and that the 
incidence of functional disorders after administration of a cumulative dose of 800 mg/m2 was 
approximately 15%. In many cases, these neurological manifestations remit or disappear after 
discontinuation of administration. Acute sensory neurological manifestations appear within several 
hours after administration, and are induced by exposure to coldness. They may appear as transient 
paraesthesia, dysaesthesia, hypoaesthesia or acute laryngopharyngeal dysaesthesia syndrome. 
In addition to nerve disorders, acute laryngopharyngeal dysaesthesia syndrome is estimated to occur 
with an incidence of 1% to 2%. It is characterized by respiratory disorders without cyanosis and 
hypoxia, sensation of dyspnoea without direct effects on the respiratory functions such as dysphagia, 
decreased SaO2, laryngospasm, and bronchospasm without wheezing in the upper and lower 
respiratory tracts. Convulsion in the jaw, abnormal feeling in the tongue, dysarthria, eye pain, and 
chest pressure sensation are also observed17). These symptoms improve reversely without treatment. 
The incidence of acute laryngopharyngeal dysaesthesia syndrome is suggested to decrease as the 
duration of administration becomes longer. 
Among these adverse reactions, nerve disorders in particular make continuous administration of OXA 
difficult, and may lead to modification of the FOLFOX therapy regimen involving molecular-targeted 
drugs. For the patients responding to the therapy, they may miss the patients of important 
opportunities of treatment (internal data). 
 


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4.1.6 
Examination of the method of administration of OXA in first-line therapy 
Reduction of neurological manifestations associated with FOLFOX as standard chemotherapy for 
unresectable, advanced/ recurrent colorectal carcinoma is urgently needed for improvement of the 
QOL of patients and for realization of long-term treatment. According to the reports of Tournigand et 
al18)., OPTIMOX1 (Stop and Go method) is able to achieve recovery from neurological manifestations 
during the period of sLV5FU2 therapy without OXA after FOLFOX. Moreover, it may be possible to 
reduce hematological toxicity and non-hematological toxicity during this period. Concerning the 
treatment effect, the response rate was 59.2% and MST was 21.2 months. Furthermore, the final report 
of OPTIMOX2 by F Maindrault-Goebel et al.19) showed that the OS in the administration schedule of 
OPTIMOX1 (Stop and Go method) was 26 months. 
 
4.2 
Rationale for the proposed study 
In Japan, mFOLFOX6 therapy is conducted most frequently as the first-line therapy for unresectable, 
advanced/ recurrent colorectal carcinoma. Peripheral nerve disorders induced by OXA contained in 
mFOLFOX6 therapy may cause a clinical problem because they become a cause of deterioration of the 
patients' QOL, thereby making continuous treatment impossible. When peripheral nerve disorders as 
mentioned above have occurred, mFOLFOX6 therapy as the baseline therapy is switched to FOLFIRI 
therapy in some cases in spite of favorable responses to the first-line therapy, instead of discontinuing 
OXA which is the cause of peripheral nerve disorders. This is deemed to lead to a loss of the opportunity 
of treatment for the patients. Moreover, it is possible that long-term administration of OXA induces 
peripheral nerve disorders. For patients who discontinue administration of OXA after having received 
the drug for a certain period and who have experienced no peripheral nerve disorders during the 
treatment period, re-introduction of OXA in the later stage of treatment may remain as a treatment option. 
With regard to the discontinuaiton and resumption of OXA administration in FOLFOX therapy as the 
first line therapy at present, the evaluation for efficacy and safety of OPTIMOX study18) have been 
presented. However, appropriate administration method of OXA in first-line therapy with mFOLFOX6 + 
panitumumab has not been revealed. 
For these reasons, this study was planned on the basis of the judgment that efficacy and safety in the 
group in which OXA is discontinued after 6 cycles of the treatment and the group in which OXA is 
continued need to be examined in the patients responding to mFOLFOX6 + panitumumab combination 
therapy. 


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5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY 
5.1 
Objective 
To exploratorily examine efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type who have been treated with 6 cycles of 
first-line mFOLFOX6 + panitumumab combination therapy and then assigned to two groups, i.e., a 
group receiving 5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + 
panitumumab combination therapy. 
 
5.2 
Endpoints 
See Section 13.1.3 for Efficacy analysis. 
5.2.1 
Primary endpoint 
• 
Efficacy 
 
Progression-free survival (PFS) at 9 months after the day of randomization 
 
5.2.2 
Secondary endpoints 
• 
Efficacy 
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Response rate (RR) 
 
Time to treatment failure (TTF) 
• 
Safety 
 
Incidence rate of adverse events, and severity by incidence rate 
 
Incidence rate of peripheral nerve disorders 
 
Incidence rate of skin disorders 
 
5.2.3 
 Additional endpoint 
• 
Percentage of maintenance of Performance Status (PS) 
• 
Percentage of continuation of OXA in mFOLFOX6 + panitumumab group (Group A) 
• 
Percentage of continuation of panitumumab in both groups 
 


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5.3 
Rationale for the endpoints 
5.3.1 
Primary endpoint 
The PFS was selected as the best indicator for evaluation of efficacy of the regimen with and without 
OXA after 6 cycles of mFOLFOX6 + panitumumab combination therapy without being affected by 
the after-treatment. 
 
5.3.2 
Secondary endpoints 
The OS was selected as the secondary endpoint because it is the true endpoint. As a help for 
interpretation of primary efficacy results, RR and TTF were selected as secondary endpoints. 
Concerning safety, the appropriateness of continuing and discontinuing OXA and panitumumab was 
evaluated in an exploratory manner. The incidence rate of adverse events, the incidences of peripheral 
nerve disorders and skin disorders were selected as secondary endpoints because they are important 
factors for the choice of treatment. 
 


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6.0 
STUDY DESIGN 
6.1 
Study design 
This is a phase II, multi-center joint, open-label, parallel-group randomized controlled study to 
exploratorily examine the efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type after treating them with 6 cycles of 
mFOLFOX6 + panitumumab combination therapy and subsequently assigning them to a group 
continuing mFOLFOX6 + panitumumab combination therapy (Group A) and a group in which OXA is 
discontinued and 5-FU/LV + panitumumab combination therapy is provided (Group B). 
Patients who are judged eligible for the study based on the inclusion criteria at the time of enrollment 
will be registered within 14 days before the first administration (1st cycle), and will be treated with 6 
cycles of mFOLFOX6 + panitumumab combination therapy (Protocol Treatment [1]). The patients for 
whom continuation of mFOLFOX6 + panitumumab combination therapy is judged appropriate on the 
basis of the examination before administration of the 7th cycle and imaging test after administration of 
the 6th cycle, who satisfy the inclusion criteria for randomization, and who do not fall under any of the 
exclusion criteria for randomization will be randomly assigned to either the mFOLFOX6 + panitumumab 
combination group (Group A) or the 5-FU/LV + panitumumab combination group (Group B) at the ratio 
of 1:1 before administration of the 7th cycle (TBD). After randomization, treatment in Group A or Group 
B will be continued according to the administration standards for Protocol Treatment [2] until the "8.8. 
Criteria for discontinuation of protocol treatment" are met. The reasons for the failure to meet the subject 
inclusion criteria at the time of randomization will be collected. The patients who fall under the criteria 
for extension of administration on the examination before administration of the 7th cycle will be 
examined again after an appropriate interval. The patients who satisfy the subject inclusion criteria on 
the re-examination will be randomized, and will receive the protocol treatment of the assigned group. 
Both inpatients and outpatients are eligible. Refer to "8.2 Treatment regimen" for details about the 
protocol treatment ([1] and [2]). 
See "13.3 Determination of the planned number of subjects" for the number of subjects. 
 
 
Figure 6.a  Outline of study design 
 


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6.2 
Rationale for study design, dose and endpoints 
6.2.1 
Study population 
The timing at which OXA-induced peripheral nerve disorders occurs most frequently has been 
reported to be the time point at which the accumulated amount of OXA administered reaches 780-850 
mg/m2 20). This amount is equivalent to 9 or 10 doses when converted using the dose of 85 mg/m2 of 
OXA administered at a time in Protocol Treatment [1] and [2]. According to the report by Hochster et 
al16). who investigated the mean number of doses administered continuously in FOLFOX therapy in 
initial therapy in routine medical care, the number was 10 times in the FOLFOX + bevacizumab 
combination therapy in first-line therapy (TREE2). In the report by Giantonio et al.21), the mean 
number of doses administered continuously in FOLFOX±bevacizumab combination therapy in the 
second-line therapy (ECOG3200) for the patients with a history of chemotherapy was 7 to 10 times. 
This study aims at comparing efficacy and safety in the group continuing OXA from the 7th cycle and 
the group discontinuing OXA in the patients receiving first-line mFOLFOX6 + panitumumab 
combination therapy before the occurrence of peripheral nerve disorders. Since the above-described 
status of the frequency of OXA administration also seems to suggest that discontinuation of OXA after 
6th administration in Protocol Treatment [1] does not greatly deviate from the situation in routine 
medical care, the number of cycles of OXA administration given before randomization was set at 6. 
Moreover, since no significant differences were seen in the duration of disease control and PFS in 
OPTIMOX study, the duration of treatment is not expected to differ significantly even when OXA is 
discontinued after 6 cycles of mFOLFOX6 + panitumumab therapy while 5-FU/LV + panitumumab 
combination therapy is continued. Furthermore, although concomitant administration of panitumumab 
does not cause differences in time to treatment failure and PFS, discontinuation of OXA before the 
occurrence of peripheral nerve disorders enables re-introduction of OXA. Therefore, differences larger 
than in OPTIMOX study may be expected for OS. In addition, it may become possible to propose, for 
combination therapy of mFOLFOX6 and panitumumab, an approach which enables long-term 
continuation of treatment through prevention of the occurrence of OXA-induced peripheral nerve 
disorders. 
 
6.2.2 
Treatment regimens and planned number of subjects 
See "13.3 Determination of the planned number of subjects" for details. 
 
6.3 
Discontinuation of entire study or discontinuation at a study site 
6.3.1 
Criteria for discontinuation of entire study 
The sponsor should immediately discontinue the study when it is notified by the data monitoring 
committee and/or the steering committee that at least one of the following criteria is applicable. 
• 
Occurrence of serious event/violation which endangers safety of subjects. 
• 
When new information or other evaluation on the safety or efficacy of protocol treatment 
becomes available which shows a change in the known risk/benefit profile of the concerned 
compound, and risks/benefits are no longer tolerable for subject participation in the study. 


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6.3.2 
Procedures of study suspension and discontinuation of entire study or study 
at a study site 
When the sponsor or the IRB such as the ethics review committee determines suspension or 
discontinuation of the entire study or the study at a certain study site, the sponsor will instruct the 
procedures specified for the relevant study. The relevant study site should observe the procedures for 
study suspension or discontinuation. 
 
6.4 
Procedures for revision of the protocol 
When a need arises to revise the protocol, the sponsor will consult with the representative researcher to 
make a decision. 
Details of the protocol revision will be notified to investigators of all study sites. 
When the investigator of each study site receives the notification, he should arrange the revised protocol 
to be reviewed by the IRB such as the ethics review committee again as necessary according to the 
stipulation at each study site and obtain approval of the director of study site. 


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7.0 
SELECTION OF STUDY SUBJECTS 
7.1 
Inclusion criteria 
7.1.1 
Inclusion criteria for enrollment 
Patients who satisfy all the criteria below will be enrolled in this study. 
(1) Patients with unresectable adenocarcinoma originating in the large intestine (excluding 
carcinoma of the appendix and anal canal cancer) 
(2) Patients with measurable lesion(s) according to the RECIST ver. 1.1 
(3) Patients who have not received chemotherapy for colorectal cancer. Patients who experience 
relapse more than 6 months after the final dose of perioperative adjuvant chemotherapy with 
fluoropyrimidine agents may be enrolled. 
(4) Aged ≥20 years at the time of informed consent 
(5) Patients classified as KRAS wild-type*. However, the criteria will be changed to all patients who 
are verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be 
covered by National Health Insurance, and the tests become feasible at medical institutions. 
*: Patients with no mutation in any of the codons shown below are considered wild type. 
KRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
NRAS** 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
**: To be considered when the test comes to be covered by insurance and becomes 
feasible at medical institutions. 
(6) Patients who satisfy the following criteria for the major organ function in tests performed within 
14 days prior to enrollment  
1) 
Neutrophil count ≥ 1,500/mm3 
2) 
White blood cell count ≥ 3,000/mm3 
3) 
Platelet count ≥ 10.0 × 104/mm3 
4) 
Hemoglobin ≥ 9.0 g/dL 
5) 
Total bilirubin ≤ 2.0 mg/dL 
6) 
AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
7) 
ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
8) 
Serum creatinine ≤ 1.5 mg/dL 
(7) ECOG performance status (PS) of 0 or 1 
(8) Life expectancy of ≥ 6 months after enrollment 
(9) Patients who have given written consent to take part in the study after detailed explanation of the 
study prior to enrollment 
 
7.1.2 
Inclusion criteria for randomization 
Patients who satisfy all the criteria below will be randomized. If possible, randomization will be 
conducted immediately before administration of the 7th cycle. 


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(1) Patients who have received 6 cycles＊ (Protocol Treatment [1]) of mFOLFOX6 + panitumumab 
combination therapy 
＊:  Defined as administration of 5-FU/LV and OXA according to the designated dosage 
regimen for Protocol Treatment [1] without discontinuation in all cycles (6 cycles) of 
Protocol Treatment [1]. However, bolus 5-FU and panitumumab are an exception.  
(2) ECOG performance status (PS) of 0-1 before administration of the 7th cycle. 
(3) Patients for whom PD or not evaluable has been denied on the Response Evaluation Criteria in 
Solid Tumors (RECIST) based on imaging tests conducted after administration of 6 cycles. 
 
7.2 
Exclusion criteria 
7.2.1 
Exclusion criteria for enrollment 
A subject who meets any of the criteria below will not be included in this study. 
(1) Radiotherapy received for a measurable lesion(s) 
(2) Radiotherapy received within 4 weeks prior to enrollment except measurable lesion(s). However, 
the treatment to relieve the pain of metastatic bone tumor is allowed. 
(3) Known brain metastasis or strongly suspected of brain metastasis 
(4) Synchronous cancers or metachronous cancers with a disease-free period of ≤ 5 years (excluding 
colorectal cancer) excluding mucosal cancers cured or be possibly cured by regional resection 
(esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.). 
(5) Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) 
(6) Patients who do not want to use contraception to prevent pregnancy, and women who are 
pregnant or breast-feeding, or test positive for pregnancy 
(7) Active hemorrhage requiring blood transfusion 
(8) Disease requiring systemic steroids for treatment (excluding topical steroids) 
(9) Intestinal resection and colostomy within 2 weeks prior to enrollment 
(10) History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial 
pneumonia, pulmonary fibrosis, etc.) 
(11) Serious drug hypersensitivity 
(12) Local or systemic active infection requiring treatment, or fever indicating infection 
(13) Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating 
symptoms despite adequate treatment) 
(14) Active hepatitis B and/or C 
(15) Known HIV infection 
(16) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the 
study 
7.2.2 
Exclusion criteria for randomization 
Patients who meet any of the criteria below will not be randomized. 
(1) Patients in whom interstitial pneumonia has been newly diagnosed during the period from 
registration to randomization 
(2) Patients who have received radiotherapy during the period from registration to randomization. 
However, the treatment to relieve the pain of metastatic bone tumor is allowed. 
(3) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the 
study 


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CONFIDENTIAL 
8.0 
TREATMENT 
The protocol treatment, contraindicated drugs/therapies, and recommended supportive care/combination 
therapies in this study are explained in this section. Commercially available drugs used at the study sites 
will be used in this study. See the latest package insert for details and handling of each drug. 
8.1 
Protocol treatment 
The study period in this study is defined as the period consisting of Protocol Treatment [1] and Protocol 
Treatment [2]. 
8.1.1 
Protocol Treatment [1] 
OXA and infusional 5-FU will be administered in all of the 6 cycles. The dose can be reduced. 
Panitumumab will also be administered in all the possible 6 cycles but suspension due to the 
occurrence of skin disorders will be allowed. 
 
8.1.2 
Protocol Treatment [2] 
Even if each drug of the criteria specified in "8.5 Criteria for dose change." is met, treatment with the 
other drugs will be continued unless any of the criteria specified in "8.8 Criteria for discontinuation of 
protocol treatment" is met. 
 
8.2 
Treatment regimen 
8.2.1 
Protocol Treatment [1] 
During the period of Protocol Treatment [1], mFOLFOX6 + panitumumab combination therapy will 
be given once in two weeks according to the following treatment regimen until any of the criteria 
specified in "8.8 Criteria for discontinuation of protocol treatment" is met (one administration will be 
regarded as one cycle). For administration of each drug, see "8.4 Criteria for initiation of protocol 
treatment (common for Protocol Treatment [1] and [2])" and "8.5 Criteria for dose change". 
For the patients aged 80 years or older at the time of enrollment, the drug can be administered at a 
dose one level lower than the designated dose from Cycle 1. 
Table 8.a  Treatment regimen of mFOLFOX6 + panitumumab combination therapy 
Drug 
Dose 
Method of 
administration 
(recommended) 
Date of administration 
Panitumumab 
6 mg/kg 
div 60 min* 
Day 1 
OXA 
85 mg/m2 
div 120 min 
Day 1 
l-LV 
200 mg/m2 
div 120 min 
Day 1 
5-FU (iv) 
400 mg/m2 
iv  <15 min 
Day 1 
5-FU (civ) 
2400 mg/m2 
civ 46 hrs 
Day 1-2 
div: intravenous drip infusion, iv: intravenous infusion, civ: continuous intravenous infusion 
*:  When the dose at one time exceeds 1000 mg, intravenously administer it over 90 min or longer after dilution with 
JP physiological saline to make approximately 150 mL. 
 


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Figure 8.a  mFOLFOX6 + panitumumab combination therapy 
 
8.2.2 
Protocol Treatment [2] 
If the dose of the drug has been reduced during the period of Protocol Treatment [1], the drug will be 
administered at the reduced dose from Cycle 7.  
 
8.2.2.1 
mFOLFOX6 + panitumumab combination therapy (Group A) 
See Section 8.2.1 for Protocol Treatment [1]. The term of Protocol Treatment [1] is regarded as 
Protocol Treatment [2]. 
8.2.2.2 
5-FU/LV + panitumumab combination therapy (Group B) 
During the period of Protocol Treatment [2], 5-FU/LV + panitumumab combination therapy will be 
given once in two weeks according to the following treatment regimen until any of the criteria 
specified in "8.8 Criteria for discontinuation of protocol treatment" is met (one administration will 
be regarded as one cycle). For administration of each drug, see "8.4 Criteria for initiation of 
protocol treatment (common for Protocol Treatment [1] and [2])" and "8.5 Criteria for dose 
change". 
Table 8.b  Treatment regimen of 5-FU/LV + panitumumab combination therapy 
Drug 
Dose 
Method of 
administration 
(recommended) 
Date of administration 
Panitumumab 
6 mg/kg 
div 60 min* 
Day 1 
l-LV 
200 mg/m2 
div 120 min 
Day 1 
5-FU (iv) 
400 mg/m2 
iv < 15 min 
Day 1 
5-FU (civ) 
2400 mg/m2 
civ 46 hrs 
Day 1-2 
div: intravenous drip infusion, iv: intravenous infusion, civ: continuous intravenous infusion 
*:  When the dose at one time exceeds 1000 mg, intravenously administer it over 90 min or longer after dilution with 
JP physiological saline to make approximately 150 mL. 
 




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Table 8.c  Criteria for initiation of treatment cycle 
Item 
Criteria for initiation 
White blood cell count 
≥ 2,500/mm3 
Neutrophil count 
≥ 1,200/mm3 
Platelet count 
≥ 7.5 x 104/mm3 
Total bilirubin 
≤ 2.0 mg/dL 
Infection 
Absence of fever (≥ 38°C) indicating infection 
Nausea, vomiting, diarrhoea, stomatitis 
≤ Grade 1 
Initiation of treatment may be postponed at the discretion of the investigator due to adverse 
events not listed above.  
 
8.5 
Criteria for dose change 
8.5.1 
Protocol Treatment [1] 
8.5.1.1 
Criteria for dose reduction/suspension of mFOLFOX6 
The criteria for dose reduction and the doses of OXA and 5-FU (bolus/infusional) during the period 
of Protocol Treatment [1] are shown in Table 8.d and Table 8.e, respectively. The dose of l-LV 
should not be changed. 
Table 8.d  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [1]) 
Adverse events in previous cycle 
Grade 
Dose adjustment of OXA and 5-FU 
Neutropenia, thrombopenia 
4 
Dose reduction of both OXA and 5-FU 
(bolus/infusional) by 1 level 
Grade 3 neutropenia or thrombopenia that 
persists for more than 7 days 
3 
Febrile neutropenia, infection, nausea, 
vomiting, diarrhoea, fatigue 
3 
Sensory nerve disorder* 
3 
Discontinuation of protocol treatment* 
2 
Discontinuation of protocol treatment* 
Or dose reduction of OXA by 1 level 
Allergic reaction 
3 
Discontinuation of protocol treatment* 
Dose reduction is allowed as necessary at the discretion of the investigator due to adverse events 
not listed above. However, protocol treatment will be discontinued at the time point of suspension 
of OXA and infusional 5-FU. 
*: When allergic reaction occurs during treatment with OXA, the treatment should be stopped immediately. The decision 
of restarting this cycle will be entrusted to the study site. If the allergic reaction is Grade 2 or less, protocol treatment 
with care is allowed under actions such as providing appropriate supportive care or slowing the infusion speed for the 
treatment after the next course. 
 


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Table 8.e  Doses of OXA and 5-FU (Protocol Treatment [1]) 
Dose reduction 
level 
OXA 
5-FU iv 
5-FU civ 
Initial dose 
85 mg/m2 
400 mg/m2 
2400 mg/m2 
-1 
65 mg/m2 
200 mg/m2 
2000 mg/m2 
-2 
50 mg/m2 
0 mg/m2 
(discontinuation) 
1600 mg/m2 
-3 
Discontinuation of 
protocol treatment* 
0 mg/m2 
(discontinuation) 
Discontinuation of 
protocol treatment* 
iv: intravenous infusion, civ: continuous intravenous infusion 
*: See "8.8 Criteria for discontinuation of protocol treatment" for details. 
 
8.5.1.2 
Criteria for dose reduction/suspension of panitumumab 
The criteria for dose reduction and the dose of panitumumab during the period of Protocol 
Treatment are shown in Table 8.f and Table 8.g, respectively. 
Table 8.f  Criteria for dose reduction of panitumumab 
Item 
Grade 
Dose adjustment of panitumumab 
Skin disorder 
3 
Dose reduction by 1 level with dose postponement 
(suspension). 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
less within 6 weeks. 
2 
Dose postponement (suspension) is allowed. (Suspension 
is not essential.) 
If the symptom has become milder than the Grade as of 
the time of onset after the suspension, the drug will be 
administered at the dose before suspension. 
1 
Hypomagnesaemia* 
3 
Dose reduction by 1 level 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
less within 6 weeks. 
Infusion reaction*** 
3 
Discontinuation of protocol treatment 
Dose reduction/suspension is allowed as necessary at the discretion of the investigator due to 
adverse events not listed above.  
*: 
When accompanied by abnormal ECG findings requiring treatment such as significant QTc 
prolongation, discontinuation or suspension of panitumumab should be considered irrespective of 
the severity of hypomagnesaemia. 
**: 
Allergic reaction, anaphylactoid reaction, and chills, fever, and dyspnea occurring within 24 hours 
after the initial dose 
***: 
When infusion reaction occurs during infusion, the treatment should be stopped immediately. The decision of 
restarting this cycle will be entrusted to the study site. If the infusion reaction is Grade 2 or less, protocol 
treatment with care is allowed under actions such as providing appropriate supportive care or slowing the 
infusion speed by 50% for the treatment after the next course. 
 


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Table 8.g  Dose of panitumumab 
Dose reduction level 
Panitumumab 
Initial dose 
6 mg/kg 
-1 
4.8 mg/kg 
-2 
3.6 mg/kg 
-3 
0 mg/kg (discontinuation) 
 
8.5.2 
Protocol Treatment [2] 
8.5.2.1 
Criteria for dose reduction/suspension of mFOLFOX6 
The criteria for dose reduction of OXA and 5-FU (bolus/infusional) during the period of Protocol 
Treatment [2] is shown in Table 8.h. Refer to Table 8.i for the doses of OXA and 5-FU 
(bolus/infusional), respectively. 
Table 8.h  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [2]) 
Adverse events in previous cycle 
Grade 
Dose adjustment of OXA and 5-FU 
Neutropenia, thrombopenia 
4 
Dose reduction of both OXA and 5-FU 
(bolus/infusional) by 1 level 
Grade 3 neutropenia or thrombopenia that 
persists for more than 7 days 
3 
Febrile neutropenia, infection, nausea, 
vomiting, diarrhoea, fatigue 
3 
Sensory nerve disorder* 
3 
Discontinuation of OXA** (no 
resumption) 
2 
Discontinuation** of OXA (no 
resumption) 
Or dose reduction of OXA by 1 level 
Allergic reaction 
3 
Discontinuation of OXA** (no 
resumption) 
Dose reduction/suspension is allowed as necessary at the discretion of the investigator due to 
adverse events not listed above. 
*: 
OXA may be resumed when nerve disorder has improved after suspension. 
**: When Allergic reaction occurs during treatment, the treatment should be stopped immediately. The decision of 
restarting this cycle will be entrusted to the study site. If the Allergic reaction is Grade 2 or less, protocol treatment 
with care is allowed under actions such as providing appropriate supportive care or slowing the infusion speed for 
the treatment after the next course. 
 


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Table 8.i  Doses of OXA and 5-FU (Protocol Treatment [2]) 
Dose reduction 
level 
OXA 
5-FU iv 
5-FU civ 
Initial dose 
85 mg/m2 
400 mg/m2 
2400 mg/m2 
-1 
65 mg/m2 
200 mg/m2 
2000 mg/m2 
-2 
50 mg/m2 
0 mg/m2 
(discontinuation) 
1600 mg/m2 
-3 
0 mg/m2 
(discontinuation) 
0 mg/m2 
(discontinuation) 
0 mg/m2 
(discontinuation) 
iv: intravenous infusion, civ: continuous intravenous infusion 
 
8.5.2.2 
Criteria for dose reduction/suspension of panitumumab 
Refer to "8.5.1.2 Criteria for dose reduction/suspension of panitumumab". 
 
8.6 
Criteria for dose increase of protocol treatment 
The dose should not be increased after dose reduction for any of the drugs. 
 
8.7 
Overdose of panitumumab 
Overdose of panitumumab is defined as below regardless of whether or not adverse events have 
occurred. 
① Administration at doses higher than the approved dose of panitumumab (6 mg/kg) 
② The next dose is administered within 10 days after the date of previous administration. 
Aiming at consistent entry of significant safety information regarding overdose in the database, the 
investigator or subinvestigator will record all cases of overdose (irrespective of the presence or absence 
of adverse events) in the page of overdose of the Case Report Forms. Adverse events associated with 
overdose will be recorded in the page of "Adverse Events" in the Case Report Forms according to "10.0 
ADVERSE EVENTS". 
Serious adverse events (SAE) associated with overdose will be reported according to the procedure 
described in "10.2.2. Collection and reporting of serious adverse events." 
In the cases of overdose of panitumumab, the investigator or subinvestigator will provide treatment 
appropriate for the symptoms. 
 
8.8 
Criteria for discontinuation of protocol treatment 
The protocol treatment specified below should be discontinued when any of the criteria for 
discontinuation of protocol treatment listed below is met. The date of discontinuation of protocol 
treatment is defined as the date when the investigator decides on discontinuation of protocol treatment. 
The investigator should record the main reason for discontinuation of protocol treatment in the case 
report form according to the classification described below. See "9.3 Records of subjects who 
discontinued before enrollment"for subjects withdrawn from the study before enrollment. 
<Common for Protocol Treatment [1] and [2]> 


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1. 
Adverse event 
When protocol treatment is postponed for 43 days or more after the day of starting the last cycle, or 
when the next protocol treatment cannot be resumed because of adverse events even after the 
passage of at least 43 days after the start of the last cycle of the protocol treatment. However, 
postponement due to holidays is allowed. 
2. 
Significant deviation from the protocol 
When study continuation may cause intolerable risk to the health of a subject because the subject 
was found not to satisfy the inclusion criteria specified in the protocol after enrollment or 
randomization of protocol treatment has not been observed. 
3. 
Lost to follow-up 
When a subject fail to make visits and cannot be contacted. That attempts were made to contact the 
subject should be recorded in the source documents. 
4. 
Voluntary discontinuation 
When a subject wishes to discontinue study participation. 
5. 
Discontinuation of entire study 
When study discontinuation is decided by the sponsor, or IRB such as the ethics review committee. 
6. 
Pregnancy 
When a female subject is found out to be pregnant. 
Note: Study participation should be immediately discontinued when pregnancy is known. 
7. 
Lack of efficacy 
When PD is evident in the clinical or imaging evaluation 
8. 
Death during protocol treatment 
Death before discontinuation of protocol treatment is decided 
9. 
When surgery aimed at curative resection (complete resection: R0 resection) of colorectal cancer is 
scheduled 
10. Other 
When protocol treatment cannot be started after subject allocation, collect the reason (e.g., the 
criteria for initiation of protocol treatment were not met 
<Protocol Treatment [1] > 
11. Not satisfying at least one of the inclusion criteria for randomization or meeting any of the 
exclusion criteria <specify the applicable inclusion/exclusion criteria> 
 
8.9 
Contraindicated drugs/therapies 
The drugs and therapies shown below are contraindicated from informed consent until 28 days (4 weeks) 
after discontinuation of protocol treatment. The investigator and/or subinvestigator (hereinafter referred 
to as the investigator) should instruct the patients not to use any drugs including over-the counter drugs 
other than the prescribed drugs without prior consultation. The following therapies are allowed to be 
started without waiting for the specified period only when the scheduled tests are performed until the 
next treatment upon starting it within 28 days (4weeks) after discontinuation of protocol treatment. 
 
Chemotherapy other than protocol treatment 
 
Hormone therapy 
 
Immunotherapy  
 Cellular immunotherapy 


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 Vaccine therapy 
 Cytokine therapy 
 Biological response modifiers (BRM) 
 Antibody therapy 
 Gene therapy 
 
Other antibody therapy 
 
Radiotherapy  
However, the treatment to relieve the pain of metastatic bone tumor is allowed. 
 
Hyperthermia therapy 
 
Denosumab* 
*: Use of bisphosphonates is allowed. 
 
Study drug and unapproved drug 
 
8.10 
Allowed supportive care and combination medications 
The supportive care and concomitant medications shown below are recommended during the study 
period (from informed consent until discontinuation of protocol treatment). The absence of concomitant 
or supporting therapy does not constitute a protocol deviation. 
• 
Neutropenia 
Administration of G-CSF products is recommended. G-CSF should be administered according to 
the NHI indications and should not be prophylactically used. 
• 
Nausea, vomiting 
Premedication including prophylactic administration of antiemetics is allowed. Premedication 
with 5-HT3 (serotonin) receptor antagonists, NK1 (neurokinin 1) receptor antagonists, steroids, 
and antihistamines may be carried out using the method employed at each study site. 
• 
Allergic reaction 
Treatment with adrenal corticosteroids, antihistamines, etc. may be considered at the time of 
onset or for premedication at the start of protocol treatment. Careful administration of 
panitumumab by slowing the infusion speed may be considered. 
• 
Interstitial pneumonia 
Interstitial pneumonia should be treated according to the severity (e.g., steroid pulse therapy).  
• 
Other 
Drugs for treatment of adverse events may be coadministered at the discretion of the investigator. 
Symptomatic therapies which have been continued from before the start of this study are allowed. 
In addition, it is recommended that the supportive care shown below be performed at the discretion of 
the investigator when any of panitumumab-related adverse events shown below is observed. The absence 
of supporting therapy does not constitute a protocol deviation. 
• 
It is recommended that oral minocycline, etc. be administered when skin disorder is observed. 
• 
At the time of onset of skin disorder 
External salicylic acid petrolatum (10%) 
External steroid therapy (example) 
Face: hydrocortisone butyrate (0.1%) 
Trunk: difluprednate (0.05%) 


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It is recommended the following skin care prophylactically against the skin disorder from the 
start of protocol treatment [1]. 
Moisturizer (example): heparin analog lotion 
Sunscreen (example): not containing 4-aminobenzoic acid, SPF (Sun Protection Factor) ≥30, PA 
(Protection grade of UVA) ≥ ++. Apply before going out to block ultraviolet rays (UVA and 
UVB). 
• 
At the time of onset of electrolyte abnormality (e.g., hypomagnesaemia, hypocalcaemia) 
ECG: ECG may be performed to determine whether there are abnormal ECG findings requiring 
treatment such as significant QTc prolongation. When any abnormal ECG findings requiring 
treatment are observed, suspension of panitumumab should be considered irrespective of the 
serum magnesium concentration. 
Magnesium supplementation (example): intravenous infusion of magnesium sulfate(10 mmol) 
over 60 min 
 
8.11 
Handling of surgery aimed at curative resection (complete resection: R0 
resection) of colorectal cancer 
Surgery is recommended for patients who can tolerate curative resection (complete resection: R0 
resection) thanks to the antitumor effect after initiation of protocol treatment. 
Protocol treatment should be discontinued when surgery aimed at curative resection (complete resection: 
R0 resection) of colorectal cancer is scheduled, and all tests and observation scheduled at discontinuation 
of protocol treatment should be conducted (see “9.1 Study calendar”). 
 
8.12 
Recommended follow-up therapy 
8.12.1 Recommended second-line treatment 
• 
Group A: Administration of bevacizumab in combination with IRI-based chemotherapy is 
recommended. 
• 
Group B: Readministration of bevacizumab in combination with OXA-based chemotherapy is 
recommended. 
 
8.12.2 Recommended third-line or subsequent treatment 
• 
Group A: All approved drugs (regorafenib, etc.) should be administered appropriately as best as 
possible. 
• 
Group B: Administration of bevacizumab in combination with the IRI-based chemotherapy is 
recommended. After that, all approved drugs (regorafenib, etc.) should be administered 
appropriately as best as possible. 
 


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9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR 
OBSERVATIONS 
9.1 
Study calendar 
The investigator should collect data according to the following procedures. The same investigator should 
perform tests/observation/evaluation of subjects in principle. 
Table 9.a  Study calendar (Protocol Treatment [1]) 
Item 
Enrollment Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Discontinuation of 
protocol treatment*7 
Informed consent 
●* 
 
 
 
 
 
 
 
Eligibility 
● 
 
 
 
 
 
 
 
Subject background 
● 
 
 
 
 
 
 
 
Clinical findings (physical 
examination) *1 
● 
● 
● 
● 
● 
● 
● 
● 
Vital signs*1 
 
● 
● 
● 
● 
● 
● 
● 
Height, body weight*1,*2 
● 
 
○ 
○ 
○ 
○ 
○ 
 
ECOG P.S. *1 
● 
● 
● 
● 
● 
● 
● 
● 
Treatment compliance 
 
● 
● 
● 
● 
● 
● 
 
Laboratory tests 
 
 
 
 
 
 
 
 
Hematology*1 
●*3 
● 
● 
● 
● 
● 
● 
● 
Serum chemistry*1 
●*3 
● 
● 
● 
● 
● 
● 
● 
Tumor markers*1 
●*3 
● 
 
 
 
 
 
○*4 
Imaging test *1 
(thoracoabdominal-pelvic 
CT/MRI) 
●*5 
● 
 
● 
 
 
 
○*6 
NRAS test 
●*8 
 
 
 
 
 
 
 
Adverse Event 
－ 
←    ●    → 
●: Mandatory, 〇: Perform as necessary 
*: 
Consent should be obtained at enrollment 
*1: Perform before initiation of each cycle of protocol treatment. 
*2: Measure and record only body weight when the dose is changed. 
*3: The test in Cycle 1 may be skipped when the entry test has been performed 0 to 2 days before treatment 
in Cycle 1. The test in Cycle 1 will be performed before treatment in Cycle 1 when the entry test has 
been performed more than 2 days before treatment in Cycle 1. 
*4: Measure only when more than 56 days (8 weeks) have passed after the previous measurement. 
*5: If the imaging test before enrollment is performed within 14 days prior to Cycle 1, the test of first cycle 
can be omitted, but an imaging test should be preferably conducted immediately before administration 
of the 1st cycle. 
*6: Perform the imaging test within 28 days (4 weeks) after decision on discontinuation for subjects 
withdrawn from the study for any reason other than PD. 
*7: Perform within 28 days (4 weeks) after discontinuation. Perform until the next treatment when it will be 
startied within 28 days (4weeks) after discontinuation. 
*8: Perform the test in the patients who agree to participate in the study before NRAS test comes to be 
covered by insurance, and the patients who agree to participate in the study after NRAS test comes to be 
covered by insurance but before the test becomes feasible at the study site and who give consents to the 
conduct of the test. The timing of submission of samples does not need to be upon registration. 
 


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Table 9.b  Study calendar (Protocol Treatment [2]) 
Item 
Randomization Cycle 
7§ 
Cycle 
8 
Cycle 
9 
Cycle 
10 
Cycle 
11~§ 
9 months after 
a 
randomization 
Discontinuation 
of protocol 
treatment**7 
Follow-up 
period *10 
Eligibility 
● 
 
 
 
 
 
 
 
 
Clinical findings 
(physical examination)*1 
● 
● 
● 
● 
● 
● 
● 
● 
 
Vital signs *1 
 
● 
● 
● 
● 
● 
● 
● 
 
Height, body weight *3 
 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
ECOG P.S.*1 
 
● 
● 
● 
● 
● 
● 
● 
 
Treatment compliance 
(incluing the test at 
discontinuation) 
 
● 
● 
● 
● 
● 
● 
● 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
Hematology *1 
 
●*2 ● 
● 
● 
● 
● 
● 
 
Serum chemistry *1 
 
●*2 ● 
● 
● 
● 
● 
● 
 
Tumor markers§, *1 
 
●*2 
 
 
 
● 
○§ 
○*8 
 
Imaging test 
(thoracoabdominal-pelvic 
CT/MRI)§ 
●*4 
 
 
 
 
●*5 
●*6 
○*9 
○ 
Follow-up therapy 
 
 
 
 
 
 
 
 
● 
Survival survey 
 
 
 
 
 
 
 
 
● 
Adverse Event 
←    ●    → 
－ 
●: Mandatory, 〇: Perform as necessary 
§: As a rule, tests of tumor markers and imaging tests will be conducted in the (4n + 3)th administration 
cycle. However, when the administration interval becomes longer because of the criteria for extension of 
administration period, the tests will be conducted at appropriate timings. 
*1: Perform before initiation of each cycle of protocol treatment. 
*2: The test in Cycle 7 may be skipped when the test at randomization has been performed 0 to 2 days 
before treatment in Cycle 7.  
*3: Measure and record only body weight when the dose is changed. 
*4: Masure between the day of administration in 6th cycle and randomization. 
*5: Reduce the frequency of imaging test to once every 112 days (16 weeks) 14 days (± 2 weeks) when two 
years have passed since initiation of protocol treatment. 
*6:  Perform the imaging test when a § rule and 9 months after a randomization 
*7: Perform within 28 days (4 weeks) after discontinuation. 
*8: Perform only when 56 days (8 weeks) or more have passed after the previous measurement. 
*9:  Perform the imaging test within 28 days (4 weeks) after decision on discontinuation for subjects 
withdrawn from the study for any reason other than PD. 
*10: Perform every 6 months (approximately) after discontinuation of protocol treatment. 
 
9.2 
Collection/test/observation items and procedures during the study 
The investigator will perform the following as scheduled in “9.1 Study calendar.” 
9.2.1 
Informed consent procedure 
The method for obtaining consent is described in "15.3 Written information and subject’s consent." 
Consent should be obtained from each subject before initiation of study procedures. 


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A unique subject ID code will be assigned to each subject when explanation is given to obtain consent. 
The subject ID code will be used throughout the study period. 
 
9.2.2 
Procedures for registration and allocation of drugs 
9.2.2.1 
Procedures for registration and initiation of protocol treatment 
The investigator will register subjects according to the following procedures. 
1) 
The investigator or study collaborator should record the necessary items in subject screening 
list for a subject who was selected to receive explanation for obtaining consent for study 
enrollment. 
2) 
The investigator or study collaborator should input the necessary items into the Web case 
registration system for a subject who has given consent.* 
*: The study collaborator may input into the Web case registration system by instruction of the 
investigator. 
3) 
Eligibility of a prospective subject is judged by the Web case registration system and a 
protocol study group will be assigned when the subject is eligible. 
4) 
The investigator and study collaborator will check the registration result and assigned protocol 
study group on the Web case registration system. The registration result and assigned protocol 
study group will be sent via e-mail from the Web case registration system to the investigator 
and study collaborator. 
5) 
The investigator should start the allocated protocol treatment within 15 days of formal 
registration (including the same day of week as the day of enrollment). 
6) 
The investigator or study collaborator should immediately contact the sponsor and input 
necessary items in the Web subject registration system when the study drug is not 
administered for reasons such as withdrawal of consent after allocation, or when a change 
related to allocation is made to the data of the registered subject. 
9.2.2.2 
Preparation and storage of allocation procedures 
The allocation manager (person designated by the sponsor) should prepare the allocation 
procedures and manage allocation information of subjects. Minimization method should be used 
for allocation of protocol treatment using the allocation factors of the study site, age (20 to 64 
years/65 to 79 years), and presence/absence of liver metastasis. The allocation information should 
be stored in a safe place and made accessible only by the authorized persons. 
 
9.2.3 
Subject demographics 
The following demographic data will be collected: date of birth and sex at the time of enrollment. 
The following data concerning the target disease of colorectal cancer will be collected. 
1) 
Tissue type 
The tissue type will be assessed based on the histological findings in the “Japanese Classification 
of Colorectal Carcinoma” and recorded in the case report form with the date and site of sampling 
for diagnosis. 
 
Date of initial diagnosis 
 
Date of diagnosis of Stage 4 (no need for input the case report form when it is the day of the 
initial diagnosis) 


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2) 
History of treatment 
 
History of surgery 
 
For subjects with a history of surgery, the date of surgery, surgery site 
(primary/metastatic lesion), and the number of lymph nodes resected. Endoscopic 
surgery, which is not considered a history of surgery, should not be entered into the 
case report form. 
 
History of radiotherapy 
 
For subjects with a history of radiotherapy, the final irradiated date. 
 
History of preoperative and/or postoperative adjuvant chemotherapy 
 
For subjects with a history of adjuvant chemotherapy, the type of preoperative and/or 
postoperative adjuvant chemotherapy, date of final treatment. 
3) 
Information on metastatic organ 
 
Number of metastatic organs (0, 1, 2 or more)* 
*: The primary lesion/regional lymph node is not included, and the distant lymph node is 
counted as “one organ” even if there is more than one. 
 
Metastatic organs (liver, lung, peritoneum, lymph node*, bone, adrenal gland, skin, other**) 
*: distant lymph node is counted as “one organ” even if there is more than one. 
**: The name of the organ will be recorded in the case report form. 
 
9.2.4 
Medical history 
A medical history is defined as any clinically problematic disease or symptom that has resolved within 
one year prior to initiation of protocol treatment. Any notable medical history will be recorded in the 
case report form. 
 
9.2.5 
Current medical condition 
A current medical condition is defined as any symptom or disease present at initiation of protocol 
treatment. Any notable current medical condition will be recorded in the case report form. Clinically 
problematic laboratory test data, ECG findings, and abnormal physical examination findings observed 
immediately before initiation of protocol treatment should be handled as a current medical condition at 
the discretion of the investigator. 
 
9.2.6 
Clinical findings (physical examination) 
The following locations and parts of the body will be examined: 
(1) eyes, (2) ears, nose, and throat, (3) cardiovascular system, (4) respiratory system, (5) 
gastrointestinal system, (6) dermatologic system, (7) extremities, (8) musculoskeletal system, (9) 
nervous system, (10) lymph nodes, (11) other. 
In particular, subjects will be checked for the following symptoms at the physical examination: 
allergic reaction, fatigue, rash acneiform, dry skin, paronychia, infusion related reaction, 
palmar-plantar erythrodysaesthesia syndrome, anorexia, diarrhoea, nausea, vomiting, oral mucositis, 
febrile neutropenia, infection, hemorrhage, pain, peripheral motor neuropathy, peripheral sensory 
neuropathy, alopecia, thromboembolism, gastrointestinal perforation, pneumonitis, and pulmonary 
fibrosis. 


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For diagnosis after initiation of protocol treatment, evaluate the clinically problematic abnormality 
compared with the result of diagnosis before initiation of protocol treatment. 
 
9.2.7 
Body weight and height 
Body weight and height will be measured before enrollment. Body weight (kg) will be measured to the 
first decimal place and rounded off to the first decimal place when the second decimal place is known. 
Height (cm) determined will be expressed in integer value (rounded off to integer). 
In principle, measurement is unnecessary during the treatment period. However, body weight should 
be recorded in the case report form when the measured value is used to change the dose of protocol 
treatment. 
 
9.2.8 
Vital signs 
The following vital signs will be measured: body temperature and blood pressure and pulse rate (bpm) 
at sitting position (after rest for 5 min or longer). In particular, subjects will be checked for fever and 
hypertension. 
 
9.2.9 
ECOG P.S. 
ECOG P.S. will be assessed according to Table 9.c. Assess again immediately before administration 
of the 1st cycle when the entry test has been performed more than 14 days away before enrollment. 
Table 9.c  Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) 
Grade 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
9.2.10 Treatment compliance (Protocol Treatment [1] and [2] implementation 
status) 
The investigator should record the compliance with protocol treatment in the case report form as 
follows: 
• 
When protocol treatment is administered: The dose and the date of treatment should be recorded. 
The reason for dose reduction should also be recorded when appropriate. 
• 
When any drug used in protocol treatment is suspended: The date of suspension should be 
recorded. 


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• 
When any drug used in protocol treatment is discontinued: The date and reason for 
discontinuation should be recorded. 
 
9.2.11 Laboratory tests 
The laboratory tests performed at each time point during the study are shown in Table 9.d to Table 9.g. 
The laboratory tests will be performed at each study site. 
The investigator should evaluate the reported laboratory test results. The representative investigator at 
each site should be administer and store the standard value of laboratory tests. 
Table 9.d  Laboratory tests performed at the time of enrollment 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
CEA 
CA19-9 
 
Immunology 
HBs antigen 
Hepatitis tests including anti-HCV 
 
Table 9.e  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment [1]) 
Hematology 
Serum chemistry 
Tumor marker 
WBC* 
Neutrophil count* 
Platelet count* 
Hemoglobin content* 
Total bilirubin* 
ALT* 
AST* 
Creatinine* 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA*, † 
CA19-9*, † 
*: The test in Cycle 1 may be skipped when the entry test has been performed  0 to 2 days 
before treatment in Cycle 1. The test in Cycle 1 will be performed before treatment in Cycle 
1 when the entry test has been performed more than 2 days before treatment in Cycle 1. 
†: Measure before the initiation of 1st cycle only. 
 


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Table 9.f  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment [2]) 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA* 
CA19-9* 
*: Perform every 8 weeks. 
 
Table 9.g  Laboratory tests performed at the time of discontinuation 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA* 
CA19-9* 
*: Measure only when more than 56 days (8 weeks) have passed after the previous 
measurement. 
 
9.2.12 Imaging test (thoracoabdominal-pelvic CT/MRI) 
Imaging test before enrollment will be performed within 28 days prior to enrollment (including the 
same day of week as the day of enrollment). The results of imaging diagnosis/test performed before 
obtaining consent may be used if it is performed within 28 days prior to enrollment.  
During the period of Protocol Treatment [1], imaging test will be performed before administration in 
the 1st cycle and the 3rd cycle. The results of imaging tests before administration in the 1st cycle will 
be handled as the image data for measurable lesion, and the test will be performed within 14 days prior 
to initiation of Protocol Treatment [1] (including the same day of week as the day of enrollment). If 
the imaging test before enrollment is performed within 14 days prior to initiation of Protocol 
Treatment [1], the imaging test can be omitted, but an imaging test should be preferably conducted 
immediately before administration of the 1st cycle.  
Imaging test before initiation of Protocol Treatment [2] will be conducted between administration of 
the 6th cycle and randomization. It will be performed every 8 weeks after initiation of Protocol 
Treatment [2] (See "Table 9.b  Study calendar (Protocol Treatment [2])" for details.) 


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Thoracoabdominal-pelvic CT (in principle, contrast CT with a slice width of 5 mm or less, but MRI is 
also acceptable) will be used for imaging test, and the modality and the date of imaging test will be 
recorded in the case report form. 
The same modality should be used during protocol treatment throughout the study period. 
The investigator should evaluate the test results according to the RECIST v1.1 and record the 
evaluation results in the case report form. 
For subjects withdrawn from the study for any reason other than imaging test results such as clinical 
PD, imaging test specified at the time of discontinuation for protocol treatment should be performed 
within 4 weeks including the day of decision (including the same day of week as the day of decision). 
 
9.2.13 NRAS test 
9.2.13.1 Subjects 
The subjects will be the patients who agree to participate in the study before NRAS test comes to be 
covered by insurance, and the patients who agree to participate in the study after NRAS test comes 
to be covered by insurance but before the test becomes feasible at the study site and who give 
consents to the conduct of the test. 
For the patients who receive NRAS test at the study site after NRAS test has come to be covered by 
insurance, test results regarding each codon shown in Table 9.h will be recorded in the case report 
forms. 
9.2.13.2 Samples and submission 
For the patients who have given a consent to the test, the tumor tissue samples which have been 
collected in surgery or biopsy performed prior to informed consent, and which are used for 
evaluation of KRAS will be used for the test. From paraffin-embedded samples, 5-μm slices will be 
obtained, and 5 pathological samples fixed on slide glasses will be submitted to 
 
. It is also acceptable to submit samples in the form of 
paraffin-embedded samples. When paraffin-embedded samples are submitted,
 will prepare a 
necessary number of slide glass samples, and will return the remaining sample to the study site. 
Investigators will use the materials prepared by 
 in advance at the beginning of the study and 
send the samples to 
. Details are described in the written procedure prepared separately. 
 
will send in advance the materials necessary for storing and sending samples to the study sites 
where enrollment of study subjects has become possible. 
Details regarding submission of tumor tissues will be described in the written procedure prepared 
separately. 
9.2.13.3 Data 
Among the subjects specified in "9.2.13.1 Subjects", the investigators will enter the following 
issues regarding the submitted tumor tissues in the case report forms for the subjects for whom the 
samples required for the test have been submitted to
. However, recording of the results of 
NRAS measurement in the case report forms will be unnecessary. 
1) 
Procedure of sample collection 
2) 
Timing of sample collection 
3) 
Number of slides submitted in the case of pathological slides 


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For the patients who are enrolled in the study after NRAS test has come to be covered by insurance 
and who receive NRAS tests at the study sites, the investigators will record the presence or absence 
of mutation of each of the following codons in the case report forms. 
Table 9.h  EXON and codon verified on NRAS test 
KRAS 
EXON 
－ 
3 
4 
codon 
－ 
59, 61 
117, 146 
NRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
 
9.2.14 Surgery aimed at curative resection (complete resection: R0 resection) of 
colorectal cancer 
When surgery is performed for patients who are expected to tolerate curative resection of colorectal 
cancer during protocol treatment, the operative procedure, date of surgery, and postoperative 
assessment of residual tumor should be recorded in the case report form. The residual tumor is 
assessed according to the table shown below, and the histological results of resection specimens 
should be recorded in the case report form wherever possible. The date when surgery aimed at curative 
resection (complete resection: R0 resection) of colorectal cancer is scheduled is considered as the date 
of discontinuation of protocol treatment 
When surgery aimed at curative resection is performed in more than one session, the number of 
sessions should be recorded in the case report form. As for the postoperative assessment of residual 
tumor, data obtained by the time of initiation of subsequent treatment should be recorded in the case 
report form. Data generated after initiation of subsequent treatment will be collected through 
monitoring and assessed by the steering committee for the validity.  
Table 9.i  Residual tumor after surgical treatment 
Classification 
Criteria 
RX 
The presence of residual tumor cannot be assessed. 
R0 
No residual tumor 
R1 
Resected, but tumor on the margins of a surgical resection specimen or the 
radial margin 
R2 
Macroscopic residual tumor 
 
9.2.15 Survival survey 
All subjects will be followed up after discontinuation of protocol treatment to confirm survival of 
subjects. Survival survey should be continued until a subject dies or the sponsor terminates the study. 
• 
Date of death or date of last confirmation of survival 
 
9.2.16 Follow-up therapy 
When follow-up therapy is performed after discontinuation of Protocol Treatment [2], the following 
information on follow-up therapy should be collected until a subject dies or the sponsor terminates the 
study. 
• 
Name of regimen (name of drugs used) 


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9.3 
Records of subjects who discontinued before enrollment 
For subjects withdrawn from the study before enrollment of protocol treatment, the main reason for 
discontinuation should be recorded in the case report form according to the following categories. 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria <specify 
the applicable inclusion/exclusion criteria> 
• 
Serious deviation from the protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation <specify the reason> 
• 
Discontinuation of the entire study 
• 
Other <specify the reason> 
The subject ID code of a subject withdrawn from the study before enrollment should not be reused.   
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
Adverse events are all untoward medical events encountered in a subject treated with a drug. They are 
not limited to the events with clear causal relationship with treatment with the concerned drug. 
In other words, adverse events are any unfavorable or unintended sign (including clinically 
problematic abnormalities of laboratory test data), symptoms or diseases that develop after 
administration of a drug irrespective of a causal relationship with the relevant drug. 
 
10.1.2 Items to be considered concerning adverse events 
Generally unfavorable findings are shown below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent event of 
the existing symptom is not considered an adverse event)  
• 
Requiring action or treatment 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation or change in the dose of protocol treatment (chemotherapy, 
panitumumab and bevacizumab) or concomitant drugs under use 
• 
Considered unfavorable by the investigator 
Diagnosis name and signs/symptoms: 
Adverse events should be recorded by a diagnosis name. Accompanying signs (including abnormal 
laboratory values, abnormal ECG findings) and symptoms should not be recorded as adverse events. 
Any adverse events that could not be expressed in medical terminology (name of diagnosis) should 
be recorded with signs or symptoms observed. 
Laboratory test findings: 
Abnormal laboratory values and ECG findings are recorded as adverse events when the investigator 
judges the course to be clinically problematic (in other words, when certain action or treatment is 
required, or the investigator judges the change to have exceeded the normal physiological variation 
range of the subject). 
Retest and continued monitoring of abnormality are not considered treatment. Also, repeated or 
additional conduct of non-invasive test for verification, evaluation and monitoring of abnormality 
are not considered treatment. 
However, when abnormal laboratory values and ECG findings are the accompanying symptoms of 
the disease diagnosed as an adverse event (e.g., increased creatinine due to renal dysfunction, etc.), 
the diagnosis name is handled as an adverse event. 
Existing symptoms (diseases and/or symptoms that have been present from before initiation of 
protocol treatment): 
Diseases and/or symptoms that have been present from before initiation of protocol treatment 
should be recorded as concurrent medical conditions and not as adverse events. When a concurrent 


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medical condition is aggravated, the aggravation is recorded as an adverse event and the 
investigator should record in the case report form that the adverse event as aggravation of the 
complication (e.g., “aggravation of hypertension”, etc.). 
When a subject has an existing symptom that is transient (e.g., asthma, epilepsy) and incidence of 
the symptom is increased, or the symptom becomes serious or severe, it should be recorded as an 
adverse event. When a subject has a chronic disease (e.g., cataract, rheumatoid arthritis) and the 
symptom is aggravated more than anticipated, it should be recorded as an adverse event. The 
investigator should record it so that a reported adverse event name is a change from the baseline 
(e.g., aggravation of XX). 
Aggravation of adverse events: 
When any secondary sign/symptom develops due to an adverse event, it should be considered as a 
new adverse event and recorded in the case report form. The investigator should record it so that a 
reported adverse event name is a change from the baseline (e.g., aggravation of XX).When the 
severity of an adverse event is changed, the event should be recorded once at the highest degree of 
severity (grade based on the CTCAE [Japanese edition JCOG version 4.03]).  
Previously planned surgery or treatment: 
Surgery or treatment planned before initiation of protocol treatment is not considered an adverse 
event. However, when the existing symptom is aggravated to require emergency surgery or 
treatment, the condition or the event is considered an adverse event. A complication which resulted 
from previously planned surgery is reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a subject 
(cosmetic surgery, etc.) is not considered an adverse event. Complications due to a non-urgent 
surgery should be reported as an adverse event. 
Progressive Disease (PD): 
PD should be considered lack of efficacy, not an adverse event. In addition, the single fact of PD 
does not necessarily constitute a serious adverse event. However, clinical or imaging progression of 
the preexisting cancer (including new metastasis) is considered a serious adverse event when the 
severity satisfies any of the criteria for seriousness specified in Section 10.1.3. 
Overdose of panitumumab: 
Overdose of panitumumab which does not accompany the occurrence of events will not be regarded 
as adverse events, but the overdose of panitumumab will be recorded in the page of overdose in the 
case report form. If any events have occurred, they will be recorded as adverse events in the page of 
adverse events in the case report form. 
 
10.1.3 Serious adverse events 
Of all the unfavorable medical events that developed by administration of drugs (irrespective of dose), 
serious adverse event is an event that: 
1. 
Results in death during protocol treatment and all deaths irrespective of a causal relationship with 
protocol treatment. 


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2. 
Results in death after discontinuation of protocol treatment for which a causal relationship with 
protocol treatment cannot be denied. 
However, death obviously due to the underlying disease is not applicable. 
3. 
Is life-threatening 
The term “life-threatening” refers to an event in which the subject was at risk of death during 
onset of the adverse event; it does not refer to an event which hypothetically might have caused 
death if it were severer. 
4. 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization described below is not considered a serious adverse event: 
(1) Preplanned inpatient hospitalization or prolongation of existing hospitalization 
(2) Inpatient hospitalization or prolongation of existing hospitalization unrelated to an adverse 
event 
5. 
Results in persistent or significant disability/incapacity. 
6. 
Leads to a congenital anomaly/birth defect. 
7. 
Other medically significant condition: medically important event which causes a risk to a subject 
even if it is not immediately life-threatening, nor does it result in death or hospitalization, or 
requires an action or treatment to prevent the results shown in 1 to 6 above.. 
 
10.1.4 Noteworthy adverse events for the sponsor 
The events listed in "Takeda Medically Significant AE List" in Table 10.a will be handled as 
noteworthy adverse events by the sponsor irrespective of the severity determined by the principal 
investigator or investigator. Of the events listed in Table 10.a, the adverse event that the principal 
investigator or investigator determines to be serious should be handled as a serious adverse event. 
Table 10.a  Takeda medically significant AE list 
Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion and 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of infection 
by a medicinal product 
Confirmed or suspected endotoxin shock 
 
10.1.5 Severity of adverse events 
The severity of adverse event is classified and defined as follows based on the CTCAE (Japanese 
edition JCOG version 4.03): 


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Table 10.b  CTCAE (Japanese edition JCOG version 4.03) Grade 
Grade 1 
Mild; asymptomatic or slightly symptomatic; only clinical or test findings; or 
requiring no treatment 
Grade 2 
Moderate; requiring the least treatment or local or non-invasive treatment; or 
interfering with age-appropriate activities of daily living except for self-care 
activities* 
Grade 3 
Severe or medically critical, but not immediately life-threatening; requiring 
hospitalization or prolongation of existing hospitalization; disabling/incapacitating; 
or interfering with self-care activities of daily living** 
Grade 4 
Life-threatening; or requiring emergent treatment 
Grade 5 
Death due to an adverse event 
*:  Activities of daily living except for self-care activities include meal preparation, shopping for daily 
necessities and clothings, phone call, and financial management. 
**: Self-care activities of daily living include bathing, dressing, eating, toilet, and oral drug intake, and 
indicate that a person is not confined to bed. 
 
10.1.6 Causality of adverse events 
Causal relationship between protocol treatment (OXA, 5-FU, or panitumumab) and adverse events is 
classified and defined as described below. Information on causal relationship with adverse event is not 
collected for any drugs other than protocol treatment. 
Related 
An adverse event with apparent temporal relation with treatment discontinuation 
(including clinical course after discontinuation). Possibly due to protocol treatment 
(chemotherapy or panitumumab) although other factors such as underlying disease, 
complications, concomitant drugs/treatment are also presumed. 
Not related 
An adverse event with no chronological correlationship with protocol treatment 
(chemotherapy or panitumumab). Very likely due to other factors such as 
underlying disease, complications, and concomitant drugs/treatment. 
 
10.1.7 Date of onset 
Judge the date of onset of adverse event according to the following criteria: 


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Adverse event, etc. 
Date of onset 
Signs, symptoms, diseases 
(diagnosis name) 
Record the date when the subject or the investigator noticed the 
first signs and symptoms of adverse event. 
Asymptomatic disease 
Record the date of obtaining a definite diagnosis after conducting 
a test for diagnosis.  
Record the date of obtaining a definite diagnosis even when the 
test findings show old findings or suggest approximate timing of 
onset.  
Aggravation of complications 
Record the date when the subject or the investigator noticed the 
signs and symptoms of adverse event for the first time. 
Abnormal laboratory findings 
after initiation of protocol 
treatment 
Record the date of test where abnormal laboratory values 
considered clinically problematic were observed.  
Abnormality was observed on 
the test at initiation of 
protocol treatment, and 
aggravation was shown on 
subsequent tests. 
Record the date of tests when values were medically judged to be 
obviously increased and decreased based on the changes in test 
values.  
 
10.1.8 Date of resolution 
The date when adverse event resolved (or resolved with sequelae). Date of death when a subject died 
of the concerned adverse event. When recovery cannot be confirmed at study completion, it is 
considered ongoing. 
 
10.1.9 Incidence 
When the investigator considers the first occurrence up to the final remission of a series of adverse 
events which repeatedly appear to be resolved or recurred as one event (e.g., constipation, diarrhoea, 
vomiting, etc.), it is considered to be “intermittent”. Other events are considered “ongoing”. 
 
10.1.10 Action taken for protocol treatment 
The action taken for OXA, 5-FU, or panitumumab in protocol treatment is classified and defined as 
follows: 
Treatment discontinued 
Treatment with OXA, 5-FU, or panitumumab in protocol treatment 
was discontinued due to the adverse event. 
Not applicable 
Treatment with OXA, 5-FU, or panitumumab in protocol treatment 
had already been completed or discontinued by the time of the onset 
of the adverse event. 
 
10.1.11 Outcome 
Outcome of adverse events is classified as follows: 


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Category 
Criteria for judgment 
Recovered 
• 
disappearance or recovery of symptoms and findings 
• 
laboratory values returned to normal or baseline 
Improved 
• 
severity was improved by one or more grades 
• 
symptoms or findings mostly disappeared 
Not recovered 
• 
no change in symptoms, findings, or laboratory data 
• 
the symptoms, findings, or laboratory data on the final day of observable 
period aggravated compared with the date of onset 
• 
irreversible congenital anomaly 
• 
when a subject died where the concerned adverse event is not a direct cause 
of death and the concerned adverse event remained not recovered (no need 
for recording the date of death in this case) 
Recovered 
with sequelae 
• 
disability which disturbs daily life 
Death 
• 
direct relationship between death and the concerned adverse event 
• 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Unknown 
• 
follow-up specified in the protocol after the date of onset was not possible 
due to change of hospitals or relocation, etc. 
 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Period for collection of adverse events 
Adverse events should be continuously collected from initiation of protocol treatment up to four 
weeks after discontinuation of protocol treatment. 
10.2.1.2 Reporting of adverse events 
At each visit, the investigator should assess the onset of subjective symptoms are present. Onset of 
any adverse event that developed after the previous visit should be checked by asking a question 
such as “how has your condition been since the last visit?” to a subject. 
The investigator should follow up all subjects who developed adverse events irrespective of a 
causal relationship with protocol treatment until disappearance of symptoms or return of abnormal 
laboratory values to the value at initiation/dose reduction of protocol treatment, or until observed 
changes can be sufficiently explained for other events (persistent/irreversible adverse event, etc.). 
All adverse events should be recorded in the case report form. The name of an adverse event, date 
of onset, date of disappearance, frequency, severity, causal relationship with protocol treatment 
(unrelated or related), action taken for protocol treatment (chemotherapy and panitumumab), 
outcome, and seriousness should be recorded. 
Follow-up period of adverse events is until recovery of an adverse event, or the investigator judges 
that further follow-up would not be necessary. 
When requested by the representative researcher, the investigator should check the additional 
necessary information and data and complete recording them in the case report form within the 
designated period. 
 


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10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it should be 
reported according to the following procedures. 
When the investigator judges that a serious adverse event has occurred based on the reporting by a 
subject, etc. and the result of various tests, imaging findings or definitive diagnosis, a report should be 
submitted to the director of the study site and the representative researcher (see attached sheet for 
contact information) within one working day and a report should be made via the sponsor to the 
investigators of other sites jointly performing the clinical study. In addition, the investigator should 
submit a formal detailed report within 10 calendar days. 
The following items are the requisite for reporting within one working day, and other items should be 
reported as best as possible. 
• 
Study title 
• 
Subject ID code 
• 
Name of study site 
• 
Name of investigator 
• 
Name of serious adverse event, course (date of onset, reason for the judgment of “serious”, 
protocol treatment given, causal relationship with protocol treatment, course, and outcome) 
• 
Action taken for the serious adverse event (suspension of new enrollment, revision of the 
written informed consent, newly obtaining consent from other subjects) 
 
10.2.3 Dissemination of a serious adverse event to study sites jointly performing 
the clinical study 
When the head of study site receives a report of a serious adverse event from the investigator, he/she 
should obtain the opinions of the IRB such as the ethics review committee, add the following item to 
the report of the investigator, and disseminate it via the sponsor to the data monitoring committee and 
the study sites jointly performing the clinical study. 
• 
Date of review by the IRB such as the ethics review committee, summary of review, result, 
and necessary actions, etc. 
 
10.3 
Follow-up of serious adverse events 
The investigator should follow-up all serious adverse events, etc. until recovery is confirmed, or the final 
outcome is determined. 
When a change such as alteration of outcome was made to the report of a serious adverse event, the 
investigator should submit a report specifying details of the change to the head of study site and the 
sponsor. When requested by the sponsor or the IRB such as the ethics review committee, related data of 
the study site (e.g., ECG, laboratory test values, summary of discharge report, result of autopsy, etc.) 
should be provided. 
 


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10.4 
Reporting of additional information on adverse events 
When the sponsor requests the principal investigator or investigator to provide additional information on 
an adverse event for reporting to regulatory authorities and other agencies, the principal investigator or 
investigator, after verifying the required additional information, must enter it in an electronic CRF 
system or submit a written report within the period determined by the sponsor. 
 
10.5 
10.5 
Notification of serious adverse events to IRB such as an ethics review 
committee and regulatory authorities 
When the director of the study site has received a report of an SAE from the principal investigator, the 
director will seek advice from the IRB such as the ethics review committee, and notify the SAE to other 
study sites via the sponsor or the contract research organization (CRO). 
If the SAE reported from the principal investigator is unexpected, the director of the study site will 
prepare a written report of the unexpected SAE containing the information reported from the principal 
investigator plus the following information, and submit the report to the Minister of Health, Labour and 
Welfare, and notify it to other clinical study sites (The director of the study site may report it to the 
Minister of Health, Labour and Welfare via the sponsor, and notify it to other clinical study sites via the 
sponsor). 
• Actions taken for the SAE 
(e.g., any interruption of enrollment of new subjects, revision of the informed consent form, 
re-consent from other subjects currently in the study) 
• Date reviewed by the IRB such as the ethics review committee, review summary, review results, 
and necessary actions to be taken, etc. 
• Notification to other study sites 
The sponsor must report an unexpected SAE, and other SAE which meets the local criteria for an 
expedited report, to regulatory authorities, the principal investigator, and the director of the study site, 
according to the regulations. 
The sponsor or the CRO must submit the expedited reporting of an unexpected or expected SAE to 
regulatory authorities in compliance with the reporting time frames determined by the regulations after 
first knowledge of the event or acquisition of the additional information. In addition, the sponsor must 
submit the expedited reporting of other important safety information which is expected to greatly affect 
the risk benefit of the study drug, continuation of the treatment with the study drug, or continuation of 
the clinical study, in the same way. The study site will submit the copy of the document of expedited 
reporting to the IRB such as the ethics review committee. 


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11.0 
COMMIITTEES ESTABLISHED FOR ADMINISTRATIVE STRUCTURE 
AND THIS STUDY 
11.1 
Research steering committee 
The research steering committee will be established to effectively promote this study. The research 
steering committee will consist of steering committee members and biostatistician, and the sponsor or the 
person designated by the sponsor will act as the secretariat. 
See the supplement for the research steering committee members. 
The research steering committee will not be informed of the treatment allocation throughout the study 
period. 
Details of the research steering committee will be specified in a separately prepared SOP. 
 
11.2 
Data monitoring committee 
The Data monitoring committee (hereinafter referred to as DMC) will be established according to the 
ICH E6 (1.25), and the person designated by the sponsor will act as the secretariat. See the supplement 
for the DMC member. 
The DMC will notify a DMC advisory report on continuation/discontinuation of the study and change of 
the study plan according to the safety analysis results for evaluation to the sponsor. The sponsor will 
determine whether to continue, discontinue, or change the study based on the results. 
The sponsor will prepare the DMC procedures (DMC charter) specifying the details such as the objective, 
roles, and responsibilities of the DMC, and management procedure. 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Detailed procedures concerning data management will be specified in the data management plan. Adverse 
events, medical history, and concurrent conditions should be coded using the MedDRA.  
12.1 
Case report form 
The investigator should prepare the case report form for all subjects who have provided informed 
consent. 
The sponsor or its designee should provide study sites with access authorization to the electronic data 
capture (hereinafter referred to as EDC). The sponsor should provide the investigator and study 
collaborators with training for utilization of EDC. The case report form will be used to report the 
information collected during the study period to the sponsor. The case report form will be prepared in 
Japanese. Data will be directly entered into the case report form. 
A change or correction of the case report form will be recorded as an audit trail that records the 
information before and after the change or correction, a person who made the change or correction, date 
of change or correction, and the reason. 
The investigator should ensure the accuracy and completeness of the case report form, and provide an 
electronic signature on the relevant page of the case report form. The investigator assumes full 
responsibility for the accuracy and reliability of all the data entered into the case report form. 
The data below will be directly recorded into the case report form. 
• 
Severity and causal relationship of adverse event with “OXA”, “5-FU”, or “panitumumab” in 
protocol treatment 
When the investigator makes a change or correction in the data entered into the case report form after 
fixation of clinical data base, a record of change or correction in the case report form (Data Clarification 
Form) provided by the sponsor should be used. The investigator should confirm that the record of change 
or correction in the case report form is accurate and complete, and sign or write name/affix a seal, and 
date it. 
The sponsor or its designee should confirm the accuracy and completeness of the case report form during 
a visit to a study site. The sponsor or its designee should access to the medical records of study subjects 
and in-house records to ensure the accuracy of the case report form. The completed case report form is 
the property of the sponsor, and the investigator should not divulge the information to a third party other 
than the regulatory authority without a written permission of the sponsor. 
 
12.2 
Time limit for data input into the EDC 
It is recommended that data obtained after informed consent be entered into the EDC within the time 
frame described below, in principle. A failure to enter the data within the time frame does not constitute 
a deviation, but it is recommended that efforts be made to adhere to the time frame. 
1) 
At enrollment: within two weeks after enrollment 
2) 
During protocol treatment: within two weeks after discontinuation of each cycle of protocol 
treatment 
3) 
At discontinuation of protocol treatment: within four weeks after discontinuation of protocol 
treatment 
4) 
Imaging test results: within two weeks after evaluation of efficacy 
5) 
Follow-up period: within two weeks after request for follow-up 


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6) 
Inquiry about data input into the EDC: within two weeks after inquiry 
 
12.3 
Storage of records 
The investigator or the head of study site should store the following materials including those specified 
in Section 12.1 and study specific documents for use by the investigation or audit by the regulatory 
authority and the sponsor or their designee. The materials include a list of subject screening, medical 
records, signed and dated original consent form, and a record of change and correction of the case report 
form (copy)/electronic copy of electronic case report form containing audit trail. The investigator and the 
head of study site should store the essential documents until five years after discontinuation or 
completion of the study. However, when the sponsor requires a longer storage period, the head of study 
site will discuss the period and methods of storage with the sponsor. 
The investigator and the head of study site will store the essential documents until the sponsor notifies 
that storage is no longer necessary. 


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13.0 
STATISTICAL ANALYSIS METHODS 
13.1 
Statistical and analytical plans 
The statistician in charge should prepare and finalize the statistical analysis plan (SAP) before data 
fixation. Detailed definition of endpoints and analysis methods should be specified in the SAP to cope 
with the purpose of all studies. 
Data review should be performed before data fixation. Data review is performed to evaluate the accuracy 
and completeness of the study data, subject evaluability, and appropriateness of the planned analysis 
methods. 
13.1.1 Analysis set 
Two analysis sets, "full analysis set" and "safety population", are used in this study. "Full analysis set" 
is defined as "randomized subjects," and the "safety population" is defined as "the subjects who 
received at least one dose of protocol treatment after randomization." 
The sponsor should confirm the definition of analysis sets and appropriateness of analytical handling 
rules of the subject data in the analysis sets before data fixation, add handling of problematic issues 
which have not been prescribed in the planning stage, and finalize the SAP.  
 
13.1.2 Analysis of demographic and other baseline characteristics 
The following analysis should be conducted in "full analysis set." 
Concerning major subject background factors, frequency analysis should be conducted for numerical 
data and summary statistics should be calculated for quantitative data for each treatment group and 
collectively for all treatment groups. 
 
13.1.3 Efficacy analysis 
13.1.3.1 Primary endpoint and analysis method 
[Primary endpoint] 
Progression-Free Survival (PFS) 
The PFS is the period from the day of randomization (Day 0) until the day of judgment of 
exacerbation from the day of randomization, or until death by all causes, whichever comes earlier. 
Progression includes both PD based on diagnostic imaging according to RECIST Guidelines (ver 
1.1) and progression of the underlying disease which cannot be confirmed on diagnostic imaging 
(clinical progression). If progression is diagnosed on the basis of diagnostic imaging, the date of 
the imaging test will be regarded as the date of progression, and the date of clinical judgment will 
be regarded as the date of progression in the case of clinical progression. Even when a condition is 
regarded as PD according to the criteria for efficacy evaluation, such as in the cases of extreme 
shrinkage of the tumor size, but "progression is obviously ruled out" from a clinical point of view, 
PD according to the efficacy evaluation criteria will be given priority and the condition will be 
regarded as progression (in this case, clinical judgment will be prioritized with respect to whether 
or not protocol treatment should be continued). When the condition is not regarded as PD 
according to the efficacy evaluation criteria but it is obviously deemed as progression from a 
clinical point of view, the clinical judgment will be prioritized and the condition will be regarded as 
progression. The study will be cut off for the surviving patients without a diagnosis of progression 
on the last day of clinical confirmation of the absence of progression (date of last confirmation of 
progression-free survival; Confirmation of the absence of progression on imaging test and sample 


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test is not essential. Clinical confirmation of the absence of progression at outpatient clinic will 
suffice. Reporting by telephone only will not be accepted). Even in the cases of protocol treatment 
discontinuation for such reasons as toxicity and patients' withdrawal in which other treatment has 
been given in the after-care, events and cutoff will be handled in the same manner. In other words, 
the timing of discontinuation of treatment or the date of the start of after care will not be regarded 
as the cut-off dates. 
[Main analysis] 
Perform the following analysis for the “full analysis set”. 
For each treatment group, calculate the progression-free survival rate at a given time point and its 
95% confidence interval (two-sided) by Kaplan-Meier method, and calculate the quartile of PFS 
and its 95% confidence interval (two-sided). At the same time, draw a Kaplan-Meier chart for the 
progression-free survival rate. If the median value of observed PFS is 9 months or more in each 
group, the treatment regimen concerned will be regarded as being of worth of further investigation. 
Moreover, for the sake of reference, calculate the hazard ratio of Group B to Group A and its 95% 
confidence interval (two-sided) on the basis of the stratified Cox regression model and apply the 
log-rank test. 
13.1.3.2 Secondary endpoints and analysis method 
[Secondary endpoints] 
Overall survival（OS） 
OS is defined as the period from the day of randomization (Day 0) until death by all causes. 
[Analysis method] 
For OS, perform the same analysis as that for the primary endpoint for the "full analysis set." 
• Response rate（RR） 
RR is defined as the percentage of subjects who have shown complete response or partial response 
as the best overall response in RECIST ver 1.1 after randomization. The overall response will be 
complete response, followed by partial response, stable disease, progression, and nonevaluable in 
this order. 
[Analysis method] 
In "full analysis set," RR and two-sided 95% confidence interval will be calculated for each group. 
At the same time, the inter-group difference of RR (Group B－Group A) and the two-sided 95% 
confidence interval will be calculated.  
• Time to treatment failure（TTF） 
TTF is defined as the period from the date of randomization (counted as Day 0) to the date of 
judgment of discontinuation of protocol treatment, the date of judgment of progression, or the date 
of death for all causes, whichever has come earliest. 
[Analysis method] 
For TTF, perform the same analysis as that for the primary endpoint for the "full analysis set." 
13.1.3.3 Other efficacy endpoints 
See "5.2 Endpoints". 
13.1.3.4 Data conversion method and handling of missing data 
The subjects who have not experienced any events at the end of study on the data cutoff date in the 
analyses of PFS and OS will be handled as the cutoff cases. 


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For the cutoff cases, the last day of available image evaluation results prior to the data cutoff date 
for image test will be regarded as the timing of cutoff in the analysis of PFS, and the data cutoff 
date or the date of last confirmation of survival, whichever comes earlier, will be regarded as the 
timing of cutoff in the analysis of OS. Date of last confirmation of progression-free survival on 
which absence of clinical progression has been confirmed. 
Details about the method of conversion of other data and handling of missing data will be specified 
separately in the SPA. 
13.1.3.5 Level of significance, confidence coefficient 
• 
Level of significance: 5% 
• 
Confidence coefficient: 95% (two-sided estimation) 
 
13.1.4 Safety analysis 
Perform the following analyses in the “safety population”. 
13.1.4.1 Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAE) are the adverse events which developed after initiation 
of protocol treatment after randomization. 
For TEAE, perform the following analyses for each treatment group. Code TEAE using the 
MedDRA to summarize them by Preferred Term (PT) and System Organ Class (SOC). 
• 
Frequency tabulation of all TEAE 
• 
Frequency tabulation of TEAE for which the causal relationship with any of the protocol 
treatments was judged as “related” 
• 
Frequency tabulation of all TEAE by severity 
• 
Frequency tabulation of TEAE by severity for which the causal relationship with any of 
protocol treatment was judged as “related” 
• 
Table of TEAE by frequency with the action taken for any of protocol treatment was handled 
as “discontinuation” 
• 
Frequency tabulation of serious TEAE 
• 
Frequency tabulation of TEAE of peripheral nerve disorders (secondary endpoint) 
Peripheral nerve disorders will be defined as the events classified with the preferred term of 
"peripheral neuropathy" according to the Standardised MedDRA Queries, and skin disorders will 
be defined as the events classified with the System Organ Class of "Skin and subcutaneous tissue 
disorders" or the events classified as with the Preferred Term of "paronychia." The interstitial 
pneumonia will be the events of the Preferred Terms of the MedDRA Standard Search Formula. 
 
13.1.5 Predetermined subgroup analysis 
In this study, the following subgroup analysis will be conducted. 
• 
Subgroup analysis based on NRAS test 


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13.2 
Criteria for interim analysis and premature discontinuation 
Interim analysis will not be conducted. 
 
13.3 
Determination of the planned number of subjects 
This study will be designed as a phase II randomized screening comparison study which does not use 
direct comparison for primary analysis22). 
In the phase III study (PRIME Study) in which FOLFOX4 therapy was combined with bi-weekly 
administration of panitumumab 6 mg/kg as a first-line therapy, the median PFS in the patients of KRAS 
wild-type as the primary endpoint was reported as 9.6 months12). Moreover, in PEAK study23) in which 
panitumumab and bevacizumab were compared as the drugs to be administered in combination with 
mFOLFOX6 therapy, the median PFS in the mFOLFOX6 therapy + panitumumab group was reported as 
10.9 months. The percentage of the cases in which any events occurred or the study was cut off within 3 
months in PRIME Study and PEAK Study was approximately 10% of all cases. 
The subjects of this study will be the patients who receive mFOLFOX6 + panitumumab combination 
therapy for 3 months, and can continue OXA administration. Since the PFS 40% point in PRIME Study 
and PEAK Study was approximately 13 months, the median PFS in Group A in this study is expected to 
be approximately 10 months, which is obtained by subtracting 3 months from the 40% point. The median 
PFS in Group B is assumed to be comparable to that in Group A. 
In the primary analysis, a test based on the method of Brookmeyer-Crowley24) will be conducted for the 
null hypothesis, "true median PFS will be lower than the threshold median PFS for judgment as 
ineffective", separately in Group A and Group B on the basis of the observed median PFS. When the 
threshold median PFS is regarded as 6 months, true median PFS as 10 months, enrollment period as 12 
months, follow-up period as 12 months, one-sided significance level as 5%, and power of test as 80%, 
the number of subjects required in Group A and Group B will become 54 subjects each. Considering the 
cases of discontinuation, the target number of subjects to be randomised was set at 60 patients for each 
group (120 patients in total).  


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of study sites 
The sponsor or its designee will perform periodic monitoring of study sites during the study to confirm 
that the study is carried out in accordance with all specifications in the protocol. Central monitoring and 
site visit monitoring, when necessary, will be performed in this study. During site visit monitoring, the 
data recorded in EDC are checked against source documents. Source documents are the original 
documents, data and records. The investigator and the head of study site will ensure that the sponsor or 
its designee and the IRB such as the ethics review committee have access to the source documents. 
The sponsor or its designee will access the records including the subject code list, medical records, 
signed and dated original consent forms to confirm that the study is appropriately conducted in 
compliance with the protocol. The investigator and other persons involved in the study will spare 
sufficient time to facilitate monitoring procedures during visits to the study site. 
14.1.1 Central monitoring 
Central monitoring will be performed to check that the study is safely conducted in accordance with 
the protocol and that data are accurately collected, based on the data collected by EDC. Central 
monitoring will be conducted twice a year in principle, and periodic monitoring report will be 
prepared. Periodic monitoring report will be evaluated by research steering committee and feedback 
will be given to study sites when necessary. 
Detailed procedures for central monitoring will be determined in the separately prepared procedures. 
 
14.1.2 Site visit monitoring 
Site visit monitoring is conducted to confirm that the study is carried out safely and in compliance 
with the protocol and the data are accurately collected by checking the data entered into the EDC 
against source documents. 
Prior to site visit monitoring, sites are randomly selected to perform Source Documents Verification 
(SDV) for the enrolled subjects. 
See separately prepared monitoring plan for the frequency and procedures of site visit monitoring. 
 
14.2 
Protocol deviations 
The investigator should record all deviations from the protocol. When a deviation is disclosed, the 
investigator will immediately notify the head of study site and the sponsor in writing. Revision of the 
protocol should be discussed with the sponsor when necessary, and when the protocol is revised, the 
revised protocol should be submitted to the head of study site and approved by the IRB such as the ethics 
review committee. 
 


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14.3 
Quality assurance and regulatory agency inspections 
The sponsor or its designee will perform audit at the study site when necessary. In such a case, the 
auditor designated by the sponsor should contact the study site in advance to determine the date of audit. 
The auditor may request a visit to the site of collecting laboratory test samples and other sites to be used 
during the study. This study may also be audited by overseas regulatory authorities (e.g., Food and Drug 
Administration [FDA], Medicines and Healthcare Products Regulatory Agency [MHRA]). The study site 
will immediately notify the sponsor when the study site is contacted by the regulatory authority 
concerning an audit. The investigator and the head of study site should ensure that the auditor has access 
to all the source documents listed in Section 14.1. 


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15.0 
ETHICAL CONDUCT OF A STUDY 
This study will be conducted in compliance with the protocol and ethical principles based on the 
Declaration of Helsinki to preserve the interest of study participants (subjects). Each investigator should 
conduct a study based on the regulatory requirements and in compliance with the “Responsibilities of the 
investigator” in Attachment A. 
15.1 
Conflict of interests 
Prior to the study, the investigator should obtain the review/approval by the IRB such as the COI 
committee that this study has no conflict of interests (COI)25)-29). 
The study site should comply with all the requirements specified by the IRB such as the ethics review 
committee. The requirements include the COI self-declaration, protocol, and informed consent form. 
 
15.2 
Approval by the institutional review board including the ethics review 
committee 
The institutional review board (IRB) including the ethics review committee is constituted according to 
local regulations applicable to the study site. The sponsor or its designee should obtain the document 
listing the name and title of each IRB member. When the IRB members are directly participating in this 
study, a document should be obtained that they are not taking part in deliberation and voting. 
The sponsor or its designee should provide related documents to the IRB such as the ethics review 
committee for review and approval of the protocol. In addition to the protocol, a copy of informed 
consent form, written materials related to subject recruitment, advertisement, and other documents 
required by regulation, when necessary, should be submitted to the central IRB or the IRB of each study 
site such as the ethics review committee to obtain approval. The sponsor or its designee should obtain 
written approval of the protocol and the informed consent form from the IRB such as the ethics review 
committee prior to initiation of protocol treatment. The IRB’s approval document should contain the 
study title, protocol number, and date of preparation/revision of the concerned study, as well as version 
numbers and approval dates of other reviewed documents (e.g., informed consent form). The sponsor 
should notify the study site and the investigator after confirming the appropriateness of the regulatory 
documents of the study site. Protocol procedures such as obtaining consent should not be started until the 
study site and the investigator receive the notification. 
The study site should comply with all the requirements specified by the IRB such as the ethics review 
committee. The requirements include notifications to the IRB such as the ethics review committee, for 
instance, revision of the protocol, revision of the informed consent form, revision of materials related to 
subject recruitment, report on safety in accordance with the regulatory requirement, report on study 
implementation state at intervals determined by the IRB such as the ethics review committee, and study 
completion report. The sponsor or its designee should obtain written approval of the abovementioned 
items and all related materials from the IRB such as the ethics review committee. 
 
15.3 
Written information and subject’s consent 
The informed consent from contains specific requirements of the Declaration of Helsinki and all 
applicable laws and regulations. The informed consent from specifies the use of personal information 
and medical information of subjects in this study (both in and outside Japan: supply to a third party), and 
disclosure. Written explanation explains in detail the general idea and purpose of the study, and its 
possible risks and benefits. The informed consent from also clarifies the conditions for study 
participation and states the fact that subjects can discontinue study participation at any time without 
giving reasons and without loss of benefits in treatment. 


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The investigator is responsible for preparation, content, and IRB approval of the informed consent form. 
The informed consent form should be approved by IRB before use. 
The informed consent from should be written in a language easily understood by subjects. The 
investigator is responsible for providing detailed explanation of the informed consent from to subjects. 
Information should be provided orally and in writing as best as possible by the method deemed 
appropriate by the IRB. 
The investigator should ensure that the subjects have (1) an opportunity to inquire about the study and 
(2) sufficient time to determine study participation. When a subject decides to participate in the study, 
the subject should sign or write name/affix seal, and date the consent form prior to study participation. 
The investigator should request the subject to sign or write name/affix seal using a legal name and not a 
popular name with black or blue ballpoint pen. The investigator should also sign or write name/affix seal, 
and date the consent form prior to subject participation. 
The investigator should store the original consent form which was signed or contains name/affixed seal. 
The investigator should document in the subject’s medical record the date when the subject signed or 
wrote name/affixed seal on the consent form. A copy of the consent form with signature or name typed 
with name seal affixed should be provided to the subject. 
The investigator should take the same procedures as those for obtaining the initial consent to newly 
obtain consent from the concerned subject when the informed consent from is revised. The date of 
obtaining new consent should be recorded in the subject’s medical record, and a copy of the revised 
consent form should be provided to the subject. 
 
15.4 
Subject confidentiality 
The sponsor and its designee should comply with the principles of protection of the subject’s right 
against invasion of privacy. The subject ID code in this study is used to connect the clinical study 
database and related study documents of the sponsor with the source data of subjects. The limited 
information of subjects such as sex, age, and date of birth may be used within the scope of all applicable 
laws and regulations for identification of subjects and confirmation of accuracy of subject ID code. 
To confirm that this study is performed in compliance with the protocol, the sponsor should request the 
investigator for the access to the original laboratory test data, ECG, record of hospitalization/discharge 
during study period, and the original medical records such as autopsy report (source data or materials) by 
a monitor or the person designated by the sponsor, representative regulatory authority, auditor designated 
by the sponsor, and the IRB. The investigator should obtain approval of subjects concerning access to the 
original medical records by a monitor and the representative regulatory authority, etc. when obtaining 
consent from a subject (see Section 15.3). 
When providing a copy of source documents to the sponsor, the investigator should delete the 
information leading to identification of an individual (name and address of subject, other personal 
information not recorded in EDC of subject). 
 
15.5 
Advantages and disadvantages to subjects 
15.5.1 Advantage to subjects 
This study is performed as part of routine clinical practice, and no advantage is expected by 
participation in this study. 
 


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15.5.2 Disadvantage to subjects 
This study is performed in the scope of ordinary medical examination, and no disadvantage is 
expected by participation in this study. 
 
15.6 
Publication, disclosure, and clinical trial registration policy 
15.6.1 Publication and disclosure 
The investigator should provide the sponsor with all the results and data obtained from the study. Only 
the sponsor may disclose the study information to other investigators or regulatory authorities during 
the study period except for a case required by laws and regulations. The sponsor will be responsible 
for publication of the protocol and study-related results (including the public web site) except for other 
cases permitted in the study contract. 
The sponsor may make public the data and information obtained from the study (including the data 
and information provided by the investigator) based on the agreement with the representative 
researcher. 
The investigator should obtain the prior written consent of the sponsor when making public the 
information obtained in this study at a specialized academic meeting, etc. 
 
15.6.2 Clinical trial registration 
Takeda Pharmaceutical Company Limited. will ensure timely publication of the information of a 
clinical study and registration of all clinical researches in patients under way all over the world at least 
to the Clinical Trials.gov and public web site (UMIN-CTR) to comply with the applicable 
laws/regulations and guidelines. The city and country where a study is performed, and the subject 
recruitment state should be registered as well as the contact information of Takeda Pharmaceutical 
Company Limited. to enable general access. 
 
15.6.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited. will post the results of a clinical study at the Clinical 
Trials.gov and public web site (UMIN-CTR) as specified by the applicable laws and regulations 
irrespective of results. 
 
15.7 
Attribution of study results and intellectual property rights 
The study results generated in this study belong to Takeda Pharmaceutical Company Limited. The 
intellectual property rights regarding the pharmaceutical products manufactured and/or distributed by 
Takeda Pharmaceutical Company Limited. also belong to Takeda Pharmaceutical Company Limited. 
Data generated from this study may be made available for secondary use (e.g., meta-analysis) without 
any link to personally identifying information only with permission from the representative researcher 
and the research steering committee. 
 
15.8 Insurance and compensation for injury 
The subjects participating in this study will be compensated for any injury resulting from participation in 
the study according to local regulations applicable to the study site. It should be noted that any treatment 
provided will be covered by health insurance, and no monetary compensation will be provided. 


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16.0 
REFERENCES 
1 
The Editorial Board of Cancer Statistics in Japan. Cancer Statistics in Japan 2013. Foundation for 
Promotion of Cancer Research: 2013. 
2 
Japanese Society for Cancer of the Colon and Rectum (JSCCR). JSCCR Guidelines 2014 for the 
Treatment of Colorectal Cancer. 
3 
Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med. 1994;330(16):1136-42. 
4 
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil 
and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 
2000;343(13):905-14. 
5 
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined 
with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal 
cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041-7. 
6 
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and 
fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin 
Oncol. 2000;18(16):2938-47. 
7 
Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, et al. Superiority of 
oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with 
progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III 
trial. J Clin Oncol. 2003;21(11):2059-69. 
8 
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A 
randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in 
patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23-30. 
9 
Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by 
FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J 
Clin Oncol. 2004;22(2):229-37. 
10 National Comprehensive CancerNetwork. Clinical Practice Guidelines in Oncology. Colon Cancer 
verslon 3, 2013 
11 Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial 
of panitumumab plus best supportive care compared with best supportive care alone in patients with 
chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658-64. 
12 Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial 
of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus 
FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal 
cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697-705. 
13 Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III 
study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with 
FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 
2010;28(31):4706-13. 
14 Muro K, Yoshino T, Doi T, Shirao K, Takiuchi H, Hamamoto Y, et al. A phase 2 clinical trial of 
panitumumab monotherapy in Japanese patients with metastatic colorectal cancer. Jpn J Clin Oncol. 
2009;39(5):321-6. 
15 Boku N, Sugihara K, Kitagawa Y, Hatake K, Gemma A, Yamazaki N, et al. Panitumumab in Japanese 
Patients with Unresectable Colorectal Cancer: A Post-marketing Surveillance Study of 3085 Patients. 
Jpn J Clin Oncol. 2014;44(3):214-223. 


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16 Hochster HS, Hart LL, Ramanathan RK, Hainsworth JD, Hedrick EE, Childs BH. Safety and efficacy 
of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of 
metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study. J Clin Oncol 2006;24(18S) 
3510. 
17 Summary of product characteristics, December 2003: Sanofi-Synthelabo. 
18 Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1:A Randomized 
Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal 
Cancer—A GERCOR Study. J Clin Oncol 2006;24(3):394-400. 
19 Maindrault-Goebel F, et al. Final results of OPTIMOX2, a large randomized phaseⅡ study of 
maintenance herapy or chemotherapy–free intervals(CFI) after FOLFOX in patients with metastatic 
colorectal cancer(MRC) : A GERCOR study. ASCO Meeting Abstructs, Jun 2007;25:4013. 
20 Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Therapeutics and 
Clinical Risk Management 2005;1(4):249–258. 
21 Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in 
combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated 
metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J 
Clin Oncol. 2007;25(12):1539-44. 
22 Buyse M. Randomized designs for early trials of new cancer treatments - an overview. Drug Inf J 
2000; 34: 387-396. 
23 Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: A Randomized, 
Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil, Leucovorin, and Oxaliplatin 
(mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With Previously Untreated, Unresectable, 
Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer. J Clin Oncol. 2014. 
24 Brookmeyer R and Crowley, JJ. A confidence interval for the median survival time. Biometrics 1982; 
38: 29-41. 
25 Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, Science 
and Technology dated November 1, 2002) 
26 Guidelines for determining the conflict of interest polity for clinical researches (Review group for 
ethical aspects of clinical researches and conflict of interest, March 2006) 
27 Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences Research 
(March 31, 2008) 
28 Guidelines for management of COI in medical reserach (COI Committee of Japan Association of 
Medical Sciences, February 2011) 
29 Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of Internal 
Medicine, Japan Society of Hepatology, Japanese Circulation Society, Japan Endocrine Society, Japan 
Diabetes Society, Japanese Respiratory Society, Japanese Society of Hematology, Japanese Society of 
Allergology, Japanese Association for Infectious Diseases, August 2011) 
 


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Appendix A 
Responsibilities of the investigator 
1 
To appropriately conduct the clinical study in compliance with the protocol and in consideration of 
the human rights, safety and welfare of subjects. 
2 
To request COI committee of each study site to review and approve that there is no COI issues with 
this study. 
3 
When assigning a part of important duties related to this study to subinvestigators or study 
collaborators, prepare a list of assigned duties and persons, submit it in advance to the head of study 
site, and to obtain approval. 
4 
To prepare the informed consent form and revise it as necessary. 
5 
To check the contents of the study contract. 
6 
To provide sufficient information on the protocol, drug and duties of each person to 
subinvestigators and study collaborators, and to provide them with guidance and supervision. 
7 
To select subjects who satisfy the protocol, give explanation using written information, and obtain 
consent in writing. 
8 
To be responsible for all medical judgments related to the study. 
9 
To ensure together with the head of study site that sufficient medical care is provided to subjects for 
all study-related clinically problematic adverse events throughout the period of subject’s study 
participation and thereafter. 
10 When a subject is treated at another medical institution or department, inform a physician of the 
medical institution or department in writing of the subject’s study participation and study 
completion/discontinuation after obtaining the subject’s consent, and then prepare the record. 
11 When emergency report of serious adverse events, etc. is required, immediately report it in writing 
to the head of the study site and the sponsor. 
12 To prepare accurate and complete EDC and submit it to the sponsor with an electronic signature. 
13 To inspect and check the contents of EDC prepared by subinvestigators, or transcribed by study 
collaborators from the source data, and submit it to the sponsor with an electronic signature. 
14 To discuss a revision of the protocol, etc. when proposed by the sponsor. 
15 To report the study completion in writing to the head of study site. 
 
 


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SAPPHIRE study 
(A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + 
panitumumab combination therapy and 5-FU/LV + panitumumab combination therapy in 
the patients with chemotherapy-naïve unresectable advanced recurrent colorectal 
carcinoma of KRAS wild-type after 6 cycles of combination therapy with mFOLFOX6 + 
panitumumab.) 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
183/NRP-005 
Product name 
Panitumumab 
Creation date 
Aug 21, 2014 
 
CONFIDENTIAL PROPERTY 


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This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Takeda.  


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1.0 
STUDY ADMINISTRATIVE STRUCTURE AND PRINCIPLES 
1.1 Study Administrative Structure 
See Appendix for the contacts and study-related responsibilities. 
1.2 Principles of the study 
This study will be conducted with the highest respect for the individual participants in accordance with 
the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference on Harmonisation E6 Good Clinical Practice (hereinafter referred to as 
“GCP”). 
• 
All applicable laws and regulations, including, without limitation, data privacy laws, conflict of 
interest guidelines, Ethical Guideline for Clinical Research (the Ministry of Health, Labour and 
Welfare, revised in 2008). 


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TABLE OF CONTENTS 
1.0 
STUDY ADMINISTRATIVE STRUCTURE AND PRINCIPLES .......................................... 3 
1.1 
Study Administrative Structure .......................................................................................... 3 
1.2 
Principles of the study......................................................................................................... 3 
2.0 
STUDY SUMMARY .............................................................................................................. 10 
3.0 
LIST OF ABBREVIATIONS ................................................................................................. 15 
4.0 
INTRODUCTION ................................................................................................................... 17 
4.1 
Background ....................................................................................................................... 17 
4.1.1 
Etiology of target disease ........................................................................................... 17 
4.1.2 
Standard treatment for target disease ......................................................................... 17 
4.1.3 
Efficacy and safety of mFOLFOX6 in patients with unresectable, advanced or recurrent 
colorectal cancer ........................................................................................................ 18 
4.1.4 
Efficacy and safety of panitumumab in patients with unresectable, advanced or 
recurrent colorectal cancer ......................................................................................... 18 
4.1.5 
Adverse reactions to OXA ......................................................................................... 21 
4.1.6 
Examination of the method of administration of OXA in first-line therapy .............. 22 
4.2 
Rationale for the proposed study ...................................................................................... 22 
5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY .............................................................. 23 
5.1 
Objective ........................................................................................................................... 23 
5.2 
Endpoints .......................................................................................................................... 23 
5.2.1 
Primary endpoint ........................................................................................................ 23 
5.2.2 
Secondary endpoints .................................................................................................. 23 
5.2.3 
Additional endpoint ................................................................................................... 23 
5.3 
Rationale for the endpoints ............................................................................................... 24 
5.3.1 
Primary endpoint ........................................................................................................ 24 
5.3.2 
Secondary endpoints .................................................................................................. 24 
6.0 
STUDY DESIGN .................................................................................................................... 25 
6.1 
Study design...................................................................................................................... 25 
6.2 
Rationale for study design, dose and endpoints ................................................................ 26 
6.2.1 
Study population ........................................................................................................ 26 
6.2.2 
Treatment regimens and planned number of subjects ................................................ 26 
6.3 
Discontinuation of entire study or discontinuation at a study site .................................... 26 
6.3.1 
Criteria for discontinuation of entire study ................................................................ 26 


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6.3.2 
Procedures of study suspension and discontinuation of entire study or study at a study 
site 27 
6.4 
Procedures for revision of the protocol ............................................................................. 27 
7.0 
SELECTION OF STUDY SUBJECTS ................................................................................... 28 
7.1 
Inclusion criteria ............................................................................................................... 28 
7.1.1 
Inclusion criteria for enrollment ................................................................................ 28 
7.1.2 
Inclusion criteria for randomization ........................................................................... 28 
7.2 
Exclusion criteria .............................................................................................................. 29 
7.2.1 
Exclusion criteria for enrollment ............................................................................... 29 
7.2.2 
Exclusion criteria for randomization .......................................................................... 29 
8.0 
TREATMENT ......................................................................................................................... 30 
8.1 
Protocol treatment ............................................................................................................. 30 
8.1.1 
Protocol Treatment [1] ............................................................................................... 30 
8.1.2 
Protocol Treatment [2] ............................................................................................... 30 
8.2 
Treatment regimen ............................................................................................................ 30 
8.2.1 
Protocol Treatment [1] ............................................................................................... 30 
8.2.2 
Protocol Treatment [2] ............................................................................................... 31 
8.3 
Recommended dose of protocol treatment ....................................................................... 32 
8.4 
Criteria for initiation of protocol treatment (common for Protocol Treatment [1] and [2])
 32 
8.5 
Criteria for dose change .................................................................................................... 33 
8.5.1 
Protocol Treatment [1] ............................................................................................... 33 
8.5.2 
Protocol Treatment [2] ............................................................................................... 35 
8.6 
Criteria for dose increase of protocol treatment................................................................ 36 
8.7 
Overdose of panitumumab ................................................................................................ 36 
8.8 
Criteria for discontinuation of protocol treatment ............................................................ 36 
8.9 
Contraindicated drugs/therapies........................................................................................ 37 
8.10 
Allowed supportive care and combination medications ................................................... 38 
8.11 
Handling of surgery aimed at curative resection (complete resection: R0 resection) of 
colorectal cancer ............................................................................................................... 39 
8.12 
Recommended follow-up therapy ..................................................................................... 39 
8.12.1 Recommended second-line treatment ........................................................................ 39 
8.12.2 Recommended third-line or subsequent treatment ..................................................... 39 


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9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR OBSERVATIONS ....... 40 
9.1 
Study calendar .................................................................................................................. 40 
9.2 
Collection/test/observation items and procedures during the study .................................. 42 
9.2.1 
Informed consent procedure ....................................................................................... 42 
9.2.2 
Procedures for registration and allocation of drugs ................................................... 42 
9.2.3 
Subject demographics ................................................................................................ 43 
9.2.4 
Medical history .......................................................................................................... 43 
9.2.5 
Current medical condition .......................................................................................... 43 
9.2.6 
Clinical findings (physical examination) ................................................................... 44 
9.2.7 
Body weight and height ............................................................................................. 44 
9.2.8 
Vital signs .................................................................................................................. 44 
9.2.9 
ECOG P.S. ................................................................................................................. 44 
9.2.10 Treatment compliance (Protocol Treatment [1] and [2] implementation status) ....... 45 
9.2.11 Laboratory tests .......................................................................................................... 45 
9.2.12 Imaging test (thoracoabdominal-pelvic CT/MRI)...................................................... 47 
9.2.13 NRAS test ................................................................................................................... 47 
9.2.14 Surgery aimed at curative resection (complete resection: R0 resection) of colorectal 
cancer ......................................................................................................................... 48 
9.2.15 Survival survey .......................................................................................................... 49 
9.2.16 Follow-up therapy ...................................................................................................... 49 
9.3 
Records of subjects who discontinued before enrollment ................................................ 49 
10.0 
ADVERSE EVENTS .............................................................................................................. 50 
10.1 
Definitions ........................................................................................................................ 50 
10.1.1 Adverse events ........................................................................................................... 50 
10.1.2 Items to be considered concerning adverse events..................................................... 50 
10.1.3 Serious adverse events ............................................................................................... 51 
10.1.4 Severity of adverse events.......................................................................................... 52 
10.1.5 Causality of adverse events ........................................................................................ 53 
10.1.6 Date of onset .............................................................................................................. 53 
10.1.7 Date of resolution ....................................................................................................... 54 
10.1.8 Incidence .................................................................................................................... 54 
10.1.9 Action taken for protocol treatment ........................................................................... 54 


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10.1.10 Outcome ..................................................................................................................... 54 
10.2 
Procedures......................................................................................................................... 55 
10.2.1 Collection and reporting of adverse events ................................................................ 55 
10.2.2 Collection and reporting of serious adverse events .................................................... 55 
10.2.3 Dissemination of a serious adverse event to study sites jointly performing the clinical 
study ........................................................................................................................... 56 
10.3 
Follow-up of serious adverse events ................................................................................. 56 
11.0 
COMMIITTEES ESTABLISHED FOR ADMINISTRATIVE STRUCTURE AND THIS 
STUDY .................................................................................................................................... 57 
11.1 
Research steering committee ............................................................................................ 57 
11.2 
Data monitoring committee .............................................................................................. 57 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS .................................................. 58 
12.1 
Case report form ............................................................................................................... 58 
12.2 
Time limit for data input into the EDC ............................................................................. 58 
12.3 
Storage of records ............................................................................................................. 59 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................................... 60 
13.1 
Statistical and analytical plans .......................................................................................... 60 
13.1.1 Analysis set ................................................................................................................ 60 
13.1.2 Analysis of demographic and other baseline characteristics ...................................... 60 
13.1.3 Efficacy analysis ........................................................................................................ 60 
13.1.4 Safety analysis ........................................................................................................... 62 
13.1.5 Predetermined subgroup analysis ............................................................................... 62 
13.2 
Criteria for interim analysis and premature discontinuation ............................................. 63 
13.3 
Determination of the planned number of subjects ............................................................ 63 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................................... 64 
14.1 
Monitoring of study sites .................................................................................................. 64 
14.1.1 Central monitoring ..................................................................................................... 64 
14.1.2 Site visit monitoring ................................................................................................... 64 
14.2 
Protocol deviations ........................................................................................................... 64 
14.3 
Quality assurance and regulatory agency inspections ....................................................... 64 
15.0 
ETHICAL CONDUCT OF A STUDY .................................................................................... 66 
15.1 
Conflict of interests ........................................................................................................... 66 
15.2 
Approval by the institutional review board including the ethics review committee ......... 66 


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15.3 
Written information and subject’s consent ....................................................................... 66 
15.4 
Subject confidentiality ...................................................................................................... 67 
15.5 
Advantages and disadvantages to subjects ....................................................................... 67 
15.5.1 Advantage to subjects ................................................................................................ 67 
15.5.2 Disadvantage to subjects ............................................................................................ 68 
15.6 
Publication, disclosure, and clinical trial registration policy ............................................ 68 
15.6.1 Publication and disclosure ......................................................................................... 68 
15.6.2 Clinical trial registration ............................................................................................ 68 
15.6.3 Clinical trial results disclosure ................................................................................... 68 
15.7 
Attribution of study results and intellectual property rights ............................................. 68 
15.8 
Insurance and compensation for injury ............................................................................. 68 
16.0 
REFERENCES ........................................................................................................................ 69 
 
Figures and Tables List 
Figure 8.a  mFOLFOX6 + panitumumab combination therapy ........................................................... 31 
Figure 8.b  5-FU/LV + panitumumab combination therapy ................................................................ 32 
 
Table 4.a  Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study ......... 19 
Table 4.b  Adverse Drug Reactions (ADRs) of special interest on Post-marketing survey in Japan ... 21 
Table 8.a  Treatment regimen of mFOLFOX6 + panitumumab combination therapy ......................... 30 
Table 8.b  Treatment regimen of 5-FU/LV + panitumumab combination therapy .............................. 31 
Table 8.c  Criteria for initiation of treatment cycle .............................................................................. 33 
Table 8.d  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [1]) ............................ 33 
Table 8.e  Doses of OXA and 5-FU (Protocol Treatment [1]) ............................................................. 34 
Table 8.f  Criteria for dose reduction of panitumumab ........................................................................ 34 
Table 8.g  Dose of panitumumab ......................................................................................................... 35 
Table 8.h  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [2]) ............................ 35 
Table 8.i  Doses of OXA and 5-FU (Protocol Treatment [2]) ............................................................. 35 
Table 9.a  Study calendar (Protocol Treatment [1]) ............................................................................. 40 
Table 9.b  Study calendar (Protocol Treatment [2]) ............................................................................. 41 
Table 9.c  Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) ........................... 44 
Table 9.d  Laboratory tests performed at the time of enrollment ......................................................... 45 


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Table 9.e  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment 
[1]) ............................................................................................................................. 46 
Table 9.f  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment 
[2]) ............................................................................................................................. 46 
Table 9.g  Laboratory tests performed at the time of discontinuation.................................................. 47 
Table 9.h  EXON and codon verified on NRAS test ............................................................................. 48 
Table 9.i  Residual tumor after surgical treatment ............................................................................... 49 
 


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2.0 
STUDY SUMMARY 
Sponsor: Takeda Pharmaceutical Company Limited 
Test product: Panitumumab 
Study title: 
A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + panitumumab combination 
therapy and 5-FU/LV + panitumumab combination therapy in the patients with chemotherapy-naïve unresectable 
advanced recurrent colorectal carcinoma of KRAS wild-type after 6 cycles of combination therapy with 
mFOLFOX6 + panitumumab 
Protocol number: 183/NRP-005 
Study type: Exploratory study 
Study design: 
 
Objective: 
To exploratorily examine efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type who have been treated with 6 cycles of first-line 
mFOLFOX6 + panitumumab combination therapy and then assigned to two groups, i.e., a group receiving 
5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + panitumumab combination 
therapy. 
Study population: 
The patients with chemotherapy-naïve unresectable, advanced/recurrent colorectal carcinoma of KRAS wild-type 
Planned number of subjects: 
mFOLFOX6 + panitumumab arm (Group A): 60 
5-FU/LV + panitumumab arm (Group B): 
60 


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Number of study sites: TBD 
Method of administration: 
In both Protocol Treatment [1] and Protocol Treatment [2] (Group A and Group B), one cycle consists of two 
weeks, and the drugs will be administered at the following doses according to the following schedule. 
Protocol Treatment [1] 
mFOLFOX6 + panitumumab combination therapy, once every two weeks, 6 cycles 
OXA: 85 mg/m2/day 1 
l-LV: 200 mg/m2/day 1 
bolus 5-FU: 400 mg/m2/day 1 
infusional 5-FU: 2400 mg/m2/day 1-3 
panitumumab: 6 mg/kg 
Protocol Treatment [2] 
Group A: mFOLFOX6 + panitumumab combination 
therapy, once every two weeks 
OXA: 85 mg/m2/day 1 
l-LV: 200 mg/m2/day 1 
bolus 5-FU: 400 mg/m2/day 1 
infusional 5-FU: 2400 mg/m2/day 1-3 
panitumumab: 6 mg/kg 
Group B: 5-FU/LV + panitumumab combination 
therapy, once every two weeks 
l-LV: 200 mg/m2/day 1 
bolus 5-FU: 400 mg/m2/day 1 
infusional 5-FU: 2400 mg/m2/day 1-3 
panitumumab: 6 mg/kg 
Duration of treatment (approximately): 10 months (Period from the day of first administration in Protocol 
Treatment [1] to PD or intolerance) 
Inclusion criteria 
Inclusion criteria for enrollment: 
(1) Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the 
appendix and anal canal cancer) 
(2) Patients with measurable lesion(s) according to the RECIST ver. 1.1 
(3) Patients who have not received chemotherapy for colorectal cancer. Patients who experience relapse more 
than 6 months after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents 
may be enrolled. 
(4) Aged ≥20 years at the time of informed consent 
(5) Patients classified as KRAS wild-type*. However, the criteria will be changed to all patients who are 
verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be covered by 
National Health Insurance, and the tests become feasible at medical institutions. 
*: 
Patients with no mutation in any of the codons shown below are considered wild type. 
KRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
NRAS** 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
**: To be considered when the test comes to be covered by insurance and becomes feasible at medical 
institutions. 
(6) Patients who satisfy the following criteria for the major organ function in tests performed within 14 days 
prior to enrollment 
1) 
Neutrophil count ≥ 1,500/mm3 
2) 
White blood cell count ≥ 3,000/mm3 
3) 
Platelet count ≥ 10.0 × 104/mm3 
4) 
Hemoglobin ≥ 9.0 g/dL 


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5) 
Total bilirubin ≤ 2.0 mg/dL 
6) 
AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
7) 
ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
8) 
Serum creatinine ≤ 1.5 mg/dL 
(7) ECOG performance status (PS) of 0 or 1 
(8) Life expectancy of ≥ 6 months after enrollment 
(9) Patients who have given written consent to take part in the study after detailed explanation of the study 
prior to enrollment 
Inclusion criteria for randomization: 
(1) Patients who have received 6 cycles＊ (Protocol Treatment [1]) of mFOLFOX6 + panitumumab 
combination therapy 
*: Protocol Treatment [1] without discontinuation in all cycles (6 cycles) of Protocol Treatment [1]. 
However, bolus 5-FU is an exception. 
(2) Patients who are deemed to be able to receive 5-FU/LV, OXA and panitumumab during the period of 
Protocol Treatment [2] on the examination before administration of the 7th cycle.  
(3) ECOG performance status (PS) of 0-1 before administration of the 7th cycle. 
(4) Patients for whom PD or not evaluable has been denied on the Response Evaluation Criteria in Solid 
Tumors (RECIST) based on imaging tests conducted after administration of 6 cycles. 
Exclusion criteria 
Exclusion criteria for enrollment: 
(1) Radiotherapy received within 4 weeks prior to enrollment 
(2) Known brain metastasis or strongly suspected of brain metastasis 
(3) Synchronous cancers or metachronous cancers with a disease-free period of ≤ 5 years (excluding colorectal 
cancer) excluding mucosal cancers cured or be possibly cured by regional resection (esophageal, stomach, 
and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.). 
(4) Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) 
(5) Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant or 
breast-feeding, or test positive for pregnancy 
(6) Active hemorrhage requiring blood transfusion 
(7) Disease requiring systemic steroids for treatment (excluding topical steroids) 
(8) Intestinal resection and colostomy within 2 weeks prior to enrollment 
(9) History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, 
pulmonary fibrosis, etc.) 
(10) Serious drug hypersensitivity 
(11) Local or systemic active infection requiring treatment, or fever indicating infection 
(12) Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating symptoms 
despite adequate treatment) 
(13) Active hepatitis B and/or C 
(14) Known HIV infection 
(15) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study 
Exclusion criteria for randomization: 
(1) Patients in whom interstitial pneumonia has been newly diagnosed during the period from registration to 
randomization 
(2) Patients who have received radiotherapy during the period from registration to randomization 


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(3) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study 
Endpoints: 
[Primary endpoint] 
 Efficacy 
Progression-Free Survival (PFS) 
[Secondary endpoints] 
 Efficacy 
 Overall survival (OS) 
 Response rate (RR) 
 Time to treatment failure (TTF) 
 Safety 
 Incidence rate of adverse events and severity by incidence rate 
 Incidence rate of peripheral nerve disorders 
 Incidence rate of skin disorders 
Statistical method: 
The purpose of this study is to explorethe the analysis of PFS compared mFOLFOX6 + panitumumab arm with 
5-FU/LV + panitumumab arm.  
The PFS is the period from the day of randomization (Day 0) until the day of judgment of exacerbation from the 
day of randomization, or until death by all causes, whichever comes earlier. 
For each treatment group, calculate the progression-free survival rate at a given time point and its 95% 
confidence interval (two-sided) by Kaplan-Meier method, and calculate the quartile of PFS and its 95% 
confidence interval (two-sided). At the same time, draw a Kaplan-Meier chart for the progression-free survival 
rate. If the median value of observed PFS is 9 months or more in each group, the treatment regimen concerned 
will be regarded as being of worth of further investigation. 
Moreover, for the sake of reference, calculate the hazard ratio of Group B to Group A and its 95% confidence 
interval (two-sided) on the basis of the stratified Cox regression model and apply the log-rank test. 
Rationale for planned number of subjects: 
This study will be designed as a phase II randomized screening comparison study which does not use direct 
comparison for primary analysis. 
In the phase III study (PRIME Study) in which FOLFOX4 therapy was combined with bi-weekly administration 
of panitumumab 6 mg/kg as a first-line therapy, the median PFS in the patients of KRAS wild-type as the 
primary endpoint was reported as 9.6 months12). Moreover, in PEAK study in which panitumumab and 
bevacizumab were compared as the drugs to be administered in combination with mFOLFOX6 therapy, the 
median PFS in the mFOLFOX6 therapy + panitumumab group was reported as 10.9 months. The percentage of 
the cases in which any events occurred or the study was cut off within 3 months in PRIME Study and PEAK 
Study was approximately 10% of all cases. 
The subjects of this study will be the patients who receive mFOLFOX6 + panitumumab combination therapy for 
3 months, and can continue OXA administration. Since the PFS 40% point in PRIME Study and PEAK Study 
was approximately 13 months, the median PFS in Group A in this study is expected to be approximately 10 
months, which is obtained by subtracting 3 months from the 40% point. The median PFS in Group B is assumed 
to be comparable to that in Group A. 
In the primary analysis, a test based on the method of Brookmeyer-Crowley will be conducted for the null 
hypothesis, "true median PFS will be lower than the threshold median PFS for judgment as ineffective", 
separately in Group A and Group B on the basis of the observed median PFS. When the threshold median PFS is 
regarded as 6 months, true median PFS as 10 months, enrollment period as 12 months, follow-up period as 12 
months, one-sided significance level as 5%, and power of test as 80%, the number of subjects required in Group 
A and Group B will become 54 subjects each. Considering the cases of discontinuation, the target number of 


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subjects to be randomised was set at 60 patients for each group (120 patients in total). 


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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Unabbreviated expression 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ALP 
alkaline phosphatase 
ASCO 
American society of clinical oncology 
BRAF 
v–raf murine sarcoma viral oncogene homolog B1 
BSC 
best supportive care 
CEA 
carcinoembryonic antigen 
COI 
conflict of interest 
CR 
complete response 
CRO 
contract research organization 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
deepness of response 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EGF 
epidermal growth factor 
EGFR 
epidermal growth factor receptor 
ETS 
early tumor shrinkage 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FFPE 
Formalin-Fixed Paraffin-Embedded 
G-CSF 
granulocyte colony stimulating factor 
γ-GTP 
γ-glutamyl transpeptidase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
IRB 
institutional review board 
JCOG 
Japan Clinical Oncology Group 
KRAS 
Kirsten rat Sarcoma-2 virus 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
l-LV 
Leucovorin 
mCRC 
metastatic colorectal cancer 


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Abbreviation 
Unabbreviated expression 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NE 
Not Evaluable 
NRAS 
 
OS 
Overall survival 
OXA 
Oxaliplatin 
PD 
progressive disease 
PFS 
Progression free survival 
PPS 
per-protocol analysis set 
PR 
partial response 
P.S. 
performance status 
PT 
Preferred Term 
PI3K 
Phosphoinositide 3-kinase 
RAS 
rat sarcoma 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TTF 
Time to Treatment Failure 
ULN 
upper limit of normal 
UMIN-CTR 
University Hospital Medical Information Network - Clinical Trials 
Registry 
UPC 
urine protein creatinine 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell 
WT 
wild type 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 
Etiology of target disease 
According to “Cancer Statistics 2013,”1) and “Site-specific Cancer Prevalence” in 2008 in Japan, 
colon cancer was the third most prevalent cancer in men (15.0%) and the second in women (15.1%). 
According to “Site-specific Cancer Deaths (2012),” in men, lung cancer was the leading cause of 
cancer death (accounting for 23.9% of cancer deaths), followed by gastric cancer (15.0%) and hepatic 
cancer (9.3%); colorectal cancer (colon cancer and rectal cancer combined) accounted for 11.9% of 
cancer deaths which exceeded the death rate of hepatic cancer, representing that colorectal cancer is 
the third leading cause of cancer death. In women, lung cancer (13.8%) was also the leading cause of 
cancer death, followed by gastric cancer (11.6%) and pancreatic cancer (9.9%); deaths from colorectal 
cancer (colon cancer and rectal cancer combined) accounted for 14.9% of cancer deaths, representing 
that colorectal cancer is the first leading cause of cancer death. 
4.1.2 
Standard treatment for target disease 
The “Guidelines for Treatment of Colorectal Cancer (2014)”2) classify the standard treatment of 
colorectal cancer according to staging as follows: endoscopic resection for Stage 0, in which the lesion 
is limited in the mucosa; surgical resection for Stage I to III with postoperative adjuvant chemotherapy 
for Stage III involving lymph nodes; and surgical resection for Stage IV and recurrent disease if liver 
or lung metastasis is resectable, and systemic chemotherapy if not.  
The first-line chemotherapy regimens for the patients with unresectable, advanced/recurrent colorectal 
carcinoma necessitating powerful treatment that have been demonstrated to be useful in clinical 
studies and are currently covered by national health insurance in Japan are presented below. There is a 
consensus that cetuximab and panitumumab should be used only for KRAS wild-type (WT) colorectal 
cancer. 
(1) FOLFOX therapy or CapeOX therapy ± bevacizumab*1 
FOLFOX therapy: combination chemotherapy with fluorouracil (hereinafter referred to as 
5-FU), Isovorin (hereinafter referred to as l-LV), and oxaliplatin (hereinafter referred to as 
OXA) 
CapeOX therapy: combination chemotherapy with capecitabine and OXA 
(2) FOLFIRI therapy ± bevacizumab*1 
FOLFIRI therapy: combination chemotherapy with irinotecan (hereinafter referred to as IRI), 
5-FU, and l-LV 
(3) FOLFOX therapy ± cetuximab*1, 2 or panitumumab*1, 2 
(4) FOLFIRI therapy ± cetuximab*1, 2 or panitumumab*1, 2 
(5) FOLFOXIRI therapy  
FOLFOXIRI therapy: combination chemotherapy with OXA, IRI, 5-FU and l-LV 
(6) FL*3, CapeOX + bevacizumab*1 or UFT + LV 
UFT: combination preparation of tegafur and uracil 
*1: Combination with molecular-targeted drugs such as bevacizumab and epidermal 
growth factor receptor (EGFR) antibody is recommended, but if this cannot be 
indicated, chemotherapy alone will be provided. 
*2:  Indicated only for KRAS wild-type. 
*3: infusional 5-FU + l-LV 


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FOLFOX-based therapy is more frequently selected as first-line chemotherapy than FOLFIRI-based 
therapy, and bevacizumab is widely used for KRAS wild-type colorectal cancer as well. As a result, 
FOLFOX + bevacizumab combination therapy is the most common first-line treatment in Japan 
(in-house document).  
It is recommended that in principle, a regimen not used in first-line treatment should be used for 
second-line treatment. More specifically, IRI-based regimens are recommended as a second-line 
treatment of patients who have received an OXA-based regimen as a first-line treatment, while 
OXA-based regimens are recommended for patients who have received an IRI-based regimen. 
This principle also applies to molecular-targeted drugs concomitantly used for second-line treatment. 
For KRAS wild-type colorectal cancer, bevacizumab is recommended as a second-line treatment of 
patients who have received an anti-EGFR antibody as a first-line treatment, while switching to an 
anti-EGFR antibody or continued use of bevacizumab is an option as a second-line treatment of 
patients who have received bevacizumab as a first-line treatment. 
For third-line treatment, regorafenib or symptomatic therapy is currently recommended. 
4.1.3 
Efficacy and safety of mFOLFOX6 in patients with unresectable, advanced 
or recurrent colorectal cancer 
As therapy for unresectable, advanced/recurrent colorectal cancer, regimens mainly based on 
fluoropyrimidine anticancer agents are considered to be the standard for a long term3). Based on the 
evidence showing that 5-FU combined with l-LV is superior to 5-FU monotherapy, the combination 
therapy with 5-FU and l-LV (hereinafter referred to as 5-FU/LV therapy) had been considered as 
standard chemotherapy for colorectal cancer for a long time. The type I topoisomerase inhibitor IRI 
and the third generation of platinum-based anticancer drug OXA were then developed, and have been 
shown to improve treatment outcome in a number of large scale controlled trials4) to 9). At present, 
continuous infusion of 5-FU/LV in combination with OXA (FOLFOX therapy) or in combination with 
IRI (FOLFIRI therapy) is the standard chemotherapy regimen for advanced/recurrent colorectal 
cancer3), 10). FOLFOX and FOLFIRI therapies were compared in the GERCOR V308 study9,) in which 
the median final overall survival (hereinafter referred to as OS) was similar between the precedent 
FOLFIRI and the precedent FOLFOX arms (21.5 months vs. 20.6 months), and thereby both of the 
therapies are used as the standard for unresectable colorectal cancer. The development of these 
therapies provided improvement of the median survival time of unresectable advanced colorectal 
cancer from 12 months with 5-FU/LV therapy to 20 months or more with 5-FU/LV therapy in 
combination with IRI or OXA. 
Among several FOLFOX regimens, FOLFOX4 therapy and modified FOLFOX6 (hereinafter referred 
to as mFOLOFX6) therapy, which include OXA at the approved dosage (85 mg/m2) in Japan, are 
covered by national health insurance, and simpler and easier mFOLFOX6 therapy is more frequently 
used. 
4.1.4 
Efficacy and safety of panitumumab in patients with unresectable, advanced 
or recurrent colorectal cancer 
4.1.4.1 
Panitumumab 
EGFR, a member of the ErbB family of transmembrane receptor tyrosine kinases constantly 
expressed in epithelial-derived tissues, has been shown to be overexpressed in various types of 
solid tumors. Colorectal cancer is characterized by high EGFR expression, and the EGFR signaling 
pathway has been shown to play in the pathogenesis and progression of tumors. Binding of 
epidermal growth factor (EGF), the major ligand of EGFR, to EGFR is considered to induce 
auto-phosphorylation of EGFR and activation of various signaling pathways, resulting in induction 
of cellular proliferation, inhibition of apoptosis, and increased production of inflammatory 
cytokines and angiogenesis factors. Panitumumab is a human IgG2 monoclonal antibody that binds 


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to EGFR with specificity and high affinity, and inhibits the proliferation of tumor cells by 
competitively inhibiting the binding of the ligand to EGFR. 
4.1.4.2 
Clinical study results for panitumumab in the U.S. and Europe 
As a clinical trial of panitumumab monotherapy for colorectal cancer, a phase III study was 
conducted to compare best supportive care (hereinafter referred to as BSC) vs. BSC + 
panitumumab therapy in patients with unresectable, recurrent or advanced, EGFR-positive 
colorectal cancer that became resistant to fluoropyrimidine agents, OXA, and IRI (BSC arm, 232 
patients; BSC + panitumumab arm, 231 patients) 11). The primary endpoint of median progression 
free survival (hereinafter referred to as PFS) was 8 weeks and significantly longer in the BSC + 
panitumumab therapy, showing the efficacy of panitumumab therapy as compared with 7.3 weeks 
in the BSC alone arm (hazard ratio [HR], 0.54; two-sided 95% confidence interval [CI], 0.44 to 
0.66; p<0.0001). The secondary endpoint of OS was not significantly different between the two 
arms (HR, 1.00; two-sided 95% CI, 0.82 to 1.22; p = 0.81); however, this may be primarily due to 
the fact that 173 subjects (75%) in the BSC arm received follow-up therapy with panitumumab. 
With regard to combination of chemotherapy and panitumumab, a phase III clinical study (PRIME 
Study) has been reported, in which FOLFOX4 monotherapy vs. FOLFOX4 therapy + panitumumab 
(given at a dose of 6 mg/kg every 2 weeks) as a first-line treatment was compared in a total of 
1,180 patients (590 in each arm)12). The primary endpoint of median PFS in KRAS wild-type 
patients was 9.6 months and significantly longer in the FOLFOX4 + panitumumab arm as 
compared with 8.0 months in the FOLFOX4 alone arm (HR, 0.80; two-sided 95% CI, 0.66 to 0.97; 
p = 0.02). Of Grade 3/4 adverse events, panitumumab-related adverse events such as dermatologic 
toxicities, diarrhoea, and hypomagnesaemia occurred more frequently in the FOLFOX4 + 
panitumumab arm, but there were no major differences in the incidence of other adverse events 
between the two arms. Grade 3 infusion reaction occurred in 2 patients (Table 4.a). 
Table 4.a  Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study 
Adverse event 
FOLFOX4 + panitumumab 
(n = 322) 
FOLFOX4 alone 
(n = 327) 
n 
(%) 
N 
(%) 
Any adverse drug reaction 
270 
84 
227 
69 
Leukopenia 
136 
42 
134 
41 
Skin disorder 
116 
36 
7 
2 
Diarrhoea 
59 
18 
29 
9 
Nerve disorder 
52 
16 
51 
16 
Hypokalaemia 
32 
10 
15 
5 
Malaise 
30 
9 
10 
3 
Stomatitis 
28 
9 
2 
<1 
Hypomagnesaemia 
20 
8 
1 
<1 
Paronychia 
11 
3 
0 
0 
Pulmonary embolism 
9 
3 
5 
2 
Febrile neutropenia 
8 
2 
7 
2 
Infusion reaction 
2 
<1 
- 
- 
With regard to second-line treatment, a phase III clinical study (Study 20050181) has been 
conducted, in which FOLFIRI monotherapy vs. FOLFIRI therapy + panitumumab (given at a dose 
of 6 mg/kg every 2 weeks) was compared. 13) The primary endpoints were PFS and OS in KRAS 
wild-type patients. In KRAS wild-type patients, the median PFS was 5.9 months and significantly 
longer in the FOLFIRI + panitumumab arm than 3.9 months in the FOLFIRI alone arm (HR, 0.73; 
two-sided 95% CI, 0.59 to 0.90; p = 0.004). On the other hand, OS was 14.5 months in the 
FOLFIRI + panitumumab arm and 12.5 months in the FOLFIRI alone arm, with no statistically 
significant difference between the two arms (HR, 0.85; two-sided 95% CI, 0.70 to 1.04; p = 0.12). 
The response rate (hereinafter referred to as RR) was 35% and higher in the FOLFIRI + 


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panitumumab arm as compared with 10% in the FOLFIRI alone arm. Of Grade 3/4 adverse events, 
the incidence of dermatologic toxicities was higher and the incidences of diarrhoea and 
hypomagnesaemia tended to be higher in the FOLFIRI + panitumumab arm; however, there were 
no major differences in the incidence of toxicities including hematologic toxicities between the two 
arms, and the incidence of infusion reaction was not more than 1%. 
Both the PRIME Study12) and Study 2005018113) described above, in which KRAS mutation status 
was prospectively studied, showed that combination therapy containing panitumumab was not 
effective in KRAS-mutant patients, suggesting that KRAS mutation is predictive of poor response to 
anti-EGFR antibody therapy. 
4.1.4.3 
Clinical study results for panitumumab in Japan 
In a Japanese phase I clinical study of panitumumab, panitumumab was administered at the same 
dosing regimens with which the drug was confirmed to be safe and effective in overseas studies; 
i.e., a dose of 2.5 mg/kg once weekly, 6 mg/kg once every 2 weeks, and 9 mg/kg once every 3 
weeks. Each of these dosing regimens was evaluated in 6 patients. Again, in this study, 
panitumumab showed a good tolerability profile. 
In a Japanese phase II clinical study of panitumumab monotherapy14), 52 patients with previously 
treated, unresectable colorectal cancer were enrolled. In this study, the 6-mg/kg biweekly regimen 
of panitumumab, which was the recommended dosing regimen in the overseas phase III clinical 
study, was well tolerated, and the incidence of adverse events was similar to that observed in the 
U.S. and Europe (Table 4.b). In addition, 7 patients (13.5%) had partial response (hereinafter 
referred to as PR), and this Japanese study yielded an RR of 13.5% (two-sided 95% CI: 5.6 to 
25.8),a time to treatment failure of 11.4 weeks (two-sided 95% CI: 8.4 to 15.0), a median PFS of 
8.0 weeks (two-sided 95% CI: 7.4 to 11.4), and a median OS of 9.3 months (two-sided 95% CI: 7.1 
to 12.8), similar to those observed in clinical studies in the U.S and Europe. 
On the basis of the above results, panitumumab was approved in April 2010 for the treatment of 
incurable/unresectable, advanced/recurrent colorectal cancer in Japan as well. 
Table 4.b  Common adverse events (≥ 20%) noted in a Japanese phase II clinical study of 
Panitumumab monotherapy 
Adverse Events 
Panitumumab Monotherapy (n = 52) 
All 
≥ Grade 3 
n 
% 
N 
% 
Any adverse drug reaction  
51 
98 
6 
12 
Skin disorder 
51 
98 
3 
6 
Acne 
42 
81 
1 
2 
Dry skin 
32 
62 
0 
 
Skin rash 
24 
46 
1 
2 
Pruritus 
17 
33 
0 
 
Paronychia 
17 
33 
1 
2 
Hypomagnesaemia 
17 
33 
0 
 
Malaise 
13 
25 
0 
 
Stomatitis 
12 
23 
0 
 
Anorexia 
11 
21 
1 
2 
 
4.1.4.4 Result of the post-marketing Surveillance (overall survey) in Japan 
In a study conducted during a certain post-marketing period by enrolling all patients15), the median 
treatment duration (first day of administration to last day of administration) in 3,085 patients 
included in safety evaluation was 113 days (range: 1-559 days), and the incidence rate of adverse 


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drug reactions was 84.1% (≥Grade 3, 25.8%). The incidence rate in 1,254 patients in the group 
treated with panitumumab monotherapy was 80.1% (≥Grade 3, 19.7%) and that in 1,831 patients in 
the group treated with panitumumab + chemotherapy was 86.9% (≥Grade 3, 30.0%). The status of 
occurrence of adverse drug reactions of special interest is shown in Table 4.b.  
Table 4.b  Adverse Drug Reactions (ADRs) of special interest on Post-marketing survey in Japan 
Overall incidence of 
Post-marketing survey 
Panitumumab Monotherapy 
(n=1,254) 
Combination therapy (n=1,831) 
All 
≥ Grade 3 
All 
≥ Grade 3 
ADRs of special interest 
n 
% 
n 
% 
n 
% 
N 
% 
Skin and subcutaneous 
tissue disorders (SOC) 
918 
73.2 
118 
9.4 
1446 
79.0 
274 
15.0 
Paronychia 
272 
21.7 
33 
2.6 
459 
25.1 
99 
5.4 
Interstitial lung disease* 
16 
1.3 
- 
- 
23 
1.3 
- 
- 
Infusion reaction 
17 
1.4 
1 
0.1 
30 
1.6 
5 
0.3 
Hypomagnesemia 
257 
20.5 
61 
4.9 
263 
14.4 
62 
3.4 
Hypocalcemia 
59 
4.7 
16 
1.3 
77 
4.2 
26 
1.4 
Cardiac disorders（SOC) 
2 
0.2 
0 
0.0 
5 
0.3 
1 
0.1 
*：Based on the evaluation of the ILD 
 
4.1.5 
Adverse reactions to OXA 
Major dose-limiting toxicities of OXA are neurological manifestations, which are peripheral sensory 
nerve disorders characterized by dysaesthesia or paraesthesia in four limbs. They may accompany 
convulsion and are induced by exposure to coldness. Hochster et al.16) reported that these symptoms 
appeared in 85% to 95% of the patients who received FOLFOX therapy in combination with 
bevacizumab, that the duration became longer as the administration cycles increased, and that the 
incidence of functional disorders after administration of a cumulative dose of 800 mg/m2 was 
approximately 15%. In many cases, these neurological manifestations remit or disappear after 
discontinuation of administration. Acute sensory neurological manifestations appear within several 
hours after administration, and are induced by exposure to coldness. They may appear as transient 
paraesthesia, dysaesthesia, hypoaesthesia or acute laryngopharyngeal dysaesthesia syndrome. 
In addition to nerve disorders, acute laryngopharyngeal dysaesthesia syndrome is estimated to occur 
with an incidence of 1% to 2%. It is characterized by respiratory disorders without cyanosis and 
hypoxia, sensation of dyspnoea without direct effects on the respiratory functions such as dysphagia, 
decreased SaO2, laryngospasm, and bronchospasm without wheezing in the upper and lower 
respiratory tracts. Convulsion in the jaw, abnormal feeling in the tongue, dysarthria, eye pain, and 
chest pressure sensation are also observed17). These symptoms improve reversely without treatment. 
The incidence of acute laryngopharyngeal dysaesthesia syndrome is suggested to decrease as the 
duration of administration becomes longer. 
Among these adverse reactions, nerve disorders in particular make continuous administration of OXA 
difficult, and may lead to modification of the FOLFOX therapy regimen involving molecular-targeted 
drugs. For the patients responding to the therapy, they may miss the patients of important 
opportunities of treatment (internal data). 
 


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4.1.6 
Examination of the method of administration of OXA in first-line therapy 
Reduction of neurological manifestations associated with FOLFOX as standard chemotherapy for 
unresectable, advanced/ recurrent colorectal carcinoma is urgently needed for improvement of the 
QOL of patients and for realization of long-term treatment. According to the reports of Tournigand et 
al18)., OPTIMOX1 (Stop and Go method) is able to achieve recovery from neurological manifestations 
during the period of sLV5FU2 therapy without OXA after FOLFOX. Moreover, it may be possible to 
reduce hematological toxicity and non-hematological toxicity during this period. Concerning the 
treatment effect, the response rate was 59.2% and MST was 21.2 months. Furthermore, the final report 
of OPTIMOX2 by F Maindrault-Goebel et al.19) showed that the OS in the administration schedule of 
OPTIMOX1 (Stop and Go method) was 26 months. 
 
4.2 
Rationale for the proposed study 
In Japan, mFOLFOX6 therapy is conducted most frequently as the first-line therapy for unresectable, 
advanced/ recurrent colorectal carcinoma. Peripheral nerve disorders induced by OXA contained in 
mFOLFOX6 therapy may cause a clinical problem because they become a cause of deterioration of the 
patients' QOL, thereby making continuous treatment impossible. When peripheral nerve disorders as 
mentioned above have occurred, mFOLFOX6 therapy as the baseline therapy is switched to FOLFIRI 
therapy in some cases in spite of favorable responses to the first-line therapy, instead of discontinuing 
OXA which is the cause of peripheral nerve disorders. This is deemed to lead to a loss of the opportunity 
of treatment for the patients. Moreover, it is possible that long-term administration of OXA induces 
peripheral nerve disorders. For patients who discontinue administration of OXA after having received 
the drug for a certain period and who have experienced no peripheral nerve disorders during the 
treatment period, re-introduction of OXA in the later stage of treatment may remain as a treatment option. 
With regard to the discontinuaiton and resumption of OXA administration in FOLFOX therapy as the 
first line therapy at present, the evaluation for efficacy and safety of OPTIMOX study18) have been 
presented. However, appropriate administration method of OXA in first-line therapy with mFOLFOX6 + 
panitumumab has not been revealed. 
For these reasons, this study was planned on the basis of the judgment that efficacy and safety in the 
group in which OXA is discontinued after 6 cycles of the treatment and the group in which OXA is 
continued need to be examined in the patients responding to mFOLFOX6 + panitumumab combination 
therapy. 


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5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY 
5.1 
Objective 
To exploratorily examine efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type who have been treated with 6 cycles of 
first-line mFOLFOX6 + panitumumab combination therapy and then assigned to two groups, i.e., a 
group receiving 5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + 
panitumumab combination therapy. 
 
5.2 
Endpoints 
See Section 13.1.3 for Efficacy analysis. 
5.2.1 
Primary endpoint 
• 
Efficacy 
 
Progression-free survival (PFS) 
 
5.2.2 
Secondary endpoints 
• 
Efficacy 
 
Overall survival (OS) 
 
Response rate (RR) 
 
Time to treatment failure (TTF) 
• 
Safety 
 
Incidence rate of adverse events, and severity by incidence rate 
 
Incidence rate of peripheral nerve disorders 
 
Incidence rate of skin disorders 
 
5.2.3 
 Additional endpoint 
• 
Percentage of maintenance of Performance Status (PS) 
• 
Percentage of continuation of OXA in mFOLFOX6 + panitumumab group (Group A) 
• 
Percentage of continuation of panitumumab in both groups 
 


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5.3 
Rationale for the endpoints 
5.3.1 
Primary endpoint 
The PFS was selected as the best indicator for evaluation of efficacy of the regimen with and without 
OXA after 6 cycles of mFOLFOX6 + panitumumab combination therapy without being affected by 
the after-treatment. 
 
5.3.2 
Secondary endpoints 
The OS was selected as the secondary endpoint because it is the true endpoint. As a help for 
interpretation of primary efficacy results, RR and TTF were selected as secondary endpoints. 
Concerning safety, the appropriateness of continuing and discontinuing OXA and panitumumab was 
evaluated in an exploratory manner. The incidence rate of adverse events, the incidences of peripheral 
nerve disorders and skin disorders were selected as secondary endpoints because they are important 
factors for the choice of treatment. 
 


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6.0 
STUDY DESIGN 
6.1 
Study design 
This is a phase II, multi-center joint, open-label, parallel-group randomized controlled study to 
exploratorily examine the efficacy and safety in the patients with chemotherapy-naïve unresectable, 
advanced/recurrent colorectal carcinoma of KRAS wild-type after treating them with 6 cycles of 
mFOLFOX6 + panitumumab combination therapy and subsequently assigning them to a group 
continuing mFOLFOX6 + panitumumab combination therapy (Group A) and a group in which OXA is 
discontinued and 5-FU/LV + panitumumab combination therapy is provided (Group B). 
Patients who are judged eligible for the study based on the inclusion criteria at the time of enrollment 
will be registered within 14 days before the first administration (1st cycle), and will be treated with 6 
cycles of mFOLFOX6 + panitumumab combination therapy (Protocol Treatment [1]). The patients for 
whom continuation of mFOLFOX6 + panitumumab combination therapy is judged appropriate on the 
basis of the examination before administration of the 7th cycle and imaging test after administration of 
the 6th cycle, who satisfy the inclusion criteria for randomization, and who do not fall under any of the 
exclusion criteria for randomization will be randomly assigned to either the mFOLFOX6 + panitumumab 
combination group (Group A) or the 5-FU/LV + panitumumab combination group (Group B) at the ratio 
of 1:1 before administration of the 7th cycle (TBD). After randomization, treatment in Group A or Group 
B will be continued according to the administration standards for Protocol Treatment [2] until the "8.8. 
Criteria for discontinuation of protocol treatment" are met. The reasons for the failure to meet the subject 
inclusion criteria at the time of randomization will be collected. The patients who fall under the criteria 
for extension of administration on the examination before administration of the 7th cycle will be 
examined again after an appropriate interval. The patients who satisfy the subject inclusion criteria on 
the re-examination will be randomized, and will receive the protocol treatment of the assigned group. 
Both inpatients and outpatients are eligible. Refer to "8.2 Treatment regimen" for details about the 
protocol treatment ([1] and [2]). 
See "13.3 Determination of the planned number of subjects" for the number of subjects. 
 
 
Figure 6.a  Outline of study design 
 


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6.2 
Rationale for study design, dose and endpoints 
6.2.1 
Study population 
The timing at which OXA-induced peripheral nerve disorders occurs most frequently has been 
reported to be the time point at which the accumulated amount of OXA administered reaches 780-850 
mg/m2 20). This amount is equivalent to 9 or 10 doses when converted using the dose of 85 mg/m2 of 
OXA administered at a time in Protocol Treatment [1] and [2]. According to the report by Hochster et 
al16). who investigated the mean number of doses administered continuously in FOLFOX therapy in 
initial therapy in routine medical care, the number was 10 times in the FOLFOX + bevacizumab 
combination therapy in first-line therapy (TREE2). In the report by Giantonio et al.21), the mean 
number of doses administered continuously in FOLFOX±bevacizumab combination therapy in the 
second-line therapy (ECOG3200) for the patients with a history of chemotherapy was 7 to 10 times. 
This study aims at comparing efficacy and safety in the group continuing OXA from the 7th cycle and 
the group discontinuing OXA in the patients receiving first-line mFOLFOX6 + panitumumab 
combination therapy before the occurrence of peripheral nerve disorders. Since the above-described 
status of the frequency of OXA administration also seems to suggest that discontinuation of OXA after 
6th administration in Protocol Treatment [1] does not greatly deviate from the situation in routine 
medical care, the number of cycles of OXA administration given before randomization was set at 6. 
Moreover, since no significant differences were seen in the duration of disease control and PFS in 
OPTIMOX study, the duration of treatment is not expected to differ significantly even when OXA is 
discontinued after 6 cycles of mFOLFOX6 + panitumumab therapy while 5-FU/LV + panitumumab 
combination therapy is continued. Furthermore, although concomitant administration of panitumumab 
does not cause differences in time to treatment failure and PFS, discontinuation of OXA before the 
occurrence of peripheral nerve disorders enables re-introduction of OXA. Therefore, differences larger 
than in OPTIMOX study may be expected for OS. In addition, it may become possible to propose, for 
combination therapy of mFOLFOX6 and panitumumab, an approach which enables long-term 
continuation of treatment through prevention of the occurrence of OXA-induced peripheral nerve 
disorders. 
 
6.2.2 
Treatment regimens and planned number of subjects 
See "13.3 Determination of the planned number of subjects" for details. 
 
6.3 
Discontinuation of entire study or discontinuation at a study site 
6.3.1 
Criteria for discontinuation of entire study 
The sponsor should immediately discontinue the study when it is notified by the data monitoring 
committee and/or the steering committee that at least one of the following criteria is applicable. 
• 
Occurrence of serious event/violation which endangers safety of subjects. 
• 
When new information or other evaluation on the safety or efficacy of protocol treatment 
becomes available which shows a change in the known risk/benefit profile of the concerned 
compound, and risks/benefits are no longer tolerable for subject participation in the study. 


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6.3.2 
Procedures of study suspension and discontinuation of entire study or study 
at a study site 
When the sponsor or the IRB such as the ethics review committee determines suspension or 
discontinuation of the entire study or the study at a certain study site, the sponsor will instruct the 
procedures specified for the relevant study. The relevant study site should observe the procedures for 
study suspension or discontinuation. 
 
6.4 
Procedures for revision of the protocol 
When a need arises to revise the protocol, the sponsor will consult with the representative researcher to 
make a decision. 
Details of the protocol revision will be notified to investigators of all study sites. 
When the investigator of each study site receives the notification, he should arrange the revised protocol 
to be reviewed by the IRB such as the ethics review committee again as necessary according to the 
stipulation at each study site and obtain approval of the director of study site. 


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7.0 
SELECTION OF STUDY SUBJECTS 
7.1 
Inclusion criteria 
7.1.1 
Inclusion criteria for enrollment 
Patients who satisfy all the criteria below will be enrolled in this study. 
(1) Patients with unresectable adenocarcinoma originating in the large intestine (excluding 
carcinoma of the appendix and anal canal cancer) 
(2) Patients with measurable lesion(s) according to the RECIST ver. 1.1 
(3) Patients who have not received chemotherapy for colorectal cancer. Patients who experience 
relapse more than 6 months after the final dose of perioperative adjuvant chemotherapy with 
fluoropyrimidine agents may be enrolled. 
(4) Aged ≥20 years at the time of informed consent 
(5) Patients classified as KRAS wild-type*. However, the criteria will be changed to all patients who 
are verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be 
covered by National Health Insurance, and the tests become feasible at medical institutions. 
*: Patients with no mutation in any of the codons shown below are considered wild type. 
KRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
NRAS** 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
**: To be considered when the test comes to be covered by insurance and becomes 
feasible at medical institutions. 
(6) Patients who satisfy the following criteria for the major organ function in tests performed within 
14 days prior to enrollment  
1) 
Neutrophil count ≥ 1,500/mm3 
2) 
White blood cell count ≥ 3,000/mm3 
3) 
Platelet count ≥ 10.0 × 104/mm3 
4) 
Hemoglobin ≥ 9.0 g/dL 
5) 
Total bilirubin ≤ 2.0 mg/dL 
6) 
AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
7) 
ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) 
8) 
Serum creatinine ≤ 1.5 mg/dL 
(7) ECOG performance status (PS) of 0 or 1 
(8) Life expectancy of ≥ 6 months after enrollment 
(9) Patients who have given written consent to take part in the study after detailed explanation of the 
study prior to enrollment 
 
7.1.2 
Inclusion criteria for randomization 
Patients who satisfy all the criteria below will be randomized. If possible, randomization will be 
conducted immediately before administration of the 7th cycle. 


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(1) Patients who have received 6 cycles＊ (Protocol Treatment [1]) of mFOLFOX6 + panitumumab 
combination therapy 
＊:  Defined as administration of 5-FU/LV and OXA according to the designated dosage 
regimen for Protocol Treatment [1] without discontinuation in all cycles (6 cycles) of 
Protocol Treatment [1]. However, bolus 5-FU is an exception. 
(2) Patients who are deemed to be able to receive 5-FU/LV, OXA and panitumumab during the 
period of Protocol Treatment [2] on the examination before administration of the 7th cycle.  
(3) ECOG performance status (PS) of 0-1 before administration of the 7th cycle. 
(4) Patients for whom PD or not evaluable has been denied on the Response Evaluation Criteria in 
Solid Tumors (RECIST) based on imaging tests conducted after administration of 6 cycles. 
 
7.2 
Exclusion criteria 
7.2.1 
Exclusion criteria for enrollment 
A subject who meets any of the criteria below will not be included in this study. 
(1) Radiotherapy received within 4 weeks prior to enrollment 
(2) Known brain metastasis or strongly suspected of brain metastasis 
(3) Synchronous cancers or metachronous cancers with a disease-free period of ≤ 5 years (excluding 
colorectal cancer) excluding mucosal cancers cured or be possibly cured by regional resection 
(esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.). 
(4) Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) 
(5) Patients who do not want to use contraception to prevent pregnancy, and women who are 
pregnant or breast-feeding, or test positive for pregnancy 
(6) Active hemorrhage requiring blood transfusion 
(7) Disease requiring systemic steroids for treatment (excluding topical steroids) 
(8) Intestinal resection and colostomy within 2 weeks prior to enrollment 
(9) History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial 
pneumonia, pulmonary fibrosis, etc.) 
(10) Serious drug hypersensitivity 
(11) Local or systemic active infection requiring treatment, or fever indicating infection 
(12) Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating 
symptoms despite adequate treatment) 
(13) Active hepatitis B and/or C 
(14) Known HIV infection 
(15) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the 
study 
 
7.2.2 
Exclusion criteria for randomization 
Patients who meet any of the criteria below will not be randomized. 
(1) Patients in whom interstitial pneumonia has been newly diagnosed during the period from 
registration to randomization 
(2) Patients who have received radiotherapy during the period from registration to randomization 
(3) Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the 
study 


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8.0 
TREATMENT 
The protocol treatment, contraindicated drugs/therapies, and recommended supportive care/combination 
therapies in this study are explained in this section. Commercially available drugs used at the study sites 
will be used in this study. See the latest package insert for details and handling of each drug. 
8.1 
Protocol treatment 
The study period in this study is defined as the period consisting of Protocol Treatment [1] and Protocol 
Treatment [2]. 
8.1.1 
Protocol Treatment [1] 
OXA and infusional 5-FU will be administered in all of the 6 cycles. The dose can be reduced. 
Panitumumab will also be administered in all the possible 6 cycles but suspension due to the 
occurrence of skin disorders will be allowed. 
 
8.1.2 
Protocol Treatment [2] 
Even if each drug of the criteria specified in "8.5 Criteria for dose change." is met, treatment with the 
other drugs will be continued unless any of the criteria specified in "8.8 Criteria for discontinuation of 
protocol treatment" is met. 
 
8.2 
Treatment regimen 
8.2.1 
Protocol Treatment [1] 
During the period of Protocol Treatment [1], mFOLFOX6 + panitumumab combination therapy will 
be given once in two weeks according to the following treatment regimen until any of the criteria 
specified in "8.8 Criteria for discontinuation of protocol treatment" is met (one administration will be 
regarded as one cycle). For administration of each drug, see "8.4 Criteria for initiation of protocol 
treatment (common for Protocol Treatment [1] and [2])" and "8.5 Criteria for dose change". 
For the patients aged 80 years or older at the time of enrollment, the drug can be administered at a 
dose one level lower than the designated dose from Cycle 1. 
Table 8.a  Treatment regimen of mFOLFOX6 + panitumumab combination therapy 
Drug 
Dose 
Method of 
administration 
(recommended) 
Date of administration 
Panitumumab 
6 mg/kg 
div 60 min* 
Day 1 
OXA 
85 mg/m2 
div 120 min 
Day 1 
l-LV 
200 mg/m2 
div 120 min 
Day 1 
5-FU (iv) 
400 mg/m2 
iv  <15 min 
Day 1 
5-FU (civ) 
2400 mg/m2 
civ 46 hrs 
Day 1-2 
div: intravenous drip infusion, iv: intravenous infusion, civ: continuous intravenous infusion 
*:  When the dose at one time exceeds 1000 mg, intravenously administer it over 90 min or longer after dilution with 
JP physiological saline to make approximately 150 mL. 
 


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Figure 8.a  mFOLFOX6 + panitumumab combination therapy 
 
8.2.2 
Protocol Treatment [2] 
If the dose of the drug has been reduced during the period of Protocol Treatment [1], the drug will be 
administered at the reduced dose from Cycle 7.  
 
8.2.2.1 
mFOLFOX6 + panitumumab combination therapy (Group A) 
See Section 8.2.1 for Protocol Treatment [1]. The term of Protocol Treatment [1] is regarded as 
Protocol Treatment [2]. 
8.2.2.2 
5-FU/LV + panitumumab combination therapy (Group B) 
During the period of Protocol Treatment [2], 5-FU/LV + panitumumab combination therapy will be 
given once in two weeks according to the following treatment regimen until any of the criteria 
specified in "8.8 Criteria for discontinuation of protocol treatment" is met (one administration will 
be regarded as one cycle). For administration of each drug, see "8.4 Criteria for initiation of 
protocol treatment (common for Protocol Treatment [1] and [2])" and "8.5 Criteria for dose 
change". 
Table 8.b  Treatment regimen of 5-FU/LV + panitumumab combination therapy 
Drug 
Dose 
Method of 
administration 
(recommended) 
Date of administration 
Panitumumab 
6 mg/kg 
div 60 min* 
Day 1 
l-LV 
200 mg/m2 
div 120 min 
Day 1 
5-FU (iv) 
400 mg/m2 
iv < 15 min 
Day 1 
5-FU (civ) 
2400 mg/m2 
civ 46 hrs 
Day 1-2 
div: intravenous drip infusion, iv: intravenous infusion, civ: continuous intravenous infusion 
*:  When the dose at one time exceeds 1000 mg, intravenously administer it over 90 min or longer after dilution with 
JP physiological saline to make approximately 150 mL. 
 




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Table 8.c  Criteria for initiation of treatment cycle 
Item 
Criteria for initiation 
White blood cell count 
≥ 2,500/mm3 
Neutrophil count 
≥ 1,500/mm3 
Platelet count 
≥ 7.5 x 104/mm3 
Total bilirubin 
≤ 2.0 mg/dL 
Infection 
Absence of fever (≥ 38°C) indicating infection 
Nausea, vomiting, diarrhoea, stomatitis 
≤ Grade 1 
Initiation of treatment may be postponed at the discretion of the investigator due to adverse 
events not listed above.  
 
8.5 
Criteria for dose change 
8.5.1 
Protocol Treatment [1] 
8.5.1.1 
Criteria for dose reduction/suspension of mFOLFOX6 
The criteria for dose reduction and the doses of OXA and 5-FU (bolus/infusional) during the period 
of Protocol Treatment [1] are shown in Table 8.d and Table 8.e, respectively. The dose of l-LV 
should not be changed. 
Table 8.d  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [1]) 
Adverse events in previous cycle 
Grade 
Dose adjustment of OXA and 5-FU 
Neutropenia, thrombopenia 
4 
Dose reduction of both OXA and 5-FU 
(bolus/infusional) by 1 level 
Grade 3 neutropenia or thrombopenia that 
persists for more than 7 days 
3 
Febrile neutropenia, infection, nausea, 
vomiting, diarrhoea, fatigue 
3 
Sensory nerve disorder* 
3 
Discontinuation of protocol treatment* 
2 
Discontinuation of protocol treatment* 
Or dose reduction of OXA by 1 level 
Allergic reaction 
3 
Discontinuation of protocol treatment* 
2 
Careful administration of OXA by 
slowing the infusion speed 
Dose reduction is allowed as necessary at the discretion of the investigator due to adverse events 
not listed above. However, protocol treatment will be discontinued at the time point of suspension 
of OXA and infusional 5-FU. 
*: See "8.8 Criteria for discontinuation of protocol treatment" for details. 
 


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Table 8.e  Doses of OXA and 5-FU (Protocol Treatment [1]) 
Dose reduction 
level 
OXA 
5-FU iv 
5-FU civ 
Initial dose 
85 mg/m2 
400 mg/m2 
2400 mg/m2 
-1 
65 mg/m2 
200 mg/m2 
2000 mg/m2 
-2 
50 mg/m2 
0 mg/m2 
(discontinuation) 
1600 mg/m2 
-3 
Discontinuation of 
protocol treatment* 
0 mg/m2 
(discontinuation) 
Discontinuation of 
protocol treatment* 
iv: intravenous infusion, civ: continuous intravenous infusion 
*: See "8.8 Criteria for discontinuation of protocol treatment" for details. 
 
8.5.1.2 
Criteria for dose reduction/suspension of panitumumab 
The criteria for dose reduction and the dose of panitumumab during the period of Protocol 
Treatment are shown in Table 8.f and Table 8.g, respectively. 
Table 8.f  Criteria for dose reduction of panitumumab 
Item 
Grade 
Dose adjustment of panitumumab 
Skin disorder 
3 
Dose reduction by 1 level with dose postponement 
(suspension). 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
less within 6 weeks. 
2 
Dose postponement (suspension) is allowed. (Suspension 
is not essential.) 
If the symptom has become milder than the Grade as of 
the time of onset after the suspension, the drug will be 
administered at the dose before suspension. 
1 
Hypomagnesaemia* 
3 
Dose reduction by 1 level 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
less within 6 weeks. 
Infusion reaction** 
3 
Discontinuation of protocol treatment 
2 
Careful administration by slowing the infusion speed*** 
1 
Careful administration by slowing the infusion speed*** 
Dose reduction/suspension is allowed as necessary at the discretion of the investigator due to 
adverse events not listed above.  
*: 
When accompanied by abnormal ECG findings requiring treatment such as significant QTc 
prolongation, discontinuation or suspension of panitumumab should be considered irrespective of 
the severity of hypomagnesaemia. 
**: 
Allergic reaction, anaphylactoid reaction, and chills, fever, and dyspnea occurring within 24 hours 
after the initial dose 
***: 
In the event that Grade 1 or 2 infusion reaction occurs during infusion, the infusion speed should be 
decreased by 50%. 
 


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Table 8.g  Dose of panitumumab 
Dose reduction level 
Panitumumab 
Initial dose 
6 mg/kg 
-1 
4.8 mg/kg 
-2 
3.6 mg/kg 
-3 
0 mg/kg (discontinuation) 
 
8.5.2 
Protocol Treatment [2] 
8.5.2.1 
Criteria for dose reduction/suspension of mFOLFOX6 
The criteria for dose reduction of OXA and 5-FU (bolus/infusional) during the period of Protocol 
Treatment [2] is shown in Table 8.h. Refer to Table 8.i for the doses of OXA and 5-FU 
(bolus/infusional), respectively. 
Table 8.h  Criteria for dose reduction of OXA and 5-FU (Protocol Treatment [2]) 
Adverse events in previous cycle 
Grade 
Dose adjustment of OXA and 5-FU 
Neutropenia, thrombopenia 
4 
Dose reduction of both OXA and 5-FU 
(bolus/infusional) by 1 level 
Grade 3 neutropenia or thrombopenia that 
persists for more than 7 days 
3 
Febrile neutropenia, infection, nausea, 
vomiting, diarrhoea, fatigue 
3 
Sensory nerve disorder* 
3 
Discontinuation of OXA** (no 
resumption) 
2 
Discontinuation** of OXA (no 
resumption) 
Or dose reduction of OXA by 1 level 
Allergic reaction 
3 
Discontinuation of OXA** (no 
resumption) 
2 
Careful administration of OXA by 
slowing the infusion speed 
Dose reduction/suspension is allowed as necessary at the discretion of the investigator due to 
adverse events not listed above. 
*: 
OXA may be resumed when nerve disorder has improved after suspension. 
**: Continue the Protocol Treatment until "8.8 Criteria for discontinuation of protocol treatment" is met. 
 
Table 8.i  Doses of OXA and 5-FU (Protocol Treatment [2]) 
Dose reduction 
level 
OXA 
5-FU iv 
5-FU civ 
Initial dose 
85 mg/m2 
400 mg/m2 
2400 mg/m2 
-1 
65 mg/m2 
200 mg/m2 
2000 mg/m2 
-2 
50 mg/m2 
0 mg/m2 
(discontinuation) 
1600 mg/m2 
-3 
0 mg/m2 
(discontinuation) 
0 mg/m2 
(discontinuation) 
0 mg/m2 
(discontinuation) 
iv: intravenous infusion, civ: continuous intravenous infusion 
 


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8.5.2.2 
Criteria for dose reduction/suspension of panitumumab 
Refer to "8.5.1.2 Criteria for dose reduction/suspension of panitumumab". 
 
8.6 
Criteria for dose increase of protocol treatment 
The dose should not be increased after dose reduction for any of the drugs. 
 
8.7 
Overdose of panitumumab 
Overdose of panitumumab is defined as below regardless of whether or not adverse events have 
occurred. 
① Administration at doses higher than the approved dose of panitumumab (6 mg/kg) 
② The next dose is administered within 10 days after the date of previous administration. 
Aiming at consistent entry of significant safety information regarding overdose in the database, the 
investigator or subinvestigator will record all cases of overdose (irrespective of the presence or absence 
of adverse events) in the page of overdose of the Case Report Forms. Adverse events associated with 
overdose will be recorded in the page of "Adverse Events" in the Case Report Forms according to "10.0 
ADVERSE EVENTS". 
Serious adverse events (SAE) associated with overdose will be reported according to the procedure 
described in "10.2.2. Collection and reporting of serious adverse events." 
In the cases of overdose of panitumumab, the investigator or subinvestigator will provide treatment 
appropriate for the symptoms. 
 
8.8 
Criteria for discontinuation of protocol treatment 
The protocol treatment specified below should be discontinued when any of the criteria for 
discontinuation of protocol treatment listed below is met. The date of discontinuation of protocol 
treatment is defined as the date when the investigator decides on discontinuation of protocol treatment. 
The investigator should record the main reason for discontinuation of protocol treatment in the case 
report form according to the classification described below. See "9.3 Records of subjects who 
discontinued before enrollment"for subjects withdrawn from the study before enrollment. 
<Common for Protocol Treatment [1] and [2]> 
1. 
Adverse event 
When protocol treatment is postponed for 43 days or more after the day of starting the last cycle, or 
when the next protocol treatment cannot be resumed because of adverse events even after the 
passage of at least 43 days after the start of the last cycle of the protocol treatment. However, 
postponement due to holidays is allowed. 
2. 
Significant deviation from the protocol 
When study continuation may cause intolerable risk to the health of a subject because the subject 
was found not to satisfy the inclusion criteria specified in the protocol after enrollment or 
randomization of protocol treatment has not been observed. 
3. 
Lost to follow-up 
When a subject fail to make visits and cannot be contacted. That attempts were made to contact the 
subject should be recorded in the source documents. 


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4. 
Voluntary discontinuation 
When a subject wishes to discontinue study participation. 
5. 
Discontinuation of entire study 
When study discontinuation is decided by the sponsor, or IRB such as the ethics review committee. 
6. 
Pregnancy 
When a female subject is found out to be pregnant. 
Note: Study participation should be immediately discontinued when pregnancy is known. 
7. 
Lack of efficacy 
When PD is evident in the clinical or imaging evaluation 
8. 
Death during protocol treatment 
Death before discontinuation of protocol treatment is decided 
9. 
When surgery aimed at curative resection (complete resection: R0 resection) of colorectal cancer is 
scheduled 
10. Other 
When protocol treatment cannot be started after subject allocation, collect the reason (e.g., the 
criteria for initiation of protocol treatment were not met 
<Protocol Treatment [1] > 
11. Not satisfying at least one of the inclusion criteria for randomization or meeting any of the 
exclusion criteria <specify the applicable inclusion/exclusion criteria> 
 
8.9 
Contraindicated drugs/therapies 
The drugs and therapies shown below are contraindicated from informed consent until 28 days (4 weeks) 
after discontinuation of protocol treatment. The investigator and/or subinvestigator (hereinafter referred 
to as the investigator) should instruct the patients not to use any drugs including over-the counter drugs 
other than the prescribed drugs without prior consultation. The following therapies are allowed to be 
started without waiting for the specified period only when the scheduled tests are performed until the 
next treatment upon starting it within 28 days (4weeks) after discontinuation of protocol treatment. 
 
Chemotherapy other than protocol treatment 
 
Hormone therapy 
 
Immunotherapy  
 Cellular immunotherapy 
 Vaccine therapy 
 Cytokine therapy 
 Biological response modifiers (BRM) 
 Antibody therapy 
 Gene therapy 
 
Other antibody therapy 
 
Radiotherapy  
 
Hyperthermia therapy 
 
Denosumab* 
*: Use of bisphosphonates is allowed. 


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 
Study drug and unapproved drug 
 
8.10 
Allowed supportive care and combination medications 
The supportive care and concomitant medications shown below are recommended during the study 
period (from informed consent until discontinuation of protocol treatment). The absence of concomitant 
or supporting therapy does not constitute a protocol deviation. 
• 
Neutropenia 
Administration of G-CSF products is recommended. G-CSF should be administered according to 
the NHI indications and should not be prophylactically used. 
• 
Nausea, vomiting 
Premedication including prophylactic administration of antiemetics is allowed. Premedication 
with 5-HT3 (serotonin) receptor antagonists, NK1 (neurokinin 1) receptor antagonists, steroids, 
and antihistamines may be carried out using the method employed at each study site. 
• 
Allergic reaction 
Treatment with adrenal corticosteroids, antihistamines, etc. may be considered at the time of 
onset or for premedication at the start of protocol treatment. Careful administration of 
panitumumab by slowing the infusion speed may be considered. 
• 
Interstitial pneumonia 
Interstitial pneumonia should be treated according to the severity (e.g., steroid pulse therapy).  
• 
Other 
Drugs for treatment of adverse events may be coadministered at the discretion of the investigator. 
Symptomatic therapies which have been continued from before the start of this study are allowed. 
In addition, it is recommended that the supportive care shown below be performed at the discretion of 
the investigator when any of panitumumab-related adverse events shown below is observed. The absence 
of supporting therapy does not constitute a protocol deviation. 
• 
It is recommended that oral minocycline, etc. be administered when skin disorder is observed. 
• 
At the time of onset of skin disorder 
External salicylic acid petrolatum (10%) 
External steroid therapy (example) 
Face: hydrocortisone butyrate (0.1%) 
Trunk: difluprednate (0.05%) 
It is recommended the following skin care prophylactically against the skin disorder from the 
start of protocol treatment [1]. 
Moisturizer (example): heparin analog lotion 
Sunscreen (example): not containing 4-aminobenzoic acid, SPF (Sun Protection Factor) ≥30, PA 
(Protection grade of UVA) ≥ ++. Apply before going out to block ultraviolet rays (UVA and 
UVB). 
• 
At the time of onset of electrolyte abnormality (e.g., hypomagnesaemia, hypocalcaemia) 
ECG: ECG may be performed to determine whether there are abnormal ECG findings requiring 
treatment such as significant QTc prolongation. When any abnormal ECG findings requiring 
treatment are observed, suspension of panitumumab should be considered irrespective of the 
serum magnesium concentration. 
Magnesium supplementation (example): intravenous infusion of magnesium sulfate(10 mmol) 
over 60 min 
 


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8.11 
Handling of surgery aimed at curative resection (complete resection: R0 
resection) of colorectal cancer 
Surgery is recommended for patients who can tolerate curative resection (complete resection: R0 
resection) thanks to the antitumor effect after initiation of protocol treatment. 
Protocol treatment should be discontinued when surgery aimed at curative resection (complete resection: 
R0 resection) of colorectal cancer is scheduled, and all tests and observation scheduled at discontinuation 
of protocol treatment should be conducted (see “9.1 Study calendar”). 
 
8.12 
Recommended follow-up therapy 
8.12.1 Recommended second-line treatment 
• 
Group A: Administration of bevacizumab in combination with IRI-based chemotherapy is 
recommended. 
• 
Group B: Readministration of bevacizumab in combination with OXA-based chemotherapy is 
recommended. 
 
8.12.2 Recommended third-line or subsequent treatment 
• 
Group A: All approved drugs (regorafenib, etc.) should be administered appropriately as best as 
possible. 
• 
Group B: Administration of bevacizumab in combination with the IRI-based chemotherapy is 
recommended. After that, all approved drugs (regorafenib, etc.) should be administered 
appropriately as best as possible. 
 


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9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR 
OBSERVATIONS 
9.1 
Study calendar 
The investigator should collect data according to the following procedures. The same investigator should 
perform tests/observation/evaluation of subjects in principle. 
Table 9.a  Study calendar (Protocol Treatment [1]) 
Item 
Enrollment Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Discontinuation of 
protocol treatment*9 
Informed consent 
●* 
 
 
 
 
 
 
 
Eligibility 
● 
 
 
 
 
 
 
 
Subject background 
● 
 
 
 
 
 
 
 
Clinical findings (physical 
examination) 
● 
● 
●*1 
●*1 
●*1 
●*1 
●*1 
● 
Vital signs 
● 
● 
●*1 
●*1 
●*1 
●*1 
●*1 
● 
Height, body weight 
● 
 
○*2 
○*2 
○*2 
○*2 
○*2 
 
ECOG P.S. 
●*3 
 
● 
● 
● 
● 
● 
● 
Treatment compliance 
 
● 
● 
● 
● 
● 
● 
 
Laboratory tests 
 
 
 
 
 
 
 
 
Hematology 
●*4 
●*4 
●*1 
●*1 
●*1 
●*1 
●*1 
● 
Serum chemistry 
●*4 
●*4 
●*1 
●*1 
●*1 
●*1 
●*1 
● 
Urinalysis 
●*4 
●*4 
●*1 
●*1 
●*1 
●*1 
●*1 
● 
Tumor markers 
●*4 
●*4 
 
 
 
 
 
○*5 
Imaging test 
(thoracoabdominal-pelvic 
CT/MRI) 
●*6 
●*7 
 
●*7 
 
 
 
○*7,*8 
NRAS test 
●*10 
 
 
 
 
 
 
 
Adverse Event 
－ 
←    ●    → 
●: Mandatory, 〇: Perform as necessary 
*: 
Consent should be obtained at enrollment 
*1: Perform before initiation of each cycle of protocol treatment. 
*2: Measure and record only body weight when the dose is changed. 
*3: Assess again immediately before administration of the 1st cycle when the entry test has been performed 
more than 14 days away before enrollment. 
*4: The test in Cycle 1 may be skipped when the entry test has been performed 1 or 2 days before treatment 
in Cycle 1. The test in Cycle 1 will be performed before treatment in Cycle 1 when the entry test has 
been performed more than 2 days before treatment in Cycle 1. 
*5: Measure only when more than 56 days (8 weeks) have passed after the previous measurement. 
*6: If the imaging test before enrollment is performed within 14 days prior to Cycle 1, the test of first cycle 
can be omitted, but an imaging test should be preferably conducted immediately before administration 
of the 1st cycle. 
*7: Use the method employed at the enrollment for measurement. 
*8: Perform the imaging test within 28 days (4 weeks) after decision on discontinuation for subjects 
withdrawn from the study for any reason other than PD. 
*9: Perform within 28 days (4 weeks) after discontinuation. Perform until the next treatment when it will be 
startied within 28 days (4weeks) after discontinuation. 


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*10: Perform the test in the patients who agree to participate in the study before NRAS test comes to be 
covered by insurance, and the patients who agree to participate in the study after NRAS test comes to be 
covered by insurance but before the test becomes feasible at the study site and who give consents to the 
conduct of the test. The timing of submission of samples does not need to be upon registration. 
 
Table 9.b  Study calendar (Protocol Treatment [2]) 
Item 
Randomization 
Every 2 weeks 
Cycle 7 and later§ 
Every 8 
weeks§ 
Discontinuation of 
protocol treatment*8 
Follow-up 
period*9 
Eligibility 
● 
 
 
 
 
Subject background 
 
 
 
 
 
Clinical findings 
(physical examination) 
● 
●*1,*2 
 
● 
 
Vital signs 
● 
●*1,*2 
 
● 
 
Height, body weight 
 
○*3 
 
 
 
ECOG P.S. 
● 
●*1,*2 
 
● 
 
Treatment compliance 
(incluing the test at 
discontinuation) 
 
● 
 
 
 
Laboratory tests 
 
 
 
 
 
Hematology 
● 
●*1,*2 
 
● 
 
Serum chemistry 
● 
●*1,*2 
 
● 
 
Tumor markers 
● 
 
● 
● 
 
Imaging test 
(thoracoabdominal-pelvic 
CT/MRI) 
●*4,*5 
 
●*4,*6 
○*4,*7 
○*10 
Follow-up therapy 
 
 
 
 
● 
Survival survey 
 
 
 
 
● 
Adverse Event 
←    ●    → 
 
●: Mandatory, 〇: Perform as necessary 
§: As a rule, tests of tumor markers and imaging tests will be conducted in the (4n + 3)th administration 
cycle. However, when the administration interval becomes longer because of the criteria for extension of 
administration period, the tests will be conducted at appropriate timings. 
 
*1: Perform before initiation of each cycle of protocol treatment. 
*2: The test in Cycle 7 may be skipped when the test at randomization has been performed 1 or 2 days 
before treatment in Cycle 7. The test in Cycle 7 will be performed before treatment in Cycle 7 when the 
test at randomization has been performed more than 2 days before treatment in Cycle 7. 
*3: Measure and record only body weight when the dose is changed. 
*4: Use the method employed at randomization for measurement. 
*5: Masure between the day of administration in 6th cycle and randomization. 
*6: Reduce the frequency of imaging test to once every 112 days (16 weeks) 14 days (± 2 weeks) when two 
years have passed since initiation of protocol treatment. 
*7: Perform the imaging test within 28 days (4 weeks) after decision on discontinuation for subjects 
withdrawn from the study for any reason other than PD. 
*8: Perform within 28 days (4 weeks) after discontinuation. 
*9: Perform every 6 months (approximately) after discontinuation of protocol treatment. 
*10: Perform only when 56 days (8 weeks) or more have passed after the previous measurement. 


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9.2 
Collection/test/observation items and procedures during the study 
The investigator will perform the following as scheduled in “9.1 Study calendar.” 
9.2.1 
Informed consent procedure 
The method for obtaining consent is described in "15.3 Written information and subject’s consent." 
Consent should be obtained from each subject before initiation of study procedures. 
A unique subject ID code will be assigned to each subject when explanation is given to obtain consent. 
The subject ID code will be used throughout the study period. 
 
9.2.2 
Procedures for registration and allocation of drugs 
9.2.2.1 
Procedures for registration and initiation of protocol treatment 
The investigator will register subjects according to the following procedures. 
1) 
The investigator or study collaborator should record the necessary items in subject screening 
list for a subject who was selected to receive explanation for obtaining consent for study 
enrollment. 
2) 
The investigator or study collaborator should input the necessary items into the Web case 
registration system for a subject who has given consent.* 
*: The study collaborator may input into the Web case registration system by instruction of the 
investigator. 
3) 
Eligibility of a prospective subject is judged by the Web case registration system and a 
protocol study group will be assigned when the subject is eligible. 
4) 
The investigator and study collaborator will check the registration result and assigned protocol 
study group on the Web case registration system. The registration result and assigned protocol 
study group will be sent via e-mail from the Web case registration system to the investigator 
and study collaborator. 
5) 
The investigator should start the allocated protocol treatment within 15 days of formal 
registration (including the same day of week as the day of enrollment). 
6) 
The investigator or study collaborator should immediately contact the sponsor and input 
necessary items in the Web subject registration system when the study drug is not 
administered for reasons such as withdrawal of consent after allocation, or when a change 
related to allocation is made to the data of the registered subject. 
9.2.2.2 
Preparation and storage of allocation procedures 
The allocation manager (person designated by the sponsor) should prepare the allocation 
procedures and manage allocation information of subjects. Minimization method should be used 
for allocation of protocol treatment using the allocation factors of the study site, age (20 to 64 
years/65 to 79 years), and presence/absence of liver metastasis. The allocation information should 
be stored in a safe place and made accessible only by the authorized persons. 
 


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9.2.3 
Subject demographics 
The following demographic data will be collected: date of birth and sex at the time of enrollment. 
The following data concerning the target disease of colorectal cancer will be collected. 
1) 
Tissue type 
The tissue type will be assessed based on the histological findings in the “Japanese Classification 
of Colorectal Carcinoma” and recorded in the case report form with the date and site of sampling 
for diagnosis. 
 
Date of initial diagnosis 
 
Date of diagnosis of Stage 4 (no need for input the case report form when it is the day of the 
initial diagnosis) 
2) 
History of treatment 
 
History of surgery 
 
For subjects with a history of surgery, the date of surgery, surgery site 
(primary/metastatic lesion), and the number of lymph nodes resected. Endoscopic 
surgery, which is not considered a history of surgery, should not be entered into the 
case report form. 
 
History of radiotherapy 
 
For subjects with a history of radiotherapy, the final irradiated date. 
 
History of preoperative and/or postoperative adjuvant chemotherapy 
 
For subjects with a history of adjuvant chemotherapy, the type of preoperative and/or 
postoperative adjuvant chemotherapy, date of final treatment. 
3) 
Information on metastatic organ 
 
Number of metastatic organs (0, 1, 2 or more)* 
*: The primary lesion/regional lymph node is not included, and the distant lymph node is 
counted as “one organ” even if there is more than one. 
 
Metastatic organs (liver, lung, peritoneum, lymph node*, bone, adrenal gland, skin, other**) 
*: distant lymph node is counted as “one organ” even if there is more than one. 
**: The name of the organ will be recorded in the case report form. 
 
9.2.4 
Medical history 
A medical history is defined as any clinically problematic disease or symptom that has resolved within 
one year prior to initiation of protocol treatment. Any notable medical history will be recorded in the 
case report form. 
 
9.2.5 
Current medical condition 
A current medical condition is defined as any symptom or disease present at initiation of protocol 
treatment. Any notable current medical condition will be recorded in the case report form. Clinically 
problematic laboratory test data, ECG findings, and abnormal physical examination findings observed 
immediately before initiation of protocol treatment should be handled as a current medical condition at 
the discretion of the investigator. 


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9.2.6 
Clinical findings (physical examination) 
The following locations and parts of the body will be examined: 
(1) eyes, (2) ears, nose, and throat, (3) cardiovascular system, (4) respiratory system, (5) 
gastrointestinal system, (6) dermatologic system, (7) extremities, (8) musculoskeletal system, (9) 
nervous system, (10) lymph nodes, (11) other. 
In particular, subjects will be checked for the following symptoms at the physical examination: 
allergic reaction, fatigue, rash acneiform, dry skin, paronychia, infusion related reaction, 
palmar-plantar erythrodysaesthesia syndrome, anorexia, diarrhoea, nausea, vomiting, oral mucositis, 
febrile neutropenia, infection, hemorrhage, pain, peripheral motor neuropathy, peripheral sensory 
neuropathy, alopecia, thromboembolism, gastrointestinal perforation, pneumonitis, and pulmonary 
fibrosis. 
For diagnosis after initiation of protocol treatment, evaluate the clinically problematic abnormality 
compared with the result of diagnosis before initiation of protocol treatment. 
 
9.2.7 
Body weight and height 
Body weight and height will be measured before enrollment. Body weight (kg) will be measured to the 
first decimal place and rounded off to the first decimal place when the second decimal place is known. 
Height (cm) determined will be expressed in integer value (rounded off to integer). 
In principle, measurement is unnecessary during the treatment period. However, body weight should 
be recorded in the case report form when the measured value is used to change the dose of protocol 
treatment. 
 
9.2.8 
Vital signs 
The following vital signs will be measured: body temperature and blood pressure and pulse rate (bpm) 
at sitting position (after rest for 5 min or longer). In particular, subjects will be checked for fever and 
hypertension. 
 
9.2.9 
ECOG P.S. 
ECOG P.S. will be assessed according to Table 9.c. Assess again immediately before administration 
of the 1st cycle when the entry test has been performed more than 14 days away before enrollment. 
Table 9.c  Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) 
Grade 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 


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Grade 
Definition 
chair 
9.2.10 Treatment compliance (Protocol Treatment [1] and [2] implementation 
status) 
The investigator should record the compliance with protocol treatment in the case report form as 
follows: 
• 
When protocol treatment is administered: The dose and the date of treatment should be recorded. 
The reason for dose reduction should also be recorded when appropriate. 
• 
When any drug used in protocol treatment is suspended: The date of suspension should be 
recorded. 
• 
When any drug used in protocol treatment is discontinued: The date and reason for 
discontinuation should be recorded. 
 
9.2.11 Laboratory tests 
The laboratory tests performed at each time point during the study are shown in Table 9.d to Table 9.g. 
The laboratory tests will be performed at each study site. 
The investigator should evaluate the reported laboratory test results. The representative investigator at 
each site should be administer and store the standard value of laboratory tests. 
Table 9.d  Laboratory tests performed at the time of enrollment 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
CEA 
CA19-9 
 
Immunology 
HBs antigen 
Hepatitis tests including anti-HCV 
 


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Table 9.e  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment [1]) 
Hematology 
Serum chemistry 
Tumor marker 
WBC* 
Neutrophil count* 
Platelet count* 
Hemoglobin content* 
Total bilirubin* 
ALT* 
AST* 
Creatinine* 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA*, † 
CA19-9*, † 
*: The test in Cycle 1 may be skipped when the entry test has been performed 1 or 2 days 
before treatment in Cycle 1. The test in Cycle 1 will be performed before treatment in Cycle 
1 when the entry test has been performed more than 2 days before treatment in Cycle 1. 
†: Measure before the initiation of 1st cycle only. 
 
Table 9.f  Laboratory tests performed before the start of each cycle of treatment (Protocol Treatment [2]) 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA* 
CA19-9* 
*: Perform every 8 weeks. 
 


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Table 9.g  Laboratory tests performed at the time of discontinuation 
Hematology 
Serum chemistry 
Tumor marker 
WBC 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
ALP 
LDH 
Albumin 
Na 
K 
Ca 
Cl 
CEA* 
CA19-9* 
*: Measure only when more than 56 days (8 weeks) have passed after the previous 
measurement. 
 
9.2.12 Imaging test (thoracoabdominal-pelvic CT/MRI) 
Imaging test before enrollment will be performed within 28 days prior to enrollment (including the 
same day of week as the day of enrollment). The results of imaging diagnosis/test performed before 
obtaining consent may be used if it is performed within 28 days prior to enrollment.  
During the period of Protocol Treatment [1], imaging test will be performed before administration in 
the 1st cycle and the 3rd cycle. The results of imaging tests before administration in the 1st cycle will 
be handled as the image data for measurable lesion, and the test will be performed within 14 days prior 
to initiation of Protocol Treatment [1] (including the same day of week as the day of enrollment). If 
the imaging test before enrollment is performed within 14 days prior to initiation of Protocol 
Treatment [1], the imaging test can be omitted, but an imaging test should be preferably conducted 
immediately before administration of the 1st cycle.  
Imaging test before initiation of Protocol Treatment [2] will be conducted between administration of 
the 6th cycle and randomization. It will be performed every 8 weeks after initiation of Protocol 
Treatment [2] (See "Table 9.b  Study calendar (Protocol Treatment [2])" for details.) 
Thoracoabdominal-pelvic CT (in principle, contrast CT with a slice width of 5 mm or less, but MRI is 
also acceptable) will be used for imaging test, and the modality and the date of imaging test will be 
recorded in the case report form. 
The same modality should be used during protocol treatment throughout the study period. 
The investigator should evaluate the test results according to the RECIST v1.1 and record the 
evaluation results in the case report form. 
For subjects withdrawn from the study for any reason other than imaging test results such as clinical 
PD, imaging test specified at the time of discontinuation for protocol treatment should be performed 
within 4 weeks including the day of decision (including the same day of week as the day of decision). 
 
9.2.13 NRAS test 
9.2.13.1 Subjects 
The subjects will be the patients who agree to participate in the study before NRAS test comes to be 
covered by insurance, and the patients who agree to participate in the study after NRAS test comes 


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to be covered by insurance but before the test becomes feasible at the study site and who give 
consents to the conduct of the test. 
For the patients who receive NRAS test at the study site after NRAS test has come to be covered by 
insurance, test results regarding each codon shown in Table 9.h will be recorded in the case report 
forms. 
9.2.13.2 Samples and submission 
For the patients who have given a consent to the test, the tumor tissue samples which have been 
collected in surgery or biopsy performed prior to informed consent, and which are used for 
evaluation of KRAS will be used for the test. From paraffin-embedded samples, 5-μm slices will be 
obtained, and 5 pathological samples fixed on slide glasses will be submitted to 
 
. It is also acceptable to submit samples in the form of 
paraffin-embedded samples. When paraffin-embedded samples are submitted, 
 will prepare a 
necessary number of slide glass samples, and will return the remaining sample to the study site. 
Investigators will use the materials prepared by 
 in advance at the beginning of the study and 
send the samples to 
. Details are described in the written procedure prepared separately. 
 
will send in advance the materials necessary for storing and sending samples to the study sites 
where enrollment of study subjects has become possible. 
Details regarding submission of tumor tissues will be described in the written procedure prepared 
separately. 
9.2.13.3 Data 
Among the subjects specified in "9.2.13.1 Subjects", the investigators will enter the following 
issues regarding the submitted tumor tissues in the case report forms for the subjects for whom the 
samples required for the test have been submitted to 
. However, recording of the results of 
NRAS measurement in the case report forms will be unnecessary. 
1) 
Procedure of sample collection 
2) 
Timing of sample collection 
3) 
Number of slides submitted in the case of pathological slides 
For the patients who are enrolled in the study after NRAS test has come to be covered by insurance 
and who receive NRAS tests at the study sites, the investigators will record the presence or absence 
of mutation of each of the following codons in the case report forms. 
Table 9.h  EXON and codon verified on NRAS test 
NRAS 
EXON 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
 
9.2.14 Surgery aimed at curative resection (complete resection: R0 resection) of 
colorectal cancer 
When surgery is performed for patients who are expected to tolerate curative resection of colorectal 
cancer during protocol treatment, the operative procedure, date of surgery, and postoperative 
assessment of residual tumor should be recorded in the case report form. The residual tumor is 
assessed according to the table shown below, and the histological results of resection specimens 
should be recorded in the case report form wherever possible. The date when surgery aimed at curative 


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resection (complete resection: R0 resection) of colorectal cancer is scheduled is considered as the date 
of discontinuation of protocol treatment 
When surgery aimed at curative resection is performed in more than one session, the number of 
sessions should be recorded in the case report form. As for the postoperative assessment of residual 
tumor, data obtained by the time of initiation of subsequent treatment should be recorded in the case 
report form. Data generated after initiation of subsequent treatment will be collected through 
monitoring and assessed by the steering committee for the validity.  
Table 9.i  Residual tumor after surgical treatment 
Classification 
Criteria 
RX 
The presence of residual tumor cannot be assessed. 
R0 
No residual tumor 
R1 
Resected, but tumor on the margins of a surgical resection specimen or the 
radial margin 
R2 
Macroscopic residual tumor 
 
9.2.15 Survival survey 
All subjects will be followed up after discontinuation of protocol treatment to confirm survival of 
subjects. Survival survey should be continued until a subject dies or the sponsor terminates the study. 
• 
Date of death or date of last confirmation of survival 
 
9.2.16 Follow-up therapy 
When follow-up therapy is performed after discontinuation of Protocol Treatment [2], the following 
information on follow-up therapy should be collected until a subject dies or the sponsor terminates the 
study. 
• 
Name of regimen (name of drugs used) 
 
9.3 
Records of subjects who discontinued before enrollment 
For subjects withdrawn from the study before enrollment of protocol treatment, the main reason for 
discontinuation should be recorded in the case report form according to the following categories. 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria <specify 
the applicable inclusion/exclusion criteria> 
• 
Serious deviation from the protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation <specify the reason> 
• 
Discontinuation of the entire study 
• 
Other <specify the reason> 
The subject ID code of a subject withdrawn from the study before enrollment should not be reused.   
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
Adverse events are all untoward medical events encountered in a subject treated with a drug. They are 
not limited to the events with clear causal relationship with treatment with the concerned drug. 
In other words, adverse events are any unfavorable or unintended sign (including clinically 
problematic abnormalities of laboratory test data), symptoms or diseases that develop after 
administration of a drug irrespective of a causal relationship with the relevant drug. 
 
10.1.2 Items to be considered concerning adverse events 
Generally unfavorable findings are shown below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent event of 
the existing symptom is not considered an adverse event)  
• 
Requiring action or treatment 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation or change in the dose of protocol treatment (chemotherapy, 
panitumumab and bevacizumab) or concomitant drugs under use 
• 
Considered unfavorable by the investigator 
Diagnosis name and signs/symptoms: 
Adverse events should be recorded by a diagnosis name. Accompanying signs (including abnormal 
laboratory values, abnormal ECG findings) and symptoms should not be recorded as adverse events. 
Any adverse events that could not be expressed in medical terminology (name of diagnosis) should 
be recorded with signs or symptoms observed. 
Laboratory test findings: 
Abnormal laboratory values and ECG findings are recorded as adverse events when the investigator 
judges the course to be clinically problematic (in other words, when certain action or treatment is 
required, or the investigator judges the change to have exceeded the normal physiological variation 
range of the subject). 
Retest and continued monitoring of abnormality are not considered treatment. Also, repeated or 
additional conduct of non-invasive test for verification, evaluation and monitoring of abnormality 
are not considered treatment. 
However, when abnormal laboratory values and ECG findings are the accompanying symptoms of 
the disease diagnosed as an adverse event (e.g., increased creatinine due to renal dysfunction, etc.), 
the diagnosis name is handled as an adverse event. 
Existing symptoms (diseases and/or symptoms that have been present from before initiation of 
protocol treatment): 
Diseases and/or symptoms that have been present from before initiation of protocol treatment 
should be recorded as concurrent medical conditions and not as adverse events. When a concurrent 


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medical condition is aggravated, the aggravation is recorded as an adverse event and the 
investigator should record in the case report form that the adverse event as aggravation of the 
complication (e.g., “aggravation of hypertension”, etc.). 
When a subject has an existing symptom that is transient (e.g., asthma, epilepsy) and incidence of 
the symptom is increased, or the symptom becomes serious or severe, it should be recorded as an 
adverse event. When a subject has a chronic disease (e.g., cataract, rheumatoid arthritis) and the 
symptom is aggravated more than anticipated, it should be recorded as an adverse event. The 
investigator should record it so that a reported adverse event name is a change from the baseline 
(e.g., aggravation of XX). 
Aggravation of adverse events: 
When any secondary sign/symptom develops due to an adverse event, it should be considered as a 
new adverse event and recorded in the case report form. The investigator should record it so that a 
reported adverse event name is a change from the baseline (e.g., aggravation of XX).When the 
severity of an adverse event is changed, the event should be recorded once at the highest degree of 
severity (grade based on the CTCAE [Japanese edition JCOG version 4.03]).  
Previously planned surgery or treatment: 
Surgery or treatment planned before initiation of protocol treatment is not considered an adverse 
event. However, when the existing symptom is aggravated to require emergency surgery or 
treatment, the condition or the event is considered an adverse event. A complication which resulted 
from previously planned surgery is reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a subject 
(cosmetic surgery, etc.) is not considered an adverse event. Complications due to a non-urgent 
surgery should be reported as an adverse event. 
Progressive Disease (PD): 
PD should be considered lack of efficacy, not an adverse event. In addition, the single fact of PD 
does not necessarily constitute a serious adverse event. However, clinical or imaging progression of 
the preexisting cancer (including new metastasis) is considered a serious adverse event when the 
severity satisfies any of the criteria for seriousness specified in Section 10.1.3. 
Overdose of panitumumab: 
Overdose of panitumumab which does not accompany the occurrence of events will not be regarded 
as adverse events, but the overdose of panitumumab will be recorded in the page of overdose in the 
case report form. If any events have occurred, they will be recorded as adverse events in the page of 
adverse events in the case report form. 
 
10.1.3 Serious adverse events 
Of all the unfavorable medical events that developed by administration of drugs (irrespective of dose), 
serious adverse event is an event that: 
1. 
Results in death during protocol treatment and all deaths irrespective of a causal relationship with 
protocol treatment. 


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2. 
Results in death after discontinuation of protocol treatment for which a causal relationship with 
protocol treatment cannot be denied. 
However, death obviously due to the underlying disease is not applicable. 
3. 
Is life-threatening 
The term “life-threatening” refers to an event in which the subject was at risk of death during 
onset of the adverse event; it does not refer to an event which hypothetically might have caused 
death if it were severer. 
4. 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization described below is not considered a serious adverse event: 
(1) Preplanned inpatient hospitalization or prolongation of existing hospitalization 
(2) Inpatient hospitalization or prolongation of existing hospitalization unrelated to an adverse 
event 
5. 
Results in persistent or significant disability/incapacity. 
6. 
Leads to a congenital anomaly/birth defect. 
7. 
Other medically significant condition: medically important event which causes a risk to a subject 
even if it is not immediately life-threatening, nor does it result in death or hospitalization, or 
requires an action or treatment to prevent the results shown in 1 to 5 above. Diseases shown in 
Takeda Medically Significant AE List (Table 10.a) are included. 
Table 10.a  Takeda medically significant AE list 
Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion and 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of infection 
by a medicinal product 
Confirmed or suspected endotoxin shock 
 
10.1.4 Severity of adverse events 
The severity of adverse event is classified and defined as follows based on the CTCAE (Japanese 
edition JCOG version 4.03): 
Table 10.b  CTCAE (Japanese edition JCOG version 4.03) Grade 
Grade 1 
Mild; asymptomatic or slightly symptomatic; only clinical or test findings; or 
requiring no treatment 
Grade 2 
Moderate; requiring the least treatment or local or non-invasive treatment; or 
interfering with age-appropriate activities of daily living except for self-care 
activities* 


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Grade 3 
Severe or medically critical, but not immediately life-threatening; requiring 
hospitalization or prolongation of existing hospitalization; disabling/incapacitating; 
or interfering with self-care activities of daily living** 
Grade 4 
Life-threatening; or requiring emergent treatment 
Grade 5 
Death due to an adverse event 
*:  Activities of daily living except for self-care activities include meal preparation, shopping for daily 
necessities and clothings, phone call, and financial management. 
**: Self-care activities of daily living include bathing, dressing, eating, toilet, and oral drug intake, and 
indicate that a person is not confined to bed. 
 
10.1.5 Causality of adverse events 
Causal relationship between protocol treatment (OXA, 5-FU, or panitumumab) and adverse events is 
classified and defined as described below. Information on causal relationship with adverse event is not 
collected for any drugs other than protocol treatment. 
Related 
An adverse event with apparent temporal relation with treatment discontinuation 
(including clinical course after discontinuation). Possibly due to protocol treatment 
(chemotherapy or panitumumab) although other factors such as underlying disease, 
complications, concomitant drugs/treatment are also presumed. 
Not related 
An adverse event with no chronological correlationship with protocol treatment 
(chemotherapy or panitumumab). Very likely due to other factors such as 
underlying disease, complications, and concomitant drugs/treatment. 
 
10.1.6 Date of onset 
Judge the date of onset of adverse event according to the following criteria: 
Adverse event, etc. 
Date of onset 
Signs, symptoms, diseases 
(diagnosis name) 
Record the date when the subject or the investigator noticed the 
first signs and symptoms of adverse event. 
Asymptomatic disease 
Record the date of obtaining a definite diagnosis after conducting 
a test for diagnosis.  
Record the date of obtaining a definite diagnosis even when the 
test findings show old findings or suggest approximate timing of 
onset.  
Aggravation of complications 
Record the date when the subject or the investigator noticed the 
signs and symptoms of adverse event for the first time. 
Abnormal laboratory findings 
after initiation of protocol 
treatment 
Record the date of test where abnormal laboratory values 
considered clinically problematic were observed.  
Abnormality was observed on 
the test at initiation of 
protocol treatment, and 
aggravation was shown on 
subsequent tests. 
Record the date of tests when values were medically judged to be 
obviously increased and decreased based on the changes in test 
values.  


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10.1.7 Date of resolution 
The date when adverse event resolved (or resolved with sequelae). Date of death when a subject died 
of the concerned adverse event. When recovery cannot be confirmed at study completion, it is 
considered ongoing. 
 
10.1.8 Incidence 
When the investigator considers the first occurrence up to the final remission of a series of adverse 
events which repeatedly appear to be resolved or recurred as one event (e.g., constipation, diarrhoea, 
vomiting, etc.), it is considered to be “intermittent”. Other events are considered “ongoing”. 
 
10.1.9 Action taken for protocol treatment 
The action taken for OXA, 5-FU, or panitumumab in protocol treatment is classified and defined as 
follows: 
Dose not changed 
The dose of chemotherapy or panitumumab in protocol treatment 
was not changed even after onset of the adverse event. 
“Dose not changed” should be selected if another adverse event was 
the reason for discontinuation or dose reduction of OXA, 5-FU, or 
panitumumab in protocol treatment. 
Dose reduced 
The dose of OXA, 5-FU, or panitumumab in protocol treatment was 
reduced due to the adverse event. 
Treatment suspended 
Treatment with OXA, 5-FU, or panitumumab in protocol treatment 
was postponed due to the adverse event and resumed later. 
Treatment discontinued 
Treatment with OXA, 5-FU, or panitumumab in protocol treatment 
was discontinued due to the adverse event. 
Not applicable 
Treatment with OXA, 5-FU, or panitumumab in protocol treatment 
had already been completed or discontinued by the time of the onset 
of the adverse event. 
Unknown 
The clinical course after the event onset is unknown, for instance, 
because no contact with the subject can be made. 
 
10.1.10 Outcome 
Outcome of adverse events is classified as follows: 
Category 
Criteria for judgment 
Recovered 
• 
disappearance or recovery of symptoms and findings 
• 
laboratory values returned to normal or baseline 
Improved 
• 
severity was improved by one or more grades 
• 
symptoms or findings mostly disappeared 


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Not recovered 
• 
no change in symptoms, findings, or laboratory data 
• 
the symptoms, findings, or laboratory data on the final day of observable 
period aggravated compared with the date of onset 
• 
irreversible congenital anomaly 
• 
when a subject died where the concerned adverse event is not a direct cause 
of death and the concerned adverse event remained not recovered (no need 
for recording the date of death in this case) 
Recovered 
with sequelae 
• 
disability which disturbs daily life 
Death 
• 
direct relationship between death and the concerned adverse event 
• 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Unknown 
• 
follow-up specified in the protocol after the date of onset was not possible 
due to change of hospitals or relocation, etc. 
 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Period for collection of adverse events 
Adverse events should be continuously collected from initiation of protocol treatment up to four 
weeks after discontinuation of protocol treatment. 
10.2.1.2 Reporting of adverse events 
At each visit, the investigator should assess the onset of subjective symptoms are present. Onset of 
any adverse event that developed after the previous visit should be checked by asking a question 
such as “how has your condition been since the last visit?” to a subject. 
The investigator should follow up all subjects who developed adverse events irrespective of a 
causal relationship with protocol treatment until disappearance of symptoms or return of abnormal 
laboratory values to the value at initiation/dose reduction of protocol treatment, or until observed 
changes can be sufficiently explained for other events (persistent/irreversible adverse event, etc.). 
All adverse events should be recorded in the case report form. The name of an adverse event, date 
of onset, date of disappearance, frequency, severity, causal relationship with protocol treatment 
(unrelated or related), action taken for protocol treatment (chemotherapy and panitumumab), 
outcome, and seriousness should be recorded. 
Follow-up period of adverse events is until recovery of an adverse event, or the investigator judges 
that further follow-up would not be necessary. 
When requested by the representative researcher, the investigator should check the additional 
necessary information and data and complete recording them in the case report form within the 
designated period. 
 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it should be 
reported according to the following procedures. 
When the investigator judges that a serious adverse event has occurred based on the reporting by a 
subject, etc. and the result of various tests, imaging findings or definitive diagnosis, a report should be 


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submitted to the director of the study site and the representative researcher (see attached sheet for 
contact information) within one working day and a report should be made via the sponsor to the 
investigators of other sites jointly performing the clinical study. In addition, the investigator should 
submit a formal detailed report within 10 calendar days. 
The following items are the requisite for reporting within one working day, and other items should be 
reported as best as possible. 
• 
Study title 
• 
Subject ID code 
• 
Name of study site 
• 
Name of investigator 
• 
Name of serious adverse event, course (date of onset, reason for the judgment of “serious”, 
protocol treatment given, causal relationship with protocol treatment, course, and outcome) 
• 
Action taken for the serious adverse event (suspension of new enrollment, revision of the 
written informed consent, newly obtaining consent from other subjects) 
 
10.2.3 Dissemination of a serious adverse event to study sites jointly performing 
the clinical study 
When the head of study site receives a report of a serious adverse event from the investigator, he/she 
should obtain the opinions of the IRB such as the ethics review committee, add the following item to 
the report of the investigator, and disseminate it via the sponsor to the data monitoring committee and 
the study sites jointly performing the clinical study. 
• 
Date of review by the IRB such as the ethics review committee, summary of review, result, 
and necessary actions, etc. 
 
10.3 
Follow-up of serious adverse events 
The investigator should follow-up all serious adverse events, etc. until recovery is confirmed, or the final 
outcome is determined. 
When a change such as alteration of outcome was made to the report of a serious adverse event, the 
investigator should submit a report specifying details of the change to the head of study site and the 
sponsor. When requested by the sponsor or the IRB such as the ethics review committee, related data of 
the study site (e.g., ECG, laboratory test values, summary of discharge report, result of autopsy, etc.) 
should be provided. 


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11.0 
COMMIITTEES ESTABLISHED FOR ADMINISTRATIVE STRUCTURE 
AND THIS STUDY 
11.1 
Research steering committee 
The research steering committee will be established to effectively promote this study. The research 
steering committee will consist of steering committee members and biostatistician, and the sponsor or the 
person designated by the sponsor will act as the secretariat. 
See the supplement for the research steering committee members. 
The research steering committee will not be informed of the treatment allocation throughout the study 
period. 
Details of the research steering committee will be specified in a separately prepared SOP. 
 
11.2 
Data monitoring committee 
The Data monitoring committee (hereinafter referred to as DMC) will be established according to the 
ICH E6 (1.25), and the person designated by the sponsor will act as the secretariat. See the supplement 
for the DMC member. 
The DMC will notify a DMC advisory report on continuation/discontinuation of the study and change of 
the study plan according to the safety analysis results for evaluation to the sponsor. The sponsor will 
determine whether to continue, discontinue, or change the study based on the results. 
The sponsor will prepare the DMC procedures (DMC charter) specifying the details such as the objective, 
roles, and responsibilities of the DMC, and management procedure. 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Detailed procedures concerning data management will be specified in the data management plan. Adverse 
events, medical history, and concurrent conditions should be coded using the MedDRA. Drug names 
should be coded using the WHO Drug Dictionary. 
12.1 
Case report form 
The investigator should prepare the case report form for all subjects who have provided informed 
consent. 
The sponsor or its designee should provide study sites with access authorization to the electronic data 
capture (hereinafter referred to as EDC). The sponsor should provide the investigator and study 
collaborators with training for utilization of EDC. The case report form will be used to report the 
information collected during the study period to the sponsor. The case report form will be prepared in 
Japanese. Data will be directly entered into the case report form. 
A change or correction of the case report form will be recorded as an audit trail that records the 
information before and after the change or correction, a person who made the change or correction, date 
of change or correction, and the reason. 
The investigator should ensure the accuracy and completeness of the case report form, and provide an 
electronic signature on the relevant page of the case report form. The investigator assumes full 
responsibility for the accuracy and reliability of all the data entered into the case report form. 
The data below will be directly recorded into the case report form. 
• 
Severity and causal relationship of adverse event with “OXA”, “5-FU”, or “panitumumab” in 
protocol treatment 
When the investigator makes a change or correction in the data entered into the case report form after 
fixation of clinical data base, a record of change or correction in the case report form (Data Clarification 
Form) provided by the sponsor should be used. The investigator should confirm that the record of change 
or correction in the case report form is accurate and complete, and sign or write name/affix a seal, and 
date it. 
The sponsor or its designee should confirm the accuracy and completeness of the case report form during 
a visit to a study site. The sponsor or its designee should access to the medical records of study subjects 
and in-house records to ensure the accuracy of the case report form. The completed case report form is 
the property of the sponsor, and the investigator should not divulge the information to a third party other 
than the regulatory authority without a written permission of the sponsor. 
 
12.2 
Time limit for data input into the EDC 
It is recommended that data obtained after informed consent be entered into the EDC within the time 
frame described below, in principle. A failure to enter the data within the time frame does not constitute 
a deviation, but it is recommended that efforts be made to adhere to the time frame. 
1) 
At enrollment: within two weeks after enrollment 
2) 
During protocol treatment: within two weeks after discontinuation of each cycle of protocol 
treatment 
3) 
At discontinuation of protocol treatment: within four weeks after discontinuation of protocol 
treatment 
4) 
Imaging test results: within two weeks after evaluation of efficacy 


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5) 
Follow-up period: within two weeks after request for follow-up 
6) 
Inquiry about data input into the EDC: within two weeks after inquiry 
 
12.3 
Storage of records 
The investigator or the head of study site should store the following materials including those specified 
in Section 12.1 and study specific documents for use by the investigation or audit by the regulatory 
authority and the sponsor or their designee. The materials include a list of subject screening, medical 
records, signed and dated original consent form, and a record of change and correction of the case report 
form (copy)/electronic copy of electronic case report form containing audit trail. The investigator and the 
head of study site should store the essential documents until five years after discontinuation or 
completion of the study. However, when the sponsor requires a longer storage period, the head of study 
site will discuss the period and methods of storage with the sponsor. 
The investigator and the head of study site will store the essential documents until the sponsor notifies 
that storage is no longer necessary. 


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13.0 
STATISTICAL ANALYSIS METHODS 
13.1 
Statistical and analytical plans 
The statistician in charge should prepare and finalize the statistical analysis plan (SAP) before data 
fixation. Detailed definition of endpoints and analysis methods should be specified in the SAP to cope 
with the purpose of all studies. 
Data review should be performed before data fixation. Data review is performed to evaluate the accuracy 
and completeness of the study data, subject evaluability, and appropriateness of the planned analysis 
methods. 
13.1.1 Analysis set 
Two analysis sets, "full analysis set" and "safety population", are used in this study. "Full analysis set" 
is defined as "randomized subjects," and the "safety population" is defined as "the subjects who 
received at least one dose of protocol treatment after randomization." 
The sponsor should confirm the definition of analysis sets and appropriateness of analytical handling 
rules of the subject data in the analysis sets before data fixation, add handling of problematic issues 
which have not been prescribed in the planning stage, and finalize the SAP.  
 
13.1.2 Analysis of demographic and other baseline characteristics 
The following analysis should be conducted in "full analysis set." 
Concerning major subject background factors, frequency analysis should be conducted for numerical 
data and summary statistics should be calculated for quantitative data for each treatment group and 
collectively for all treatment groups. 
 
13.1.3 Efficacy analysis 
13.1.3.1 Primary endpoint and analysis method 
[Primary endpoint] 
Progression-Free Survival (PFS) 
The PFS is the period from the day of randomization (Day 0) until the day of judgment of 
exacerbation from the day of randomization, or until death by all causes, whichever comes earlier. 
Progression includes both PD based on diagnostic imaging according to RECIST Guidelines (ver 
1.1) and progression of the underlying disease which cannot be confirmed on diagnostic imaging 
(clinical progression). If progression is diagnosed on the basis of diagnostic imaging, the date of 
the imaging test will be regarded as the date of progression, and the date of clinical judgment will 
be regarded as the date of progression in the case of clinical progression. Even when a condition is 
regarded as PD according to the criteria for efficacy evaluation, such as in the cases of extreme 
shrinkage of the tumor size, but "progression is obviously ruled out" from a clinical point of view, 
PD according to the efficacy evaluation criteria will be given priority and the condition will be 
regarded as progression (in this case, clinical judgment will be prioritized with respect to whether 
or not protocol treatment should be continued). When the condition is not regarded as PD 
according to the efficacy evaluation criteria but it is obviously deemed as progression from a 
clinical point of view, the clinical judgment will be prioritized and the condition will be regarded as 
progression. The study will be cut off for the surviving patients without a diagnosis of progression 
on the last day of clinical confirmation of the absence of progression (date of last confirmation of 
progression-free survival; Confirmation of the absence of progression on imaging test and sample 


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test is not essential. Clinical confirmation of the absence of progression at outpatient clinic will 
suffice. Reporting by telephone only will not be accepted). Even in the cases of protocol treatment 
discontinuation for such reasons as toxicity and patients' withdrawal in which other treatment has 
been given in the after-care, events and cutoff will be handled in the same manner. In other words, 
the timing of discontinuation of treatment or the date of the start of after care will not be regarded 
as the cut-off dates. 
[Main analysis] 
Perform the following analysis for the “full analysis set”. 
For each treatment group, calculate the progression-free survival rate at a given time point and its 
95% confidence interval (two-sided) by Kaplan-Meier method, and calculate the quartile of PFS 
and its 95% confidence interval (two-sided). At the same time, draw a Kaplan-Meier chart for the 
progression-free survival rate. If the median value of observed PFS is 9 months or more in each 
group, the treatment regimen concerned will be regarded as being of worth of further investigation. 
Moreover, for the sake of reference, calculate the hazard ratio of Group B to Group A and its 95% 
confidence interval (two-sided) on the basis of the stratified Cox regression model and apply the 
log-rank test. 
13.1.3.2 Secondary endpoints and analysis method 
[Secondary endpoints] 
Overall survival（OS） 
OS is defined as the period from the day of randomization (Day 0) until death by all causes. 
[Analysis method] 
For OS, perform the same analysis as that for the primary endpoint for the "full analysis set." 
• Response rate（RR） 
RR is defined as the percentage of subjects who have shown complete response or partial response 
as the best overall response in RECIST ver 1.1 after randomization. The overall response will be 
complete response, followed by partial response, stable disease, progression, and nonevaluable in 
this order. 
[Analysis method] 
In "full analysis set," RR and two-sided 95% confidence interval will be calculated for each group. 
At the same time, the inter-group difference of RR (Group B－Group A) and the two-sided 95% 
confidence interval will be calculated.  
• Time to treatment failure（TTF） 
TTF is defined as the period from the date of randomization (counted as Day 0) to the date of 
judgment of discontinuation of protocol treatment, the date of judgment of progression, or the date 
of death for all causes, whichever has come earliest. 
[Analysis method] 
For TTF, perform the same analysis as that for the primary endpoint for the "full analysis set." 
13.1.3.3 Other efficacy endpoints 
See "5.2 Endpoints". 
13.1.3.4 Data conversion method and handling of missing data 
The subjects who have not experienced any events at the end of study on the data cutoff date in the 
analyses of PFS and OS will be handled as the cutoff cases. 


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For the cutoff cases, the last day of available image evaluation results prior to the data cutoff date 
for image test will be regarded as the timing of cutoff in the analysis of PFS, and the data cutoff 
date or the date of last confirmation of survival, whichever comes earlier, will be regarded as the 
timing of cutoff in the analysis of OS. Date of last confirmation of progression-free survival on 
which absence of clinical progression has been confirmed. 
Details about the method of conversion of other data and handling of missing data will be specified 
separately in the SPA. 
13.1.3.5 Level of significance, confidence coefficient 
• 
Level of significance: 5% 
• 
Confidence coefficient: 95% (two-sided estimation) 
 
13.1.4 Safety analysis 
Perform the following analyses in the “safety population”. 
13.1.4.1 Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAE) are the adverse events which developed after initiation 
of protocol treatment after randomization. 
For TEAE, perform the following analyses for each treatment group. Code TEAE using the 
MedDRA to summarize them by Preferred Term (PT) and System Organ Class (SOC). 
• 
Frequency tabulation of all TEAE 
• 
Frequency tabulation of TEAE for which the causal relationship with any of the protocol 
treatments was judged as “related” 
• 
Frequency tabulation of all TEAE by severity 
• 
Frequency tabulation of TEAE by severity for which the causal relationship with any of 
protocol treatment was judged as “related” 
• 
Table of TEAE by frequency with the action taken for any of protocol treatment was handled 
as “discontinuation” 
• 
Frequency tabulation of serious TEAE 
• 
Frequency tabulation of TEAE of peripheral nerve disorders (secondary endpoint) 
Peripheral nerve disorders will be defined as the events classified with the preferred term of 
"peripheral neuropathy" according to the Standardised MedDRA Queries, and skin disorders will 
be defined as the events classified with the System Organ Class of "Skin and subcutaneous tissue 
disorders" or the events classified as with the Preferred Term of "paronychia." The interstitial 
pneumonia will be the events of the Preferred Terms of the MedDRA Standard Search Formula. 
 
13.1.5 Predetermined subgroup analysis 
In this study, the following subgroup analysis will be conducted. 
• 
Subgroup analysis based on NRAS test 


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13.2 
Criteria for interim analysis and premature discontinuation 
Interim analysis will not be conducted. 
 
13.3 
Determination of the planned number of subjects 
This study will be designed as a phase II randomized screening comparison study which does not use 
direct comparison for primary analysis22). 
In the phase III study (PRIME Study) in which FOLFOX4 therapy was combined with bi-weekly 
administration of panitumumab 6 mg/kg as a first-line therapy, the median PFS in the patients of KRAS 
wild-type as the primary endpoint was reported as 9.6 months12). Moreover, in PEAK study23) in which 
panitumumab and bevacizumab were compared as the drugs to be administered in combination with 
mFOLFOX6 therapy, the median PFS in the mFOLFOX6 therapy + panitumumab group was reported as 
10.9 months. The percentage of the cases in which any events occurred or the study was cut off within 3 
months in PRIME Study and PEAK Study was approximately 10% of all cases. 
The subjects of this study will be the patients who receive mFOLFOX6 + panitumumab combination 
therapy for 3 months, and can continue OXA administration. Since the PFS 40% point in PRIME Study 
and PEAK Study was approximately 13 months, the median PFS in Group A in this study is expected to 
be approximately 10 months, which is obtained by subtracting 3 months from the 40% point. The median 
PFS in Group B is assumed to be comparable to that in Group A. 
In the primary analysis, a test based on the method of Brookmeyer-Crowley24) will be conducted for the 
null hypothesis, "true median PFS will be lower than the threshold median PFS for judgment as 
ineffective", separately in Group A and Group B on the basis of the observed median PFS. When the 
threshold median PFS is regarded as 6 months, true median PFS as 10 months, enrollment period as 12 
months, follow-up period as 12 months, one-sided significance level as 5%, and power of test as 80%, 
the number of subjects required in Group A and Group B will become 54 subjects each. Considering the 
cases of discontinuation, the target number of subjects to be randomised was set at 60 patients for each 
group (120 patients in total).  


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of study sites 
The sponsor or its designee will perform periodic monitoring of study sites during the study to confirm 
that the study is carried out in accordance with all specifications in the protocol. Central monitoring and 
site visit monitoring, when necessary, will be performed in this study. During site visit monitoring, the 
data recorded in EDC are checked against source documents. Source documents are the original 
documents, data and records. The investigator and the head of study site will ensure that the sponsor or 
its designee and the IRB such as the ethics review committee have access to the source documents. 
The sponsor or its designee will access the records including the subject code list, medical records, 
signed and dated original consent forms to confirm that the study is appropriately conducted in 
compliance with the protocol. The investigator and other persons involved in the study will spare 
sufficient time to facilitate monitoring procedures during visits to the study site. 
14.1.1 Central monitoring 
Central monitoring will be performed to check that the study is safely conducted in accordance with 
the protocol and that data are accurately collected, based on the data collected by EDC. Central 
monitoring will be conducted twice a year in principle, and periodic monitoring report will be 
prepared. Periodic monitoring report will be evaluated by research steering committee and feedback 
will be given to study sites when necessary. 
Detailed procedures for central monitoring will be determined in the separately prepared procedures. 
 
14.1.2 Site visit monitoring 
Site visit monitoring is conducted to confirm that the study is carried out safely and in compliance 
with the protocol and the data are accurately collected by checking the data entered into the EDC 
against source documents. 
Prior to site visit monitoring, sites are randomly selected to perform Source Documents Verification 
(SDV) for the enrolled subjects. 
See separately prepared monitoring plan for the frequency and procedures of site visit monitoring. 
 
14.2 
Protocol deviations 
The investigator should record all deviations from the protocol. When a deviation is disclosed, the 
investigator will immediately notify the head of study site and the sponsor in writing. Revision of the 
protocol should be discussed with the sponsor when necessary, and when the protocol is revised, the 
revised protocol should be submitted to the head of study site and approved by the IRB such as the ethics 
review committee. 
 
14.3 
Quality assurance and regulatory agency inspections 
The sponsor or its designee will perform audit at the study site when necessary. In such a case, the 
auditor designated by the sponsor should contact the study site in advance to determine the date of audit. 
The auditor may request a visit to the site of collecting laboratory test samples and other sites to be used 
during the study. This study may also be audited by overseas regulatory authorities (e.g., Food and Drug 
Administration [FDA], Medicines and Healthcare Products Regulatory Agency [MHRA]). The study site 
will immediately notify the sponsor when the study site is contacted by the regulatory authority 


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concerning an audit. The investigator and the head of study site should ensure that the auditor has access 
to all the source documents listed in Section 14.1. 


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15.0 
ETHICAL CONDUCT OF A STUDY 
This study will be conducted in compliance with the protocol and ethical principles based on the 
Declaration of Helsinki to preserve the interest of study participants (subjects). Each investigator should 
conduct a study based on the regulatory requirements and in compliance with the “Responsibilities of the 
investigator” in Attachment A. 
15.1 
Conflict of interests 
Prior to the study, the investigator should obtain the review/approval by the IRB such as the COI 
committee that this study has no conflict of interests (COI)25)-29). 
The study site should comply with all the requirements specified by the IRB such as the ethics review 
committee. The requirements include the COI self-declaration, protocol, and informed consent form. 
 
15.2 
Approval by the institutional review board including the ethics review 
committee 
The institutional review board (IRB) including the ethics review committee is constituted according to 
local regulations applicable to the study site. The sponsor or its designee should obtain the document 
listing the name and title of each IRB member. When the IRB members are directly participating in this 
study, a document should be obtained that they are not taking part in deliberation and voting. 
The sponsor or its designee should provide related documents to the IRB such as the ethics review 
committee for review and approval of the protocol. In addition to the protocol, a copy of informed 
consent form, written materials related to subject recruitment, advertisement, and other documents 
required by regulation, when necessary, should be submitted to the central IRB or the IRB of each study 
site such as the ethics review committee to obtain approval. The sponsor or its designee should obtain 
written approval of the protocol and the informed consent form from the IRB such as the ethics review 
committee prior to initiation of protocol treatment. The IRB’s approval document should contain the 
study title, protocol number, and date of preparation/revision of the concerned study, as well as version 
numbers and approval dates of other reviewed documents (e.g., informed consent form). The sponsor 
should notify the study site and the investigator after confirming the appropriateness of the regulatory 
documents of the study site. Protocol procedures such as obtaining consent should not be started until the 
study site and the investigator receive the notification. 
The study site should comply with all the requirements specified by the IRB such as the ethics review 
committee. The requirements include notifications to the IRB such as the ethics review committee, for 
instance, revision of the protocol, revision of the informed consent form, revision of materials related to 
subject recruitment, report on safety in accordance with the regulatory requirement, report on study 
implementation state at intervals determined by the IRB such as the ethics review committee, and study 
completion report. The sponsor or its designee should obtain written approval of the abovementioned 
items and all related materials from the IRB such as the ethics review committee. 
 
15.3 
Written information and subject’s consent 
The informed consent from contains specific requirements of the Declaration of Helsinki and all 
applicable laws and regulations. The informed consent from specifies the use of personal information 
and medical information of subjects in this study (both in and outside Japan: supply to a third party), and 
disclosure. Written explanation explains in detail the general idea and purpose of the study, and its 
possible risks and benefits. The informed consent from also clarifies the conditions for study 
participation and states the fact that subjects can discontinue study participation at any time without 
giving reasons and without loss of benefits in treatment. 


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CONFIDENTIAL 
The investigator is responsible for preparation, content, and IRB approval of the informed consent form. 
The informed consent form should be approved by IRB before use. 
The informed consent from should be written in a language easily understood by subjects. The 
investigator is responsible for providing detailed explanation of the informed consent from to subjects. 
Information should be provided orally and in writing as best as possible by the method deemed 
appropriate by the IRB. 
The investigator should ensure that the subjects have (1) an opportunity to inquire about the study and 
(2) sufficient time to determine study participation. When a subject decides to participate in the study, 
the subject should sign or write name/affix seal, and date the consent form prior to study participation. 
The investigator should request the subject to sign or write name/affix seal using a legal name and not a 
popular name with black or blue ballpoint pen. The investigator should also sign or write name/affix seal, 
and date the consent form prior to subject participation. 
The investigator should store the original consent form which was signed or contains name/affixed seal. 
The investigator should document in the subject’s medical record the date when the subject signed or 
wrote name/affixed seal on the consent form. A copy of the consent form with signature or name typed 
with name seal affixed should be provided to the subject. 
The investigator should take the same procedures as those for obtaining the initial consent to newly 
obtain consent from the concerned subject when the informed consent from is revised. The date of 
obtaining new consent should be recorded in the subject’s medical record, and a copy of the revised 
consent form should be provided to the subject. 
 
15.4 
Subject confidentiality 
The sponsor and its designee should comply with the principles of protection of the subject’s right 
against invasion of privacy. The subject ID code in this study is used to connect the clinical study 
database and related study documents of the sponsor with the source data of subjects. The limited 
information of subjects such as sex, age, and date of birth may be used within the scope of all applicable 
laws and regulations for identification of subjects and confirmation of accuracy of subject ID code. 
To confirm that this study is performed in compliance with the protocol, the sponsor should request the 
investigator for the access to the original laboratory test data, ECG, record of hospitalization/discharge 
during study period, and the original medical records such as autopsy report (source data or materials) by 
a monitor or the person designated by the sponsor, representative regulatory authority, auditor designated 
by the sponsor, and the IRB. The investigator should obtain approval of subjects concerning access to the 
original medical records by a monitor and the representative regulatory authority, etc. when obtaining 
consent from a subject (see Section 15.3). 
When providing a copy of source documents to the sponsor, the investigator should delete the 
information leading to identification of an individual (name and address of subject, other personal 
information not recorded in EDC of subject). 
 
15.5 
Advantages and disadvantages to subjects 
15.5.1 Advantage to subjects 
This study is performed as part of routine clinical practice, and no advantage is expected by 
participation in this study. 
 


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15.5.2 Disadvantage to subjects 
This study is performed in the scope of ordinary medical examination, and no disadvantage is 
expected by participation in this study. 
 
15.6 
Publication, disclosure, and clinical trial registration policy 
15.6.1 Publication and disclosure 
The investigator should provide the sponsor with all the results and data obtained from the study. Only 
the sponsor may disclose the study information to other investigators or regulatory authorities during 
the study period except for a case required by laws and regulations. The sponsor will be responsible 
for publication of the protocol and study-related results (including the public web site) except for other 
cases permitted in the study contract. 
The sponsor may make public the data and information obtained from the study (including the data 
and information provided by the investigator) based on the agreement with the representative 
researcher. 
The investigator should obtain the prior written consent of the sponsor when making public the 
information obtained in this study at a specialized academic meeting, etc. 
 
15.6.2 Clinical trial registration 
Takeda Pharmaceutical Company Limited. will ensure timely publication of the information of a 
clinical study and registration of all clinical researches in patients under way all over the world at least 
to the Clinical Trials.gov and public web site (UMIN-CTR) to comply with the applicable 
laws/regulations and guidelines. The city and country where a study is performed, and the subject 
recruitment state should be registered as well as the contact information of Takeda Pharmaceutical 
Company Limited. to enable general access. 
 
15.6.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited. will post the results of a clinical study at the Clinical 
Trials.gov and public web site (UMIN-CTR) as specified by the applicable laws and regulations 
irrespective of results. 
 
15.7 
Attribution of study results and intellectual property rights 
The study results generated in this study belong to Takeda Pharmaceutical Company Limited. The 
intellectual property rights regarding the pharmaceutical products manufactured and/or distributed by 
Takeda Pharmaceutical Company Limited. also belong to Takeda Pharmaceutical Company Limited. 
Data generated from this study may be made available for secondary use (e.g., meta-analysis) without 
any link to personally identifying information only with permission from the representative researcher 
and the research steering committee. 
 
15.8 Insurance and compensation for injury 
The subjects participating in this study will be compensated for any injury resulting from participation in 
the study according to local regulations applicable to the study site. It should be noted that any treatment 
provided will be covered by health insurance, and no monetary compensation will be provided. 


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CONFIDENTIAL 
16.0 
REFERENCES 
1 
The Editorial Board of Cancer Statistics in Japan. Cancer Statistics in Japan 2013. Foundation for 
Promotion of Cancer Research: 2013. 
2 
Japanese Society for Cancer of the Colon and Rectum (JSCCR). JSCCR Guidelines 2014 for the 
Treatment of Colorectal Cancer. 
3 
Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med. 1994;330(16):1136-42. 
4 
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil 
and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 
2000;343(13):905-14. 
5 
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined 
with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal 
cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041-7. 
6 
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and 
fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin 
Oncol. 2000;18(16):2938-47. 
7 
Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, et al. Superiority of 
oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with 
progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III 
trial. J Clin Oncol. 2003;21(11):2059-69. 
8 
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A 
randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in 
patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23-30. 
9 
Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by 
FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J 
Clin Oncol. 2004;22(2):229-37. 
10 National Comprehensive CancerNetwork. Clinical Practice Guidelines in Oncology. Colon Cancer 
verslon 3, 2013 
11 Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial 
of panitumumab plus best supportive care compared with best supportive care alone in patients with 
chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658-64. 
12 Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial 
of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus 
FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal 
cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697-705. 
13 Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III 
study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with 
FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 
2010;28(31):4706-13. 
14 Muro K, Yoshino T, Doi T, Shirao K, Takiuchi H, Hamamoto Y, et al. A phase 2 clinical trial of 
panitumumab monotherapy in Japanese patients with metastatic colorectal cancer. Jpn J Clin Oncol. 
2009;39(5):321-6. 
15 Boku N, Sugihara K, Kitagawa Y, Hatake K, Gemma A, Yamazaki N, et al. Panitumumab in Japanese 
Patients with Unresectable Colorectal Cancer: A Post-marketing Surveillance Study of 3085 Patients. 
Jpn J Clin Oncol. 2014;44(3):214-223. 


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CONFIDENTIAL 
16 Hochster HS, Hart LL, Ramanathan RK, Hainsworth JD, Hedrick EE, Childs BH. Safety and efficacy 
of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of 
metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study. J Clin Oncol 2006;24(18S) 
3510. 
17 Summary of product characteristics, December 2003: Sanofi-Synthelabo. 
18 Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1:A Randomized 
Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal 
Cancer—A GERCOR Study. J Clin Oncol 2006;24(3):394-400. 
19 Maindrault-Goebel F, et al. Final results of OPTIMOX2, a large randomized phaseⅡ study of 
maintenance herapy or chemotherapy–free intervals(CFI) after FOLFOX in patients with metastatic 
colorectal cancer(MRC) : A GERCOR study. ASCO Meeting Abstructs, Jun 2007;25:4013. 
20 Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Therapeutics and 
Clinical Risk Management 2005;1(4):249–258. 
21 Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in 
combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated 
metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J 
Clin Oncol. 2007;25(12):1539-44. 
22 Buyse M. Randomized designs for early trials of new cancer treatments - an overview. Drug Inf J 
2000; 34: 387-396. 
23 Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: A Randomized, 
Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil, Leucovorin, and Oxaliplatin 
(mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With Previously Untreated, Unresectable, 
Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer. J Clin Oncol. 2014. 
24 Brookmeyer R and Crowley, JJ. A confidence interval for the median survival time. Biometrics 1982; 
38: 29-41. 
25 Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, Science 
and Technology dated November 1, 2002) 
26 Guidelines for determining the conflict of interest polity for clinical researches (Review group for 
ethical aspects of clinical researches and conflict of interest, March 2006) 
27 Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences Research 
(March 31, 2008) 
28 Guidelines for management of COI in medical reserach (COI Committee of Japan Association of 
Medical Sciences, February 2011) 
29 Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of Internal 
Medicine, Japan Society of Hepatology, Japanese Circulation Society, Japan Endocrine Society, Japan 
Diabetes Society, Japanese Respiratory Society, Japanese Society of Hematology, Japanese Society of 
Allergology, Japanese Association for Infectious Diseases, August 2011) 
 


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Appendix A 
Responsibilities of the investigator 
1 
To appropriately conduct the clinical study in compliance with the protocol and in consideration of 
the human rights, safety and welfare of subjects. 
2 
To request COI committee of each study site to review and approve that there is no COI issues with 
this study. 
3 
When assigning a part of important duties related to this study to subinvestigators or study 
collaborators, prepare a list of assigned duties and persons, submit it in advance to the head of study 
site, and to obtain approval. 
4 
To prepare the informed consent form and revise it as necessary. 
5 
To check the contents of the study contract. 
6 
To provide sufficient information on the protocol, drug and duties of each person to 
subinvestigators and study collaborators, and to provide them with guidance and supervision. 
7 
To select subjects who satisfy the protocol, give explanation using written information, and obtain 
consent in writing. 
8 
To be responsible for all medical judgments related to the study. 
9 
To ensure together with the head of study site that sufficient medical care is provided to subjects for 
all study-related clinically problematic adverse events throughout the period of subject’s study 
participation and thereafter. 
10 When a subject is treated at another medical institution or department, inform a physician of the 
medical institution or department in writing of the subject’s study participation and study 
completion/discontinuation after obtaining the subject’s consent, and then prepare the record. 
11 When emergency report of serious adverse events, etc. is required, immediately report it in writing 
to the head of the study site and the sponsor. 
12 To prepare accurate and complete EDC and submit it to the sponsor with an electronic signature. 
13 To inspect and check the contents of EDC prepared by subinvestigators, or transcribed by study 
collaborators from the source data, and submit it to the sponsor with an electronic signature. 
14 To discuss a revision of the protocol, etc. when proposed by the sponsor. 
15 To report the study completion in writing to the head of study site. 
 
 

SAP_000.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 
Note; This document was translated into English and the language in original document was Japanese.


Page 1 of 19 
SAPPHIRE study 
(A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + 
panitumumab combination therapy and 5-FU/LV + panitumumab combination therapy 
in the patients with chemotherapy-naïve unresectable advanced recurrent colorectal 
carcinoma of KRAS wild-type after 6 cycles of combination therapy with mFOLFOX6 + 
panitumumab.)
Statistical Analysis Plan 
Version 6.0 
Created By: 
 
 
 
 
Takeda Pharmaceutical Company Limited 
 
  
 
Date of Creation: 20 December 2017 


Page 2 of 19 
 
 
Table of Contents 
1. 
History of creation and revision .......................................................................................... 4 
2. 
Purpose of Statistical Analytical Plan .................................................................................. 6 
3. 
Time Point of Analysis ....................................................................................................... 7 
4. 
Population for Analysis ...................................................................................................... 7 
5. 
Data Handling ................................................................................................................... 7 
5.1. 
Handling of Patient Data ............................................................................................ 7 
5.2. 
Significant Digits ....................................................................................................... 8 
6. 
Statistical Software ............................................................................................................ 8 
7. 
Statistical Methodology ..................................................................................................... 8 
7.1. 
Patient Analysis ......................................................................................................... 8 
7.1.1. 
Eligibility and Analysis Sets ................................................................................... 8 
7.1.2. 
Analysis of Demographics and Other Baseline Characteristics ................................... 8 
7.1.3. 
Treatment Status .................................................................................................... 9 
7.1.3.1. 
Treatment Completion Status .................................................................................. 9 
7.1.3.2. 
Reasons for Discontinuation ................................................................................. 10 
7.1.3.3. 
Dose Reduction Status .......................................................................................... 10 
7.1.3.4. 
Follow-up Status ................................................................................................... 11 
7.2. 
Efficacy Analysis ...................................................................................................... 11 
7.2.1. 
Primary Endpoint and Analysis Methods................................................................. 11 
7.2.2. 
Secondary Endpoints and Analysis Methods........................................................... 12 
7.2.3. 
Other Efficacy Evaluation Endpoints ..................................................................... 13 
7.2.4. 
Predefined Subgroup Analysis ............................................................................... 14 
7.2.5. 
Method of Data Conversion and Handling of Missing Data ..................................... 14 
7.3. 
Safety Analysis ........................................................................................................ 15 
7.3.1. 
Treatment-emergent AEs (TEAEs) ........................................................................ 15 
7.3.2. 
Follow-up Analysis of TEAEs ............................................................................... 16 
7.4. 
Sensitivity Analysis .................................................................................................. 16 
7.4.1. 
Sensitivity Analysis of Primary Endpoint ............................................................... 16 
7.4.2. 
Sensitivity Analysis of Secondary Endpoints .......................................................... 16 
7.4.3. 
Sensitivity Analysis of Other Efficacy Evaluation Items .......................................... 16 
7.5. 
Additional Analysis .................................................................................................. 17 
7.5.1. 
Creation of Waterfall plot ..................................................................................... 17 
7.5.2. 
Evaluation of Depth of Response (DpR) ................................................................ 17 
7.5.3. 
Evaluation of Early Tumor Shrinkage (ETS) .......................................................... 17 
7.5.4. 
Additional Definition of Primary Tumor Location: Right and Left ........................... 18 


Page 3 of 19 
 
 
8. 
References ...................................................................................................................... 18 
 
 
 
 
 


Page 4 of 19 
 
 
1. History of creation and revision 
Version 
Approval Date 
Created By 
Reason for Revision 
1.0 
October 8, 2014 
 
Not applicable due to being the first version 
1.1 
November 25, 2014 
 
Details for additional analyses were added 
2.0 
February 27, 2015 
 
5.1. Data Handling (1) Description of continuous 
data was deleted;  
(2) Adverse event (AE) grade handling and final 
grade definitions were clarified. 
7.1.2. Analysis of Demographics and Other 
Baseline Characteristics, and 7.1.3. Treatment 
Compliance: added Safety Data Analysis Set 
(SAS) to both sections. 
7.1.3.1. Treatment Completion Status: added 
definition of relative dose intensity (RDI). 
Combined 
sections 
7.1.3.2. 
Reasons 
for 
Discontinuation 
and 
7.1.3.3. 
Reasons 
for 
Discontinuation and Other Details. 
7.2.1. Primary Endpoint and Analysis Methods: 
added handling rules for patients without 
progression confirmed by imagining, and without 
disease progression beyond 9 months; added that 
the difference in PFS rate between treatment 
groups will be calculated as part of Primary 
Endpoint analysis. 
7.2.2. 
Secondary 
Endpoints 
and 
Analysis 
Methods:  
added an analysis adjusting for stratification 
factors as explanatory variables in a Cox 
regression model.  
7.3. Safety Analysis: (a) additional inclusion of 
two types of AE analyses that will be conducted, 
for AEs that occurred after enrolment (Set 1) and 
for AEs that after randomization (Set 2); (b) 
amended the AE tables to be consistent with the 
AE entry Form. 
7.4. Sensitivity Analysis: inclusion of additional 
analysis to be performed when patients are 
censored at start of subsequent therapy. 
3.0 
 
April 18, 2017 
 
6.4. In the definition of Full Analysis Set (FAS), 
added that patients in violation of ICH-GCP will 


Page 5 of 19 
 
 
be excluded. 
7.1.2. Inclusion of additional analyses. 
7.1.3.1. Inclusion of graphs to be created. 
7.1.2. Clarified criteria for determining the 
absence of disease progression at 9 months after 
randomization. Specifically, patients without 
image data will be handled as follows: “Patients 
without 
image 
data 
at 
9 
months 
after 
randomization will be treated as progression free 
if the absence of progression is confirmed by 
imaging immediately before and after 9 months. 
Patients who discontinue treatment before 9 
months, withdraw their consent, or become 
intractable, will be included in the denominator, 
but will not be treated as progression free.” 
7.2.2. Specified study site as a stratification 
factor. 
7.2.3. Clarified that performance status (PS) at the 
the seventh cycle is defined as PS at time of 
randomization. 
7.2.4. Added analysis according to primary tumor 
site to subgroup analysis. 
7.2.5. Specified the handling of censoring for 
analysis of oxaliplatin (OXA) and panitumumab 
duration. 
7.3.1. Added methods for tabulating AEs. 
4.0 
August 1, 2017 
 
4. Clarified that SAS is a subset of FAS.  
Added a citation to a separate document entitled 
“Inclusion and Exclusion Criteria and Data 
Handling Rules” to definition of analysis sets and 
handling rules for analyses of patient data within 
each analysis set. 
7.1.2. (1) Added “others” to the classification of 
primary tumor site. Defined the proximal 2/3 of 
the transverse colon as the right side, and the 
distal 1/3 of the transverse colon as the left side. 
Added a handling rule for patients where the 
primary tumor site exists astride the right and left 
sides. 
7.3.1 Revised “Frequency table of non-serious 
AEs with incidence rate of ≥5% in either 


Page 6 of 19 
 
 
treatment 
group” 
to 
“Frequency 
table 
of 
non-serious AEs with incidence rate of >5% in 
either treatment group.” 
7.4.2. Revised start date to Protocol treatment [1] 
start date. 
7.4.3. Revised start date to Protocol treatment [1] 
start date. 
5.0 
November 10, 2017 
 
7.2.1 Added the decision by SAPPHIRE study 
steering committee meeting on February 22, 2017 
on the handling of patients without imaging data 
at  9 month, but who had imaging data from 3 
days earlier than allowance. 
6.0 
December 20, 2017 
 
The following analyses were added as a new 
section, 7.5. 
7.5.1 Creation of waterfall plot 
7.5.2 Depth of Response (DpR) evaluation 
7.5.3 Early tumor shrinkage (ETS) evaluation 
7.5.4 Additional definitions for right and left 
classification of primary tumor sites 
 
 
2. Purpose of Statistical Analytical Plan 
“A phase II randomized study comparing the efficacy and safety of mFOLFOX6 + panitumumab 
combination therapy and 5-FU/LV + panitumumab combination therapy in patients with 
chemotherapy-naïve, unresectable, advanced recurrent colorectal carcinoma of KRAS wild-type after 
6 cycles of combination therapy with mFOLFOX6 + panitumumab Statistical Analysis Plan” 
specifies the plan of the final statistical analysis of “A phase II randomized study comparing the 
efficacy and safety of mFOLFOX6 + panitumumab combination therapy and 5-FU/LV + 
panitumumab combination therapy in patients with chemotherapy-naïve unresectable, advanced, 
recurrent colorectal carcinoma of KRAS wild-type after 6 cycles of combination therapy with 
mFOLFOX6 + panitumumab Clinical Study Implementation Plan”.  


Page 7 of 19 
 
 
 
 
3. Time Point of Analysis  
This analysis will be conducted when patient enrolment has been completed and when all enrolled 
patients have completed evaluation at 9 months post-randomization (initial analysis), and when all 
observations are complete (final analysis). 
 
4. Population for Analysis 
In this study, there will be two analysis sets, referred to as the Full Analysis Set (FAS) and the 
Safety Data Analysis Set (SAS). The FAS is defined as “all randomized patients, excluding patients 
in violation of ICH-GCP”, and the SAS is defined as “all patients who receive at least one protocol 
treatment following randomization”. In addition, all patients enrolled in this study are defined as “all 
enrolled patients”. However, if the same patient is re-enrolled after discontinuing the study before 
receiving a treatment, the patient will be treated as one case and will not be duplicated. 
Prior to database lock, the statistical analysis officer and analyst will confirm the validity of the 
handling rules for analyses of patient data within each analysis set (see Attached document, 
“Inclusion and Exclusion Criteria, and Data Handling Rules”), and will provide any supplementary 
information required regarding the handling of issues not specified in the planning stage, prior to 
finalizing the statistical analysis plan. 
 
5. Data Handling 
5.1. Handling of Patient Data 
(1)  Clinical laboratory test values, and subjectively or objectively observed adverse events (AEs) 
AEs described in the AE Form will be renamed according to MedDRA and summarized by 
System Organ Class (SOC) and Preferred Term (PT). “Peripheral neuropathy” includes AEs in the 
PT “peripheral neuropathy” in the Standardized MedDRA Query, and “skin disorders” includes AEs 


Page 8 of 19 
 
 
within the SOC “Skin and subcutaneous tissue disorders” or PT “paronychia”. 
 
(2) AE grading  
If more than one occurrence of an AE is recorded in the same patient, the highest grade and 
earliest onset date will be utilized for analysis of each AE. 
 
(3) Missing or unused data  
Unless otherwise specified for individual analyses, missing data will not be interpolated. In 
addition, if data are removed, the relevant data and reasons for removal will be clarified in a listing. 
However, handling of patients without events for progression-free survival (PFS), overall survival 
(OS), time to treatment failure (TTF), and performance status (PS) maintenance period is described 
in Section 7.2.5. 
  
5.2. Significant Digits 
Unless otherwise specified for individual analyses, the proportion (%) of the frequency 
distribution will be rounded to one decimal place.  
 For descriptive statistics, both the mean and standard deviation will be rounded to one less digit 
than that of the original data.  
 P-value will be expressed to four decimal places by rounding the fifth decimal place. However, 
when the p-value is less than 0.0001, it will be expressed as “p <0.0001.” The hazard ratio (HR) and 
its 95% confidence interval will be expressed to two decimal places by rounding the third decimal 
place. 
 
6. Statistical Software 
SAS Version 9.4 (SAS Institute, Cary, NC, USA) will be used for the statistical analysis. 
 
7. Statistical Methodology 
7.1. Patient Analysis 
7.1.1. Eligibility and Analysis Sets 
All enrolled patients, patients allocated to treatment arms, the breakdown of analysis sets, as well 
as patients who were excluded from the analysis sets and the reasons for exclusion, will be compiled 
into a CONSORT (CONsolidated Standards Of Reporting Trials) diagram.1 
 
7.1.2. Analysis of Demographics and Other Baseline Characteristics  
For the key patient demographics and baseline characteristics, the following values will be 
tabulated for each treatment group, and all the groups combined. Values for all enrolled patients, 


Page 9 of 19 
 
 
FAS and SAS will be tabulated. 
(1) Discrete data 
Frequency distribution and proportion (%) calculated using the target population as the 
denominator will be reported for discrete data. Items to be tabulated are as follows. 
• 
Age (≥70 years or <70 years), gender, histologic type at Stage IV diagnosis (including: 
well-differentiated adenocarcinoma [papillary adenocarcinoma and tubular adenocarcinoma 
(well 
differentiated 
type)]; 
moderately 
differentiated 
adenocarcinoma 
[tubular 
adenocarcinoma (well differentiated type)]; poorly differentiated adenocarcinoma [poorly 
differentiated adenocarcinoma (solid type) or poorly differentiated adenocarcinoma 
(non-solid type)]; mucinous carcinoma; signet-ring cell carcinoma, etc.), history of previous 
surgery (yes or no), history of radiotherapy (yes or no), history of preoperative and/or 
postoperative adjuvant chemotherapy (yes or no), number of metastatic sites (0, 1, or ≥2), 
site of metastases (liver, lung, peritoneum, distant lymph nodes, bone, adrenal glands, skin, 
etc.), ECOG PS at enrolment, single or multiple tumor sites, the site of the primary lesion 
(right side, left side, or other; “right side” includes cecum, ascending colon, proximal 2/3 of 
the transverse colon; “left side” includes distal 1/3 of the transverse colon, descending colon, 
sigmoid colon, recto-sigmoid and rectum; “other” is defined as unknown lesion location, etc. 
If there are multiple primary lesions across right side, left side, or other, the steering 
committee will decide the location for each patient). 
• 
Treatment status for Protocol treatment [1] (presence or absence of any dose reduction, 
presence or absence of any dose delays), clinical laboratory test values and observations 
during Protocol treatment [1] (Grade 1, 2, or ≥3), peripheral neuropathy (Grade 1, 2 or ≥3), 
RECIST category at randomization (complete response [CR], partial response [PR], or 
stable disease [SD]), NRAS and KRAS mutation status (mutation positive or wild type), 
curative resection during Protocol treatment [1] (yes or no) (for all enrolled patients), 
reasons for discontinuation of Protocol treatment [1] (for all enrolled patients), ECOG PS at 
the seventh cycle. 
 
(2) Continuous data 
Descriptive statistics (number of patients, mean, median, standard deviation, minimum value, 
maximum value) will be reported for continuous data. 
• 
Age 
 
7.1.3. Treatment Status 
7.1.3.1. Treatment Completion Status 
The number of completed treatments in the FAS and SAS will be tallied according to treatment 


Page 10 of 19 
 
 
group, for cycles designated for each drug (up to cycle 6, cycles 7, 8, 9, 10, 11, and 12), and 
frequency distribution with proportion (%) will be calculated using the number of patients in each 
analysis set as the denominator. In addition, for cycles designated for each drug (up to cycle 6, cycle 
7, 8, 9, 10, 11, and 12), the cumulative dose as well as the relative dose intensity (RDI) will be 
calculated for each drug; the changes in mean RDI (%) with time will be plotted in a graph. 
Descriptive statistics will be calculated for total cumulative dose and total RDI over all 12 cycles, 
including the number of patients, mean, median, standard deviation, minimum value, and maximum 
value. Total cumulative dose and total RDI will be calculated in two ways: including the Protocol 
treatment period [1]; or from randomization (and excluding treatment period for Protocol treatment 
[1]). RDI will be derived using the following formula. 
RDI (%) = (actual dose / first scheduled dose) × (14 / actual number of days taken to complete the 
specified cycle) × 100 
Total RDI (%) = (actual total dose / expected total dose) × (expected total number of cycle days† / 
actual total number of cycle days‡) × 100 
†14 × 12 cycles when protocol treatment [1] is included, 14 × 6 cycles if not. 
‡Actual total number of cycle days:  
• 
when including Protocol treatment period [1], defined as (start date of drug administration 
for the final cycle) - (start date of drug administration for the 1st cycle) + 14 
• 
when not including Protocol treatment period [1], defined as (start date of drug 
administration for the final cycle) - (start date of drug administration for the 7th cycle) + 14 
 
7.1.3.2. Reasons for Discontinuation  
For the FAS and SAS, reasons for discontinuation for each treatment group will be collected for 
each cycle (up to cycle 6, cycles 7, 8, 9, 10, 11, and 12), and the proportion (%) calculated using the 
number of patients in each analysis set as a denominator. For patients whose reasons for 
discontinuation is “other”, the reasons for discontinuation by treatment completion status will be 
summarized and tabulated. 
 
7.1.3.3. Dose Reduction Status 
For the FAS and SAS, the frequency distribution and proportion (%) of patients who required dose 
reduction will be tabulated according to drug and treatment group. Similarly, the and proportion (%) 
of patients who undergo dose reduction at each specified cycles (up to cycle 6, cycle 7, 8, 9, 10, 11, 
and 12) will be calculated, and the frequency distribution according to reasons of dose reduction will 
be calculated. 
 


Page 11 of 19 
 
 
7.1.3.4. Follow-up Status 
For the FAS and SAS, the quartiles of follow-up period will be calculated either according to 
treatment groups, or all treatment groups combined. The follow-up period is calculated from the day 
of randomization to the end of follow-up. For calculating quartiles, the reverse Kaplan-Meier 
method will be used.2 
 
7.2. Efficacy Analysis 
7.2.1. Primary Endpoint and Analysis Methods 
〔Primary endpoint]〕 
• 
PFS rate at 9 months 
The primary endpoint is PFS rate at 9 months, defined as the proportion of subjects who are alive 
and for whom progression of disease at 9 months after randomization was absent. The presence or 
absence of progression will be evaluated based on information from diagnostic imaging, clinical 
decision, or survival up to 9 months after randomization. Patients without image data at 9 months 
after randomization will be treated as progression free if the absence of progression is confirmed by 
imaging immediately before and after 9 months. Patients who discontinued treatment before 9 
months, withdraw their consent, or become intractable, will be included in the denominator but will 
not be treated as progression free. 
In the SAPPHIRE study Steering Committee meeting on February 22, 2017, it was determined 
that a patient (case no. 1044-003) without image data at 9 months but with imaging data from 3 days 
before the allowance date, that the latter image data will be used as the 9-month imaging data. The 
minutes of the meeting are attached for reference. 
 
Disease progression is defined as follows. 
 
[Definition of Disease Progression] 
Disease worsening includes both progressive disease (PD), based on diagnostic imaging and 
defined by RECIST v1.1, as well as clinical deterioration, defined as progression of the original 
disease that cannot be confirmed by diagnostic imaging. If disease worsening is determined based on 
diagnostic imaging, the examination date on which the imaging test was performed is to be 
designated as the worsening date, and if disease worsening is determined based on clinical 
deterioration, the date on which clinical deterioration was determined is to be designated the 
worsening date. In cases in which tumor diameter becomes extremely small but PD is determined 
according to RECIST, even if the patient is clearly not deteriorating clinically, priority will be given 
to determination of PD according to RECIST and the patient will be deemed as having disease 
worsening (clinical judgement will be prioritized as to whether protocol treatment should be 


Page 12 of 19 
 
 
continued). Conversely, in patients who are not determined as PD according to RECIST but who are 
clearly deteriorating clinically, clinical judgement will be prioritized and the patient will be deemed 
as having disease worsening.  
Censoring will occur on the final date that PD or clinical deterioration was confirmed to be absent 
(final PFS confirmation date) for surviving subjects without disease worsening (confirmation of lack 
of progression by imaging or biopsy is not required, and may be done via clinical examinations 
during outpatient visits, etc; communication by telephone is not acceptable). If patients received 
additional subsequent treatment having discontinued protocol therapy due to e.g. toxicity or patient 
refusal, PFS events and censoring will be handled in the same way; i.e. patients will not be censored 
at the time of treatment discontinuation or the start of subsequent treatment. 
 
[Primary analysis] 
The following analysis will be performed using the FAS. 
For each treatment group, the total number of patients with, without, or unknown progression of 
disease at 9 months will be tabulated, and the proportion of patients without progression will be 
calculated as the PFS rate at 9 months. The numerator is the number patients without progression, 
and the denominator is the total number of patients with, without, or unknown progression of disease. 
A binomial test will be performed on the PFS rates at 9 months for each treatment group under the 
null hypothesis that “the true PFS rate is less than the threshold rate of 30% and the treatment judged 
as ineffective.” The significance level in the main analyses shall be 10% on each side. For interval 
estimation, a two-sided 80% confidence interval (CI) using the Agresti-Coul method will be used.3 
In addition, a two-sided 95% CI of the intergroup differences (group B - group A) of PFS rate at 9 
months will be calculated using the method of Agresti-Caffo.4 
 
7.2.2. Secondary Endpoints and Analysis Methods 
[Secondary endpoints] 
 
Progression-free survival (PFS) 
PFS is defined as the time from date of randomization (day 0) to the date of disease progression or 
death from any cause, whichever is earlier. The definition for disease progression is described in 
7.2.1. 
 
[Analysis method] 
For the FAS, PFS curves for each treatment group will be developed using the Kaplan-Meier 
method, and quartiles and 95% CI on both sides will be calculated. The 95% CI of the quartiles of 
PFS will be calculated using Log-Log transformation by the method of Brookmeyer and Crowley.3 
For reference, the hazard ratio (HR) for group B versus group A and the 95% CI on both sides based 


Page 13 of 19 
 
 
on the Cox regression model will be calculated, and a log-rank test will be performed. Analysis will 
also be conducted adjusting for stratification factors other than study site as variables in the Cox 
regression model, and the adjusted HR for group B versus group A and the 95% CI on both sides will 
be calculated. 
 
 
Overall Survival (OS) 
OS is defined as the time from the date of randomization (day 0) to the date of death by any cause. 
 
[Analysis method] 
 Analyses similar to those specified for PFS will be performed for OS using the FAS. 
 
• 
Response Rate (RR) 
RR is defined as the proportion of patients who have a best overall response of a CR or a PR 
according to RECIST v1.1 after randomization. Quality of response per RECIST, from highest to 
lowest, is in the order of CR, PR, SD, PD, and inability to evaluate. 
 
[Analysis method] 
 RR and 95% CI on both sides will be calculated for each treatment group using the FAS. The 
differences in RR between the treatment groups, i.e. group B – group A, and the 95% CI on both 
sides of difference in RR will also be calculated. For calculating the CI of the RR, the Agresti-Coull 
method will be used; for calculating the CI of the difference in RR between treatment groups, the 
Agresti-Caffo method will be used.6 
 
• 
Time to Treatment Failure (TTF) 
TTF is defined as the time from the date of randomization (day 0) to the date on which a decision 
to discontinue protocol treatment was made, disease worsening was acknowledged, or death due to 
any cause, whichever occurred earliest. 
 
[Analysis method] 
 Analyses similar to those specified for PFS will be performed for TTF using the FAS. 
 
7.2.3. Other Efficacy Evaluation Endpoints 
• 
Performance Status (PS) Maintenance Period  
The PS maintenance period is defined as the time from the date of randomization (day 0) to the 
date on which PS worsened by 1 point or more, discontinuation of protocol treatment, disease 
worsening was acknowledged, or death due to any cause, whichever occurred earliest. However, PS 


Page 14 of 19 
 
 
at the seventh cycle is regarded as being equivalent to PS at randomization. 
 
[Analysis method] 
 Analyses similar to those specified for PFS will be performed using the FAS. 
 
• 
Duration of oxaliplatin (OXA) treatment in mFOLFOX6 + Panitumumab Group 
Duration of OXA is defined as the time from the date of randomization (day 0) to the date of 
discontinuation of OXA from protocol treatment for patients enrolled in Group A, disease worsening 
was acknowledged, or death due to any cause, whichever occurred earliest. 
 
[Analysis method] 
 Analyses similar to those specified for PFS will be performed using the FAS. 
 
• 
Duration of Panitumumab Treatment in Both Groups 
Duration of panitumumab treatment is defined as the time from the date of randomization (day 0) to 
the date of discontinuation of panitumumab, disease worsening was acknowledged, or death due to 
any cause, whichever occurred earliest. 
 
[Analysis method] 
 Analyses similar to those specified for PFS will be performed using the FAS. 
 
7.2.4. Predefined Subgroup Analysis 
In this study, analyses described in sections 7.2.1 and 7.2.2. will be carried out on the following 
subgroups. 
• 
Subgroup analysis based on NRAS/KRAS status (‘mutant’ or ‘wild type’) 
• 
Subgroup analysis based on stratification factors other than study site: age at the time of 
registration (≥20 years and ≤69 years or ≥70 years), number of metastatic sites at the time of 
registration (0 and 1 or ≥2), RECIST response status at randomization (CR, PR or SD) 
• 
The location of the primary lesion (‘right side’, ‘left side’, or ‘other’) 
 
7.2.5. Method of Data Conversion and Handling of Missing Data 
In the PFS, OS and TTF analyses, patients who do not develop events described in 7.2.2. and 7.2.3. 
by the end of the study are censored. 
The date of censorship is defined as the final PFS confirmation date confirming the absence of 
disease progression in the analysis of PFS, the final survival confirmation date in the analysis of the 
OS, the final protocol treatment start date in the analysis of TTF, the final ECOG PS confirmation 


Page 15 of 19 
 
 
date for analysis of PS maintenance. In addition, in the analysis of treatment duration for OXA and 
panitumumab, censorship will occur on completion of study if treatment is continued beyond the 
study; the date of censorship is defined as the first day of drug administration of the last cycle of 
treatment. 
 
7.3. Safety Analysis 
AEs occurring after enrolment (Set 1) or after randomization (Set 2) will be tabulated using the SAS. 
 
7.3.1. Treatment-emergent AEs (TEAEs) 
The frequency and proportion for the following items will be reported for each treatment group. 
• 
Frequency of each TEAE and the total sum of frequencies 
• 
Frequency of TEAEs having a causal relationship (“related”) with any study drug 
• 
Frequency of TEAEs having a causal relationship (“related”) with each study drug 
• 
Frequency of TEAEs requiring discontinuation (“discontinue administration") of any study 
drug 
• 
Frequency of TEAEs requiring discontinuation (“discontinue administration") of each study 
drug 
• 
Frequency of all TEAEs by severity 
• 
Frequency of TEAEs having a causal relationship (“related”) with any study drug by severity 
• 
Frequency of TEAEs having a causal relationship (“related”) with each study drug by 
severity 
• 
Frequency of TEAEs requiring discontinuation (“discontinue administration") of any study 
drug by severity 
• 
Frequency of TEAEs requiring discontinuation (“discontinue administration") for each study 
drug by severity 
• 
Frequency of serious TEAEs 
• 
Frequency of serious TEAEs having a causal relationship (“related”) with any study drug 
• 
Frequency of serious TEAEs having a causal relationship (“related”) with each study drug 
• 
Frequancy of non-serious TEAE with occurrence in > 5% of patients in any of the treatment 
groups 
In addition, the worst Grades for each patient will be calculated, and incidence of TEAE Grade ≥3 
(or Grade ≥2 for peripheral neuropathy) and 95% CI using the Agresti-Coul method will be 
calculated. Similarly, the incidence rate and 95% CI will be calculated using the TEAE recording 
periods as the denominator, and the incidence of Grade ≥3 TEAEs (or Grade ≥2 for peripheral 
neuropathy) as the numerator. The 95% CI will be calculated using the following formula. 


Page 16 of 19 
 
 
95% CI of incidence rate = Incidence rate ± 1.96ඨ
Incidence rate
Collection period of TEAEs 
 
7.3.2. Follow-up Analysis of TEAEs 
For TEAEs of Grade ≥3 (or Grade ≥2 for peripheral neuropathy), a graph of the cumulative 
incidence will be prepared using the Kaplan-Meier method. Occurrence of a Grade ≥3 TEAE (or 
Grade ≥2 peripheral neuropathy) will be defined as an event, and the day from randomization to the 
occurrence of the TEAE will be defined as the time to event. In the absence of a Grade ≥3 TEAE (or 
Grade ≥2 peripheral neuropathy), the patient will be censored at the end of the AE collection period. 
For TEAEs classified as peripheral neuropathy and skin disorder, the cumulative expression rates 
will be plotted as above. 
In addition, the cumulative incidence of peripheral neuropathy and skin disorder will be plotted 
over the cumulative dosage of OXA or panitumumab, respectively, on the horizontal axis. Grade ≥2 
peripheral neuropathy or Grade ≥3 skin disorder are deemed as events and the cumulative dosages 
are the time to event will be plotted as Kaplan-Meier graphs. If there are no events, the patients will 
be censored at the cumulative dosage at the end of protocol treatment. 
 
7.4. Sensitivity Analysis 
7.4.1. Sensitivity Analysis of Primary Endpoint 
For calculation of the primary endpoint of PFS rate at 9 months, results obtained after censoring 
patients at the start of subsequent therapy will be compared with results from the main analysis, to 
confirm any differences between the results. 
 
7.4.2. Sensitivity Analysis of Secondary Endpoints 
For the analyses described in section 7.2.2, results calculated using the start date of Protocol 
Treatment [1] as day 0 will be compared to the main analysis results. 
In addition, comparisons between results will be calculated as described in 7.4.1, to confirm any 
differences between the results. 
 
7.4.3. Sensitivity Analysis of Other Efficacy Evaluation Items 
For “Treatment duration of OXA in mFOLFOX6 + panitumumab group” and “Treatment duration 
of panitumumab in both groups”, results calculated using the start date of Protocol Treatment [1] as 
day 0 will be compared with the results from the main analysis. 
 


Page 17 of 19 
 
 
7.5. Additional Analysis 
7.5.1. Creation of Waterfall plot 
For patients in the FAS, calculation of the (a) ratio of the sum of diameters of target lesion at 
enrolment, to the sum of the shortest diameters of target lesion at its minimum value from the time 
of enrolment, and (b) ratio in the sum of diameters of target lesion at enrolment, to the sum of the 
target lesion diameters at its minimum value after randomization, will be analyzed as follows. 
 
[Analysis method] 
 
A waterfall plot will be prepared for each treatment group, and the descriptive statistics of depth 
of response (DpR) including number of patients, mean, median, standard deviation, maximum 
value and minimum value, will be calculated. 
 
A waterfall plot for each treatment group will be created separately according to the primary 
site of the tumor (right or left) and the descriptive statistics including number of patients, mean, 
median, standard deviation, maximum value and minimum value, will be calculated. 
 
7.5.2. Evaluation of Depth of Response (DpR) 
 For patients in the FAS, calculation of the (a) ratio of the sum of diameters of target lesion at 
enrolment, to the sum of the shortest diameters of target lesion at its minimum value from the time 
of enrolment, and (b) ratio of the sum of diameters of target lesion at enrolment, to the sum of the 
target lesion diameters at its minimum value after randomization, will be analyzed as follows. 
 
[Analysis method] 
 
Mann-Whitney test will be performed for comparisons between treatment groups. 
 
Mann-Whitney test will be separately performed for comparisons between treatment groups, 
according to the site of primary tumor (right or left). 
 
7.5.3. Evaluation of Early Tumor Shrinkage (ETS)  
For patients in the FAS, the change in the diameter of the target lesion at 8 weeks after enrolment 
will be calculated, and the patient classified as achieving ‘ETS’ if the change is ≥20%, and ‘no ETS’ 
if <20%, and used for the following analysis. If the change in diameter of the target lesion at 8 weeks 
after enrolment cannot be calculated, ETS will be classified as unknown. 
 
[Analysis method] 
 
The analyses described in 7.2.1. and 7.2.2 will be performed separately for ‘ETS’ and ‘no ETS’ 
groups. The confidence interval will be 95% for both groups. 
 


Page 18 of 19 
 
 
7.5.4. Additional Definition of Primary Tumor Location: Right and Left 
 Although primary tumor location is defined in section 7.1.2, the following additional definitions are 
used to perform the analyses in sections 7.2.1 and 7.2.2. 
 
(1) Definition 2: The transverse colon is classified as “right” 
1) 
Right Side 
• 
cecum, ascending colon, proximal 2/3 of transverse colon and distal 1/3 of transverse 
colon 
2) 
Left Side  
• 
descending colon, sigmoid colon, rectal sigmoid and rectum 
3) 
Other 
• 
multiple primary sites across the left and right side 
• 
unknown primary tumor location 
 
(2) Definition 3: The transverse colon is classified as “other” 
1) 
Right Side 
• 
cecum and ascending colon 
2) 
Left Side 
• 
descending colon, sigmoid colon, rectal sigmoid and rectum 
3) 
Other 
• 
proximal 2/3 of transverse colon, distal 1/3 of transverse colon 
• 
multiple primary sites across the left and right side  
• 
unknown primary tumor location 
 
8. References 
1）Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, 
Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting 
parallel group randomised trials. BMJ 2010;340:c869. 
2）Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials 1996; 17: 343–46. 
3）Agresti A, Coull BA. Approximate is better than 'exact' for interval estimation of binomial 
proportions. American Statistician 1998; 52: 119–126. 
4）Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 1982; 
38: 29–41. 
5）Agresti A, Caffo B. Simple and effective confidence intervals for proportions and differences of 
proportions result from adding two successes and two failures. American Statistician 2000; 54: 


Page 19 of 19 
 
 
280–288.