Conditions: Colorectal Cancer
Keywords: Metastatic colorectal cancer, Panitumumab, mFOLFOX6, Bevacizumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 823
Healthy volunteers: no

Brief summary:
The purpose of this study is to verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naive patients with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer.

Detailed description:
The purpose of this study is to verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naive patients with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer.

This study will enroll a total of approximately 800 participants (400 per group).

Participants will be randomized to either the mFOLFOX6 + panitumumab arm (Group P) or mFOLFOX6 + bevacizumab arm (Group B) at 1:1 ratio at the time of registration.

Group P and Group B treatment regimen shown below should be administered once every two weeks, following dose, schedule and route of administration.

Group P; mFOLFOX6 + panitumumab combination therapy, once every two weeks OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 panitumumab: 6 mg/kg

Group B; mFOLFOX6 + bevacizumab combination therapy, once every two weeks OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 bevacizumab: 5 mg/kg

This trial is conducted by multicenter and is scheduled for 12 months as whole administration period.

Arms:
arm 1: OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 panitumumab: 6 mg/kg mFOLFOX6 + panitumumab combination therapy, once every two weeks. arm 2: OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 bevacizumab: 5 mg/kg/ mFOLFOX6 + bevacizumab combination therapy, once every two weeks.

Interventions: intervention 1: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab intervention 2: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, bevacizumab
Intervention descriptions: intervention 1: oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion intervention 2: oxaliplatin (OXA), levofolinate calcium (l-LV), bevacizumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion

Protocol document:
Prot_000.pdf: 
 
 
Title: A phase 3, randomized, controlled study of mFOLFOX6 + bevacizumab 
combination therapy versus mFOLFOX6 + panitumumab combination therapy in 
chemotherapy-naïve patients with RAS (KRAS/NRAS) wild-type, unresectable, 
advanced/recurrent colorectal cancer 
 
NCT Number: NCT02394795 
Protocol Approve Date: 05-Jan-2022 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue 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). 
 


Panitumumab-3001 
Fifth Edition 
2/1/2022 
 
 
 
 
PROTOCOL 
 
 
A phase 3, randomized, controlled study of mFOLFOX6 + bevacizumab combination 
therapy versus mFOLFOX6 + panitumumab combination therapy in chemotherapy-
naïve patients with RAS (KRAS/NRAS) wild-type, unresectable, advanced/recurrent 
colorectal cancer 
 
PARADIGM Study 
PAnitumumab and RAS, DIagnostically-useful Gene Mutation for mCRC 
 
 
 
 
 
 
 
Secondary sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Panitumumab-3001 
Version 
Fifth Edition 
Product name 
Panitumumab 
Creation date 
Fifth 1, 2022 
 
 
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Panitumumab-3001 
Fifth Edition 
2/1/2022 
 
 
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 except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered. Furthermore, the information is only meant for review 
and compliance by the recipient, his or her staff, and the Certified Review Board and regulatory agencies 
to enable conduct of the study. 
 
 
 
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1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY 
MANAGEMENT INFORMATION 
1.1 
Clinical study principles 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol. This study will also be conducted as a 
“specified clinical trial” according to the Clinical Research Act (Act No. 16 of 2017)* and also in 
accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki 
• 
Clinical Research Act (Act No. 16 of 2017)* 
• 
International Conference on Harmonisation E6 Good Clinical Practice (hereinafter referred to 
as ICH-GCP) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
conflict of interest guidelines 
*: After approval by the Certified Review Board, the clinical study protocol, after amendment 
(second edition), will be 2017)* used from the time of registration in the database 
established by the Ministry of Health, Labour and Welfare (jRCT: Japan Registry of 
Clinical Trials). 
1.2 
Clinical study administrative structure 
This study will be conducted under the following administrative structure. 
Clinical research steering committee: 
Research steering committee chairman (person presiding over the study): 
 
 
Research steering committee members: 
 
 
 
 
 
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Statistics Representative:  
 
Certified Review Board: 
 
 
 
Also, terms used in this protocol will be defined as follows. 
Study site: 
Institution where this clinical study will be conducted. 
Investigator: 
The person conducting a specified clinical trial and presiding over the study-related activities 
within the study site where the person is employed. 
Subinvestigator: 
A physician taking some of the responsibilities for study-related activities under the direction of 
the investigator at the study site where this person is employed. 
Representative investigator: 
An investigator who acts as the representative of all the investigators at multiple study sites when 
a multicenter study is conducted. 
Supervisor at a study site: 
A person managing and supervising the investigator at the study site where the investigator is 
employed. 
Certified Review Board: 
A committee engaged in reviewing and giving opinions about the conduct of clinical studies 
established in compliance with the Clinical Research Act. 
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Person engaged in coordination and management: 
A person who can smoothly operate clinical studies based on knowledge and methods regarding 
the planned and efficient operational management of clinical studies. 
Person engaged in presiding over the study: 
A person presiding over the study who raises study funds for the clinical study, etc. 
Study participant: 
A person (including the deceased) to whom either of the following applies: 
1. A person who is being studied (including a person who has been requested to be studied) 
2. A person who has given existing samples/information to be used in the study 
 
1.3 
Secondary sponsor 
Takeda Pharmaceutical Company Limited, 
  
 
 
 
 
Takeda Pharmaceutical Company Limited (hereinafter referred to as “Takeda”) will take 
responsibility for drafting of the study and procurement of the study funds as well as all matters 
related to the conduct of this clinical study for which the representative investigator is responsible, in 
collaboration with the representative investigator. The method of supervising the consignee related 
to this clinical study will be described in a separately prepared procedure. 
The expenses related to the operation of this clinical study* will be borne by Takeda. 
*: According to the “business consignment contract,” the expenses related to the activities of the 
research secretariat office, monitoring, registration/allocation, data management, statistical 
analysis, and audit will be paid to the consignee related to this clinical study. The expenses on 
which agreement has been reached with the study site will be paid to the study site on the basis of 
the separately prepared “Calculation criteria for study costs.” 
 
 
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TABLE OF CONTENTS 
1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY MANAGEMENT 
INFORMATION ..................................................................................................................... 3 
1.1 
Clinical study principles ................................................................................................... 3 
1.2 
Clinical study administrative structure ............................................................................. 3 
1.3 
Secondary Sponsor ........................................................................................................... 5 
2.0 
STUDY SUMMARY ............................................................................................................ 13 
3.0 
LIST OF ABBREVIATIONS ............................................................................................... 23 
4.0 
INTRODUCTION ................................................................................................................. 25 
4.1 
Background .................................................................................................................... 25 
4.1.1 
Etiology of colon cancer .......................................................................................... 25 
4.1.2 
Standard treatment for colon cancer ........................................................................ 25 
4.1.3 
Efficacy and safety of mFOLFOX6 in patients with unresectable, 
advanced/recurrent colorectal cancer....................................................................... 26 
4.1.4 
Efficacy and safety of panitumumab in patients with unresectable, 
advanced/recurrent colorectal cancer....................................................................... 27 
4.1.5 
Efficacy and safety of bevacizumab in patients with unresectable, 
advanced/recurrent colorectal cancer....................................................................... 31 
4.1.6 
RAS (KRAS/NRAS) mutation and panitumumab in unresectable, 
advanced/recurrent colorectal cancer....................................................................... 33 
4.2 
Rationale for the proposed study .................................................................................... 35 
5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY ............................................................ 37 
5.1 
Objective ........................................................................................................................ 37 
5.2 
Definition of endpoints ................................................................................................... 37 
5.2.1 
Primary endpoint ..................................................................................................... 37 
5.2.2 
Secondary endpoints ................................................................................................ 37 
5.2.3 
Additional endpoint ................................................................................................. 37 
5.3 
Rationale for the endpoints ............................................................................................. 38 
5.3.1 
Primary endpoint ..................................................................................................... 38 
5.3.2 
Secondary endpoints ................................................................................................ 38 
5.4 
Additional research ......................................................................................................... 38 
6.0 
CLINICAL STUDY DESIGN .............................................................................................. 39 
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6.1 
Clinical study design ...................................................................................................... 39 
6.2 
Rationale for study design .............................................................................................. 40 
6.2.1 
Study population ...................................................................................................... 40 
6.2.2 
Treatment regimens and planned number of patients .............................................. 40 
6.3 
Discontinuation of entire clinical study or discontinuation of clinical study at a study 
site .................................................................................................................................. 46 
6.3.1 
Criteria for discontinuation of entire clinical study ................................................. 46 
6.3.2 
Criteria for discontinuation of clinical study at a study site .................................... 46 
6.3.3 
Procedures of clinical study suspension and discontinuation of entire clinical study 
or study at a study site ............................................................................................. 46 
6.4 
Procedures for protocol amendment ............................................................................... 47 
7.0 
SELECTION OF STUDY PARTICIPANTS AND ENROLLMENT .................................. 48 
7.1 
Inclusion criteria at enrollment ....................................................................................... 48 
7.2 
Exclusion criteria at enrollment ...................................................................................... 49 
7.3 
Procedures for registration and allocation of drugs ........................................................ 50 
7.3.1 
Procedures for registration and initiation of protocol treatment .............................. 50 
7.3.2 
Contacts for enrollment procedure .......................................................................... 51 
7.3.3 
Preparation and storage of allocation procedures .................................................... 51 
8.0 
PROTOCOL TREATMENT ................................................................................................. 52 
8.1 
Definition of protocol treatment ..................................................................................... 52 
8.2 
Drugs used in protocol treatment.................................................................................... 52 
8.2.1 
mFOLFOX6 + panitumumab combination therapy ................................................. 52 
8.2.2 
mFOLFOX6 + bevacizumab combination therapy ................................................. 53 
8.3 
Recommended dose of protocol treatment ..................................................................... 54 
8.4 
Criteria for administration .............................................................................................. 54 
8.5 
Criteria for protocol treatment change ............................................................................ 56 
8.5.1 
Criteria for dose reduction/suspension of mFOLFOX6........................................... 56 
8.5.2 
Criteria for dose reduction/suspension of panitumumab ......................................... 57 
8.5.3 
Criteria for discontinuation of bevacizumab ........................................................... 58 
8.6 
Criteria for dose increase of protocol treatment ............................................................. 59 
8.7 
Criteria for discontinuation of protocol treatment for individual patients ...................... 59 
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8.8 
Procedures for discontinuation or withdrawal of a patient ............................................. 60 
8.9 
Contraindicated drugs/therapies ..................................................................................... 61 
8.10 
Recommended supportive care and combination medications ....................................... 61 
8.11 
Handling of surgery aimed at curative resection (complete resection: R0 resection) of 
colorectal cancer ............................................................................................................. 63 
8.12 
Recommended follow-up therapy .................................................................................. 63 
8.12.1 Recommended second-line treatment ...................................................................... 63 
8.12.2 Recommended third-line or subsequent treatment .................................................. 63 
9.0 
PROTOCOL, EVALUATION ITEMS, AND PROCEDURES FOR OBSERVATIONS ... 64 
9.1 
Study calendar ................................................................................................................ 64 
9.2 
Collection/test/observation items and procedures during the study ............................... 65 
9.2.1 
Informed consent procedure .................................................................................... 65 
9.2.2 
Registration and allocation of protocol treatment .................................................... 66 
9.2.3 
Patient demographics ............................................................................................... 66 
9.2.4 
Concurrent medical condition.................................................................................. 67 
9.2.5 
Clinical findings (included adverse events) ............................................................. 67 
9.2.6 
Height, body weight ................................................................................................ 68 
9.2.7 
Eastern Cooperative Oncology Group Performance Status ..................................... 68 
9.2.8 
Protocol treatment implementation status................................................................ 69 
9.2.9 
Laboratory tests ....................................................................................................... 69 
9.2.10 Imaging test (thoracoabdominal-pelvic CT/MRI) ................................................... 74 
9.2.11 Surgery aimed at curative resection (complete resection: R0 resection) of colorectal 
cancer ....................................................................................................................... 74 
9.2.12 Follow-up treatment ................................................................................................ 75 
9.2.13 Survival survey ........................................................................................................ 76 
9.2.14 Pregnancy ................................................................................................................ 76 
9.3 
Records of subjects who discontinued before randomization ........................................ 76 
10.0 
ADVERSE EVENTS ............................................................................................................ 78 
10.1 
Definitions ...................................................................................................................... 78 
10.1.1 Adverse events ......................................................................................................... 78 
10.1.2 Items to be considered concerning adverse events .................................................. 78 
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10.1.3 Serious adverse events ............................................................................................. 80 
10.1.4 Special interest adverse events ................................................................................ 81 
10.1.5 Severity of adverse events ....................................................................................... 82 
10.1.6 Causality of adverse events ..................................................................................... 82 
10.1.7 Action taken for protocol treatment ......................................................................... 83 
10.1.8 Outcome .................................................................................................................. 83 
10.2 
Procedures ...................................................................................................................... 84 
10.2.1 Collection and reporting of adverse events.............................................................. 84 
10.2.2 Collection and reporting of serious adverse events ................................................. 84 
10.2.3 Follow-up of serious adverse events ........................................................................ 85 
10.2.4 Reporting of additional information concerning adverse events ............................. 86 
10.2.5 Reporting of serious adverse events, etc., to regulatory authorities ........................ 86 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................................ 87 
11.1 
Research steering committee .......................................................................................... 87 
11.2 
Independent data monitoring committee ........................................................................ 87 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS................................................ 88 
12.1 
Case report form ............................................................................................................. 88 
12.2 
Time limit for data input into the EDC ........................................................................... 89 
12.3 
Storage of records ........................................................................................................... 89 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................................. 90 
13.1 
Statistical and analytical plans ........................................................................................ 90 
13.1.1 Analysis set .............................................................................................................. 90 
13.1.2 Analysis of demographic and other baseline characteristics ................................... 90 
13.1.3 Efficacy analysis ...................................................................................................... 90 
13.1.4 Safety analysis ......................................................................................................... 94 
13.2 
Criteria for interim analysis and premature discontinuation .......................................... 94 
13.3 
Determination of the planned number of participants .................................................... 95 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 96 
14.1 
Monitoring of study sites ................................................................................................ 96 
14.1.1 Central monitoring ................................................................................................... 96 
14.1.2 Site visit monitoring ................................................................................................ 96 
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14.1.3 Deviations from the Clinical Research Act, ICH-GCP, and protocol (non-
compliance) ............................................................................................................. 97 
14.2 
Quality assurance............................................................................................................ 97 
15.0 
ETHICAL CONDUCT OF CLINICAL STUDY.................................................................. 98 
15.1 
Application to the Certified Review Board .................................................................... 98 
15.2 
Conflict of interests ........................................................................................................ 98 
15.3 
Written information and patient’s consent ..................................................................... 98 
15.4 
Patient confidentiality ................................................................................................... 100 
15.5 
Contacts for inquiries from patients and concerned people .......................................... 101 
15.6 
Advantages and disadvantages to participants ............................................................. 101 
15.6.1 Advantage to participants ...................................................................................... 101 
15.6.2 Disadvantage to participants .................................................................................. 101 
15.7 
Attribution of study results and access rights ............................................................... 101 
15.7.1 Attribution of study results .................................................................................... 101 
15.7.2 Data access rights .................................................................................................. 102 
15.8 
Reporting of results, publication, disclosure, and clinical study registration policy .... 102 
15.8.1 Reporting of results, publication, and disclosure ................................................... 102 
15.8.2 Clinical study registration ...................................................................................... 102 
15.8.3 Clinical trial results disclosure............................................................................... 103 
15.8.4 Method of storage and destruction of material/information concerning clinical study
 ............................................................................................................................... 103 
15.9 
Insurance and compensation for injury ........................................................................ 103 
16.0 
REFERENCES .................................................................................................................... 104 
 
LIST OF IN-TEXT TABLES 
Table 4.a Grade 3/4 adverse events reported in patients with KRAS wild-type cancer in the PRIME 
Study ................................................................................................................................ 28 
Table 4.b Common adverse events (≥20%) noted in a Japanese phase 2 clinical study of 
panitumumab monotherapy .............................................................................................. 30 
Table 4.c Common adverse events in specified drug use surveillance in Japan ................................. 31 
Table 4.d Incidence of serious adverse events (≥ grade 3) reported with bevacizumab ..................... 32 
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Table 6.a Overall survival (OS) (median) with mFOLFOX6 + bevacizumab combination therapy 
reported so far .................................................................................................................. 41 
Table 8.a Treatment regimen of mFOLFOX6 + panitumumab combination therapy ........................ 52 
Table 8.b Treatment regimen of mFOLFOX6 + bevacizumab combination therapy ......................... 53 
Table 8.c Criteria for initiation of treatment course ............................................................................ 55 
Table 8.d Criteria for initiation of treatment with panitumumab ........................................................ 56 
Table 8.e Criteria for initiation of treatment with bevacizumab ......................................................... 56 
Table 8.f Criteria for dose reduction/suspension of OXA and 5-FU .................................................. 57 
Table 8.g Doses of OXA and 5-FU .................................................................................................... 57 
Table 8.h Criteria for dose reduction/suspension of panitumumab .................................................... 58 
Table 8.i Dose of panitumumab .......................................................................................................... 58 
Table 8.j Criteria for discontinuation of bevacizumab ........................................................................ 58 
Table 9.a Study calendar ..................................................................................................................... 64 
Table 9.b Allowance range for protocol treatment and laboratory tests ............................................. 65 
Table 9.c Eastern Cooperative Oncology Group Performance Status ................................................ 68 
Table 9.d Laboratory tests performed at the time of enrollment ......................................................... 69 
Table 9.e Laboratory tests performed before the start of each course of treatment ............................ 73 
Table 9.f Laboratory tests performed at the time of discontinuation .................................................. 73 
Table 9.g Histological changes ........................................................................................................... 75 
Table 9.h Residual tumor after surgical treatment .............................................................................. 75 
Table 10.a Takeda medically significant adverse event list ................................................................ 81 
Table 10.b CTCAE (Japanese edition JCOG version 4.03) grade ...................................................... 82 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a Overall survival in patients with RAS wild-type cancer in the PRIME study ...................... 33 
Figure 4.b Overall survival in panitumumab and bevacizumab arms in the PEAK Study ................. 35 
Figure 6.a Outline of study design ...................................................................................................... 39 
Figure 8.a mFOLFOX6 + panitumumab combination therapy ........................................................... 53 
Figure 8.b mFOLFOX6 + bevacizumab combination therapy ........................................................... 54 
Figure 9.a JSH guidelines for the management of hepatitis B virus infection .................................... 70 
 
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2.0 
STUDY SUMMARY 
 
Test product: Panitumumab 
Study title: A phase 3, randomized, controlled study of mFOLFOX6 + bevacizumab combination 
therapy versus mFOLFOX6 + panitumumab combination therapy in chemotherapy-naïve patients with 
RAS (KRAS/NRAS) wild-type, unresectable, advanced/recurrent colorectal cancer 
PARADIGM Study (PAnitumumab and RAS, DIagnostically-useful Gene Mutation for mCRC) 
Protocol number: Panitumumab-3001 
Clinical study design: 
 
Untreated mCRC with RAS wild type, chemotherapy-naïve patients with RAS wild-type, unresectable, 
advanced/recurrent colorectal cancer; R, registration/randomization with allocation factors of study 
site, age at the time of entry (20 to 64 years/65 to 79 years), and liver metastasis 
(presence/absence). 
Objective: 
To verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + 
bevacizumab combination therapy in first-line treatment of chemotherapy-naïve patients with RAS 
wild-type, unresectable, advanced/recurrent colorectal cancer. 
Study population: chemotherapy-naïve patients with RAS wild-type, unresectable, 
advanced/recurrent colorectal cancer 
Planned number of participants: 
Number of randomized patients 
mFOLFOX6 + panitumumab arm: 400 
mFOLFOX6 + bevacizumab arm: 400 
Total: approximately 800 patients 
Number of study sites:  
Approximately 200 
Method of administration: 
The two groups will receive treatment for 2 weeks (14 days) as 1 course according to the dosage, 
schedule, and route of administration as follows. 
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mFOLFOX6 + panitumumab group: 
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: 2,400 mg/m2/day 1-3 
panitumumab: 6 mg/kg 
mFOLFOX6 + bevacizumab group: 
mFOLFOX6 + bevacizumab 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: 2,400 mg/m2/day 1-3 
bevacizumab: 5 mg/kg 
Duration of treatment (as a guide): 12 months (continue 
administration until the criteria for discontinuation of protocol 
treatment are met) 
Period of evaluation: 
Approximately 95 months 
Inclusion criteria at enrollment: 
Patient’s eligibility will be determined on the basis of the following criteria: 
1. 
Patients who, in the opinion of the investigator* or the subinvestigator, are capable 
of understanding and complying with protocol requirements 
*: A person who takes part in conducting the study and presides over the study-
related activities within a study site 
2. 
Patients who sign and date a written informed consent form (ICF) prior to the 
initiation of any study procedures 
3. 
Patients aged ≥20 and <80 years at the time of informed consent 
4. 
Patients with unresectable adenocarcinoma originating in the large intestine 
(excluding carcinoma of the appendix and anal canal cancer) 
5. 
Patients with lesion(s) that can be evaluated† 
†: It is not required that the lesion be measurable with the Response Evaluation 
Criteria in Solid Tumours (RECIST, version 1.1) 
6. 
Patients who have not received chemotherapy. Patients who experience relapse more 
than 24 weeks (168 days) after the final dose of perioperative adjuvant chemotherapy 
with fluoropyrimidine agents may be enrolled‡ 
‡: Patients who have received perioperative adjuvant chemotherapy that includes 
OXA cannot be enrolled. 
7. 
Patients classified as KRAS/NRAS wild type§ by KRAS/NRAS testing** 
§: KRAS/NRAS test will be performed with the in vitro diagnostic that has been 
approved for marketing. 
**: All codons listed below are required to be wild type. If any codon is unmeasured 
or unmeasurable, it will not be defined as wild type. 
KRAS 
Exon 
2 
3 
4 
Codon 
12, 13 
59, 61 
117, 146 
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NRAS 
Exon 
2 
3 
4 
Codon 
12, 13 
59, 61 
117, 146 
8. 
Patients who satisfy the following criteria for major organ function in tests 
performed within 2 weeks (14 days) prior to enrollment 
(1) 
Neutrophil count ≥1.5×103/µL 
(2) 
Platelet count ≥10.0×104/µL 
(3) 
Hemoglobin ≥9.0 g/dL 
(4) 
Total blood bilirubin ≤2.0 mg/dL 
(5) 
AST ≤100 IU/L (≤200 IU/L if liver metastases are present) 
(6) 
ALT ≤100 IU/L (≤200 IU/L if liver metastases are present) 
(7) 
Serum creatinine ≤1.5 mg/dL  
(8) 
PT-INR <1.5 (<3.0 for patients treated with oral warfarin) 
(9) 
Urine protein: meet at least one of the following 
i. 
Urine protein (dip stick method) ≤1+ 
ii. 
UPC (urine protein creatinine) ratio ≤1.0 
iii. 
Measurement of 24-hour urine protein ≤1,000 mg 
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) has been 
determined to be 0 to 1 
10. Life expectancy of ≥3 months (90 days) after enrollment 
 
Exclusion criteria at enrollment: 
A patient who meets any of the criteria below will not be included in this study. 
1. 
Patients who have received radiotherapy within 4 weeks (28 days) prior to enrollment, 
except therapy received for pain relief of bone metastasis site 
2. 
Patients with known brain metastasis or strongly suspected of brain metastasis 
3. 
Patients with synchronous cancers or metachronous cancers with a disease-free period of 
≤5 years (excluding colorectal cancer), excluding mucosal cancers cured or possibly 
cured by regional resection (esophageal, stomach, and cervical cancer; non-melanoma 
skin cancer; bladder cancer, etc.) 
4. 
Patients with 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, are breast-feeding, or test positive for pregnancy 
6. 
Patients with non-healing surgical wound(s) (excluding implanted venous reservoirs) 
7. 
Patients with active hemorrhage requiring blood transfusion 
8. 
Patients with disease requiring systemic steroids for treatment (excluding topical 
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steroids) 
9. 
Patient with stent placement in colon 
10. Patients who have received intestinal resection within 4 weeks (28 days) prior to 
enrollment or colostomy within 2 weeks (14 days) prior to enrollment 
11. Patients with history of interstitial pulmonary disease or obvious and extensive 
computerized tomography (CT) findings of interstitial pulmonary disease (interstitial 
pneumonia, pulmonary fibrosis, etc.) 
12. Patients with arterial thromboembolism, such as unstable angina pectoris, cardiac 
infarction, cerebral hemorrhage, or cerebral infarction, or who have had arterial 
thromboembolism within the 24 weeks (168 days) before registration 
13. Patients with serious drug hypersensitivity 
14. Patients with local or systemic active infection requiring treatment or fever indicating 
infection 
15. Patients with heart failure or serious heart disease of ≥ class II by New York Heart 
Association 
16. Patients with intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea 
(incapacitating symptoms despite adequate treatment) 
17. Patients with poorly controlled hypertension 
18. Patients with poorly controlled diabetes mellitus 
19. Patients with active hepatitis B 
20. Patients with known HIV infection 
21. Patients with peripheral neuropathy (peripheral motor neuropathy and/or peripheral 
sensory neuropathy) of ≥ grade 2 by Common Terminology Criteria for Adverse Events 
(CTCAE, Japanese edition JCOG version 4.03)  
22. Other patients judged by the investigator or subinvestigator to be ineligible for 
enrollment in the study (such as patients who may be coerced to give consent) 
Endpoints: 
Primary endpoint: 
The following item concerning all sites and a primary tumor occupying a left-sided site* 
(hereinafter referred to as “left-side”) 
Overall survival (OS) 
*: Primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and 
rectum. 
Secondary endpoints: 
Efficacy 
The following items concerning all and left-sided sites 
Progression-free survival (PFS) 
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Response rate (RR) 
Duration of response (DOR) 
Percentage of curative resection (complete excision, R0 resection) 
Safety 
Incidence of adverse events 
Exploratory endpoints: 
 
 
 
 
 
Statistical method: 
The primary objective of this clinical study is to verify the OS prolongation in the panitumumab group 
as compared with the bevacizumab group. In order to meet the targeted number of events of 570 cases, 
800 cases will be randomized in a ratio of 1:1 by using the minimization method with study sites, age 
(<65 or ≥65), and liver metastasis (presence/absence) as allocation factors. Details of the algorithm of 
the minimization method will be defined separately in the allocation specifications. 
The primary endpoint, OS, will be analyzed in the “full analysis set.” 
A stratified log-rank test will be applied with allocation factors other than study sites as the stratum for 
OS intergroup comparison. Also, a stratified Cox model with allocation factors other than study sites 
as the stratum will be used to calculate the intergroup hazard ratio and its 95% confidence interval 
(two-sided) and the confidence interval corresponding to the level of significance at the time of 
analysis for summary index of difference in two groups. The Kaplan-Meier method will be used to 
calculate the median and its 95% confidence interval (two-sided) and the confidence interval 
corresponding to the level of significance at the time of analysis. 
In this clinical study, one interim analysis is planned for OS, and interim analysis will also be 
performed for all and left-sided sites to evaluate the efficacy by using data at the time when 70% 
(399 events) of the overall targeted number of events have been observed. The level of significance 
for the interim analysis and final analysis will be set by using the O'Brien-Fleming type alpha-
spending function. 
Rationale for planned number of participants: 
Table 6.a shows the OS (median) in clinical studies of mFOLFOX6 + bevacizumab combination 
therapy in chemotherapy-naïve patients with advanced/recurrent colorectal cancer. The OS (median) 
was reported to be between 21.0 and 30.9 months in the NO16966 Study, the HORIZON III Study, 
and the SOFT Study, and all studies were performed in patients with advanced/recurrent colorectal 
cancer not limited to KRAS wild type. The OS (median) of patients with KRAS wild-type cancer was 
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24.3 months in the PEAK Study, which was a randomized, controlled, phase 2 study of mFOLFOX6 + 
panitumumab combination therapy versus mFOLFOX6 + bevacizumab combination therapy as a first-
line treatment of unresectable, advanced/recurrent colorectal cancer. Also, in the 
CALGB/SWOG80405 Study, 28) a phase 3 study of chemotherapy + cetuximab combination versus 
chemotherapy + bevacizumab combination therapy as a first-line treatment of unresectable, 
advanced/recurrent colorectal cancer, the OS (median) of the FOLFOX group was 26.9 months among 
patients with KRAS wild-type cancer. 
Therefore, the OS (median) with mFOLFOX6 + bevacizumab combination therapy was assumed to be 
29 months in the present study in patients with RAS wild-type, unresectable, advanced/recurrent 
colorectal cancer. 
 
 
OS (median) with mFOLFOX6 + bevacizumab combination therapy reported so far 
Study name 
Phase 
Number of 
patients 
OS, median, 
months 
KRAS 
NO16966 
3  
349  
21.0 
Wild type / variant 
HORIZON III 
3  
713  
21.3 
Wild type / variant 
SOFT 
3  
159  
30.9 
Wild type / variant 
PEAK 
2  
143  
24.3 
Wild type 
PEAK 
2  
82  
28.9 
Wild type (including NRAS) 
CALGB/SWOG80405 
(FOLFOX group) 
3 
409  
26.9 
Wild type 
CALGB/SWOG80405 
(FOLFOX group) 
3  
192  
29.0 
Wild type (including NRAS) 
 
The median OS among patients with RAS wild-type cancer in the FOLFIRI + cetuximab group and the 
FOLFIRI + bevacizumab group was 33.1 and 25.6 months, respectively, in the FIRE-3 Study (phase 3 
study for comparing FOLFIRI + cetuximab with FOLFIRI + bevacizumab as a first-line treatment in 
patients with KRAS wild-type cancer with unresectable, advanced/recurrent colorectal cancer) of 
cetuximab, which has the same mechanism of action as panitumumab. The survival curve for each 
treatment group was almost overlapping up to 18 months, and showed tendency to change from then 
on. Also, the CALGB/SWOG80405 Study showed differences in the survival curve from the middle 
of the administration period, similar to that seen in the FIRE-3 Study. 
Based on the above, in this clinical study, as the survival curve is presumed to show group differences 
after 18 months, piecewise exponential distribution will be assumed and it will be assumed that the 
survival rate after 18 months would be 75% and the survival rate after 48 months would be 22% for 
the bevacizumab group and 32% for the panitumumab group. In order to verify the OS prolongation in 
FOLFOX + panitumumab combination therapy compared with FOLFOX + bevacizumab combination 
therapy based on the log-rank test with a one-sided significance level of 2.5%, by assuming the 
enrollment period to be 24 months with a constant rate of patient registration and enrollment, 
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assuming the follow-up period to be 36 months from the enrollment of the last patient, and assuming 
the drop-out rate to be 5%, a total of 800 patients (400 patients per group) were to be enrolled. By 
accumulating a total of 570 death events, a detection power of approximately 80% will be ensured. 
Therefore, a total of 800 patients (400 patients per group) were scheduled to be enrolled. 
[Detection power of main analysis of changed primary endpoint] (Added in the second version) 
The number of patients with a left-sided site is presumed to be 600, and death events are assumed to 
be 400 assuming that the total number of patients is 760 (800, taking a 5% drop-out rate into account) 
and the total number of death events is 570. The main objective of the protocol, after modification, is 
to verify the OS prolongation by mFOLFOX6 + panitumumab combination therapy versus 
mFOLFOX6 + bevacizumab combination therapy either in all sites or for left-sided sites. The 
following is the detection power with the log-rank test and a one-sided significance level of 1.25% for 
both all and left-sided sites. For left-sided sites, the hazard ratio for mFOLFOX6 + bevacizumab 
combination therapy and mFOLFOX6 + panitumumab combination therapy is presumed to be 0.68, 
0.70, 0.72, and 0.74, and the hazard of mFOLFOX6 + bevacizumab combination therapy is calculated 
based on the median survival time of the TRICOLORE Study (Table 1).  
For a primary tumor with occupying site on the right side (primary tumors occupying a right-sided site 
include cecum, ascending colon, transverse colon. Hereinafter referred to as “right side”), the median 
survival time for the right side of the FIRE-3 Study is used (Table 2). 
 
Efficacy of the treatment reported so far by primary tumor (RAS wild type, left side) 
Study 
CRYSTAL 
(Phase 3) 
PRIME 
(Phase 3) 
CALGB/SWOG 
80405 (Phase 3) 
FIRE-3 
(Phase 3) 
PEAK 
(Phase 2) 
Treatment 
group 
FOLFIRI 
FOLFIRI 
 + Cmab 
FOLFOX 
FOLFOX 
+ Pmab 
FOLFOX/ 
FOLFIRI 
+Bmab 
FOLFOX/ 
FOLFIRI 
+Cmab 
FOLFIRI 
+ Bmab 
FOLFIRI 
+ Cmab 
FOLFOX 
+ Pmab 
FOLFOX
+ Bmab 
No. of 
patients 
138 
142 
159 
169 
152 
173 
149 
157 
53 
54 
OS, 
median, 
months 
21.7 
28.7 
23.6 
30.3 
32.6 
32.9 
28.0 
38.3 
43.4 
32.0 
HR 
0.65 
0.73 
0.77 
0.63 
0.84 
95% CI 
0.50–0.86 
0.57–0.93 
0.59–0.99 
0.48–0.85 
0.22–3.27 
P value 
0.02 
not reported 
0.04 
0.002 
not reported 
 
Table 1. OS in the median survival time of the TRICOLORE Study 
TRICOLORE 
Treatment group 
mFOLFOX6 or CAPEOX 
+ bevacizumab combination therapy 
No. of patients 
243 
OS, median, months 
33.6 
 
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Table 2. OS in the median survival time of each group of the FIRE-3 Study (RAS wild type, right side) 
 
FIRE-3 
Treatment group 
FOLFIRI 
+ bevacizumab combination 
therapy 
FOLFIRI 
+ cetuximab combination 
therapy 
No. of patients 
50 
38 
OS, median, months 
23.0 
18.3 
 
The log-rank test with a one-sided significance level of 1.25% will be conducted for both all and left-
sided sites. The Monte Carlo simulation will be conducted, assuming an enrollment period of 
24 months and assuming 800 patients for all and 600 for left-sided sites in case of a follow-up period 
of 36 months from enrollment of the last patient, accumulating a total of 570 death events for all and 
400 for left-sided sites. As the result, the detection powers when “the log-rank test was significant in 
either all or left-sided sites” were as follows (Table 3). 
 
Table 3. Result of Monte Carlo simulation 
No. of patients 
Level of 
significance 
HR between the 
two groups in the 
left-sided site 
Detection 
power 
760 patients in all sites (380 
patients/group) 
600 patients in left-sided site 
(300 patients/group) 
One-sided 
1.25%, 
respectively* 
0.68 
91% 
0.70 
86% 
0.72 
79% 
0.74 
71% 
 
*: A significant group difference in either all or left-sided site will represent a significant difference 
between the mFOLFOX6 + bevacizumab combination therapy and mFOLFOX6 + panitumumab 
combination therapy. 
 
[Level of significance and detection power of main analysis of changed primary endpoint] (Added in 
the third version) 
 
Main analysis: 
For the OS concerning left-sided sites, a stratified log-rank test will be performed with stratification 
according to allocation factors other than study site. If the analysis for left-sided sites shows a 
significant intergroup difference, then the stratified log-rank test for all sites will be performed with a 
hierarchical testing procedure. 
 
Significance level for the main analysis: 
The number of death events for left-sided sites for the final analysis planned for 2021 is assumed to be 
420. The significance level for the final main analysis is discussed below.  
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In the previous (second) version of the protocol, which detailed plans to perform the interim analysis 
for both all sites and left-sided sites, the planned information time at interim analysis and the amount 
of alpha to be spent at interim analysis, as well as the computed planned nominal significance level for 
the final analysis were as follows: 
 
Nominal significance level for all sites (second version): 
Time of analysis 
Fraction of total events 
Nominal significance level 
(one-sided) 
Interim analysis 
71.2% 
0.00308 
Final analysis 
100.0% 
0.01154* 
 
Nominal significance level for left-sided sites (second version):  
Time of analysis 
Fraction of total events 
Nominal significance level 
(one-sided) 
Interim analysis 
70.5% 
0.00293 
Final analysis 
100.0% 
0.01159* 
 
*: The nominal significance level planned for the final analysis based on the amount of alpha to be 
spent at the interim analysis planned in the second version of the protocol. 
 
With a protocol amendment, the final main analysis was changed to be performed for left-sided sites, 
and, if the analysis shows a significant difference, then the stratified log-rank test for all sites will be 
performed with a hierarchical testing procedure. The nominal significance level for the analysis on 
left-sided sites is calculated as follows:  
(0.0125 − 0.00308) + 0.01159 = 0.02101 
Thus, the nominal significance level is set to one-sided 2.101% (corresponding to two-sided 4.202%). 
The rationale for this is as follows: 
Although the protocol was amended to perform the final main analysis only for left-sided sites, the 
interim analysis was conducted for all sites and left-sided sites. Because it is difficult to explicitly 
calculate correlation between the test statistic for left-sided sites at final analysis and the test statistic 
for all sites at interim analysis, the conservative range “0.0125－0.00308” is used. To this value, the 
nominal significance level of 0.01159 that can be spent for left-sided sites is added, and the resultant 
value is employed as the significance level for the final main analysis. 
 
Detection power for the main analysis: 
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When the log-rank test for left-sided sites is conducted with a one-sided significance level of 2.101% 
(two-sided 4.202%), the detection power is as follows: 
The hazard ratio for the mFOLFOX6 + bevacizumab combination therapy group was assumed on the 
basis of the median survival in the TRICOLORE Study (33.6 months). The Monte Carlo simulation was 
used to calculate the detection power of the log-rank test for 420 death events for left-sided sites. 
 
Table 2. Result of Monte Carlo simulation 
No. of patients 
Level of 
significance  
HR between the 
two groups in the 
left-sided site 
Detection 
power 
604 Patients in left-sided site 
One-sided 
2.101% 
0.70 
91% 
0.72 
87% 
0.74 
80% 
0.76 
71% 
 
 
Study period: 
Total study period: Approximately 95 months* 
Enrollment period: Approximately 27 months* 
Follow-up period: Approximately 56 months** after completion of enrollment 
Statistical period: Approximately 12 months after completion of follow-up 
*: After marketing approval of KRAS/NRAS test, enrollment will start when KRAS/NRAS can be 
measured at each site. 
**: Follow-up period can be ended once target events for final analysis have been observed. 
 
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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Unabbreviated expression 
5-FU 
fluorouracil  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BBP 
bevacizumab beyond first progression 
BSC 
best supportive care 
CEA 
carcinoembryonic antigen 
COI 
conflict of interest 
CR 
complete response 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
DCR 
disease control rate 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
G-CSF 
granulocyte colony stimulating factor 
HB 
hepatitis B 
HBc 
hepatitis B virus core antigen 
HBs 
hepatitis B surface 
HBv 
hepatitis B virus 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICH-GCP 
International Conference on Harmonisation E6 Good 
Clinical Practice 
IDMC 
independent data monitoring  
committee 
ICF 
informed consent form 
IRI 
irinotecan 
JAPIC 
Japan Pharmaceutical Information Center 
JCOG 
Japan Clinical Oncology Group 
jRCT 
Japan Registry of Clinical Trials 
KRAS 
Kirsten rat sarcoma-2 virus 
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Abbreviation 
Unabbreviated expression 
l-LV 
levofolinate calcium 
mCRC 
metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NE 
not all evaluated 
NRAS 
neuroblastoma rat sarcoma 
OS 
overall survival 
OXA 
oxaliplatin 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response 
P.S. 
performance status 
PT-INR 
prothrombin time–international normalized ratio 
RAS 
rat sarcoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
response rate 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
SoD 
sum of diameters 
SOP 
standard operating procedures 
TEAE 
treatment-emergent adverse event 
TTF 
time to treatment failure 
UPC 
urine protein creatinine 
VEGF 
vascular endothelial growth factor 
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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 
Etiology of colon cancer 
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. Overall, colorectal 
cancer is the third leading cause of cancer death among men in Japan. In women, lung cancer 
(13.8%) was also the leading cause of cancer death, followed by gastric cancer (11.6%) and colon 
cancer (11.1%); deaths from colorectal cancer (colon cancer and rectal cancer combined) 
accounted for 14.9% of cancer deaths. Overall, colorectal cancer is the first leading cause of 
cancer death among women in Japan. 
4.1.2 
Standard treatment for colon cancer 
The “Guidelines for Treatment of Colorectal Cancer (2014)” 2) classifies 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 Stages 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 treatments for unresectable, advanced/recurrent colorectal cancer that have been 
demonstrated to be useful in clinical studies and are currently covered by national health insurance 
in Japan are presented below. Also, cetuximab and panitumumab should be used for indications 
limited to Kirsten rat sarcoma-2 virus wild type (hereinafter referred to as KRAS). 
1. FOLFOX therapy + bevacizumab or CAPEOX therapy + bevacizumab* 
FOLFOX therapy: combination chemotherapy with fluorouracil (hereinafter referred to 
as 5-FU), levofolinate calcium (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† 
FOLFIRI therapy: combination chemotherapy with irinotecan (hereinafter referred to as 
IRI), 5-FU, and l-LV 
3. FOLFOX therapy + cetuximab*,† or panitumumab*,† 
4. FOLFIRI therapy + cetuximab*,† or panitumumab*,†  
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5. FOLFOXIRI therapy 
FOLFOXIRI therapy: combination chemotherapy with OXA, IRI, 5-FU, and l-LV 
6. FL‡ or capecitabine + bevacizumab* or UFT + l-LV  
UFT: combination preparation of tegafur and uracil 
*: 
Combination with molecular-targeted drugs such as bevacizumab or anti-epidermal 
growth factor receptor (hereinafter referred to as EGFR) antibody is recommended, but 
if combination therapy is not indicated then monochemotherapy will be conducted 
†: 
Indication only for KRAS wild type 
‡: 
Infusional 5-FU + l-LV 
FOLFOX-based therapy is more frequently selected as first-line treatment 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 for 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 for 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 for patients who have received bevacizumab as a first-line treatment. 
For third-line treatment, IRI + cetuximab or panitumumab combination therapy, cetuximab or 
panitumumab monotherapy, and regorafenib monotherapy, or symptomatic therapies, are 
currently recommended for patients with KRAS wild-type cancer. 
 
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 the long term. 3) On the 
basis of evidence showing that 5-FU combined with l-LV is superior to 5-FU monotherapy, the 
combination therapy of 5-FU and l-LV (hereinafter referred to as 5-FU/LV therapy) had been 
considered the standard chemotherapy for colorectal cancer for a long time. The type I 
topoisomerase inhibitor IRI and the third-generation platinum-based anticancer drug OXA were 
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then developed, and have been shown to improve treatment outcome in a number of large-scale 
controlled trials. 4)⁓9) At present, continuous infusion of 5-FU/LV in combination with OXA 
(FOLFOX therapy) or IRI (FOLFIRI therapy) is the standard chemotherapy regimen for 
advanced/recurrent colorectal cancer. 3), 10) FOLFOX and FOLFIRI therapies were compared in 
the GERCOR V308 study, 9) in which the median of final overall survival (hereinafter referred to 
as OS) was similar between the FOLFIRI-first and the FOLFOX-first arms (21.5 months vs 
20.6 months), and therefore both of the therapies are used as the standard for unresectable 
colorectal cancer. The development of these therapies increased 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 mFOLFOX6) therapy, which include OXA at the approved dosage (85 mg/m2) in 
Japan, are covered by national health insurance. The simpler and easier mFOLFOX6 therapy is 
more frequently used. 
4.1.4 
Efficacy and safety of panitumumab in patients with 
unresectable, advanced/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 a role in the pathogenesis and progression of tumors. 
Binding of epidermal growth factor, the major ligand of EGFR, to EGFR is considered to induce 
autophosphorylation 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 to EGFR with specificity and high affinity, and inhibits the proliferation of tumor cells by 
competitively inhibiting the binding of the ligand to EGFR. 11) 
4.1.4.2 Clinical study results for panitumumab in the US and Europe 
As a clinical trial of panitumumab monotherapy for colorectal cancer, a phase 3 study was 
conducted to compare best supportive care (hereinafter referred to as BSC) versus BSC + 
panitumumab therapy in patients with unresectable, recurrent/advanced, EGFR-positive colorectal 
cancer that became resistant to fluoropyrimidine agents, OXA, and IRI (BSC group, 232 patients; 
BSC + panitumumab group, 231 patients). 12) The median of the primary endpoint of progression-
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free survival (hereinafter referred to as PFS) with BSC alone was 7.3 weeks, whereas with BSC + 
panitumumab therapy it was 8 weeks, which is significantly longer than that of BSC and shows 
the efficacy of panitumumab therapy (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 groups (HR, 1.00; two-sided 95% CI, 0.82 to 1.22; p=0.81); however, this may 
be attributed to the 173 patients (75%) in the BSC group who received follow-up therapy with 
panitumumab. 
With regard to clinical study of the combination of chemotherapy and panitumumab, a phase 3 
clinical study (PRIME Study) has been reported, in which FOLFOX4 monotherapy was compared 
with FOLFOX4 therapy + panitumumab (given at a dose of 6 mg/kg every 2 weeks) as a first-line 
treatment in a total of 1,180 patients (590 in each group). 13) The primary endpoint of median PFS 
in patients with KRAS wild-type cancer was 9.6 months in the FOLFOX4 + panitumumab group, 
which is significantly longer than the 8.0 months in the FOLFOX4 alone group (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, diarrhea, and hypomagnesemia occurred more frequently 
in the FOLFOX4 + panitumumab group, but there were no major differences in the incidence of 
other adverse events between the two groups. Grade 3 infusion reaction occurred in two patients 
(Table 4.a). 
Table 4.a Grade 3/4 adverse events reported in patients with KRAS wild-type cancer 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 
Diarrhea 
59 
18 
29 
9 
Nerve disorder 
52 
16 
51 
16 
Hypokalemia 
32 
10 
15 
5 
Malaise 
30 
9 
10 
3 
Stomatitis 
28 
9 
2 
<1 
Hypomagnesemia 
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 
- 
- 
 
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With regard to second-line treatment, a phase 3 clinical study (Study 20050181) has been 
conducted, in which FOLFIRI monotherapy was compared with FOLFIRI therapy + 
panitumumab (given at a dose of 6 mg/kg every 2 weeks).14) The primary endpoints were PFS and 
OS in patients with KRAS wild-type cancer. In patients with KRAS wild-type cancer, PFS was 
5.9 months and significantly longer in the FOLFIRI + panitumumab group than 3.9 months in the 
FOLFIRI alone group (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 group and 12.5 months in the FOLFIRI 
alone group, with no statistically significant difference between the two groups (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 + panitumumab group as compared with 10% in the FOLFIRI alone 
group. Of grade 3/4 adverse events, the incidence of dermatologic toxicities was higher and the 
incidences of diarrhea and hypomagnesemia tended to be higher in the FOLFIRI + panitumumab 
group; however, there were no major differences in the incidence of toxicities including 
hematologic toxicities between the two groups, and the incidence of infusion reaction was not 
more than 1%. 
Both the PRIME Study 13) and Study 20050181 14) 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 1 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; 
ie, 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 six patients, and tolerance was ratified. 
In a Japanese phase 2 clinical study of panitumumab monotherapy,15) 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 3 clinical 
study, was well tolerated, and the incidence of adverse events was similar to that observed in the 
US and Europe (Table 4.b). In addition, seven 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 PFS of 
8.0 weeks (two-sided 95% CI: 7.4 to 11.4), and an OS of 9.3 months (two-sided 95% CI: 7.1 to 
12.8), similar to those observed in clinical studies in the US and Europe. 
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On the basis of the above results, panitumumab was approved in April 2010 for the treatment of 
unresectable, advanced/recurrent colorectal cancer in Japan. 
Table 4.b Common adverse events (≥20%) noted in a Japanese phase 2 clinical study of 
panitumumab monotherapy 
Adverse events 
Panitumumab monotherapy (n=52) 
Any grade 
Grade 3 or higher 
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 
Hypomagnesemia 
17 
33 
0 
- 
Malaise 
13 
25 
0 
- 
Stomatitis 
12 
23 
0 
- 
Anorexia 
11 
21 
1 
2 
4.1.4.4 Specified drug use surveillance results (all patients surveillance) in Japan 
In the post-marketing surveillance conducted for a fixed period where all the patients treated were 
registered, 16) the median treatment period (first day of treatment to the final day of treatment) for 
the 3,085 patients who were patient to safety evaluation was 113 days, incidence of adverse 
reaction was 84.1% (25.8% ≥ grade 3), of which the panitumumab monotherapy group with 
1,254 patients was 80.1% (19.7% ≥ grade 3), and the panitumumab + chemotherapy combination 
group with 1,831 patients was 86.9% (30.0% ≥ grade 3). The occurrence status of intensively 
investigated adverse reaction items are listed in Table 4.c. 
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Table 4.c Common adverse events in specified drug use surveillance in Japan 
All patient surveillance  
Panitumumab monotherapy group 
(n=1,254) 
Panitumumab + chemotherapy 
combination group (n=1,831) 
All grades 
≥ Grade 3  
All grades 
≥ Grade 3  
Intensively investigated 
item 
n 
% 
n 
% 
n 
% 
n 
% 
Skin & subcutaneous 
tissue disorders (SOC) 
918 
73.2 
118 9.4 
1,446 
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. 
*: Interstitial pneumonia subcommittee criteria 
4.1.5 
Efficacy and safety of bevacizumab in patients with 
unresectable, advanced/recurrent colorectal cancer 
Bevacizumab is an IgG1 humanized monoclonal antibody that binds to vascular endothelial 
growth factor (hereinafter referred to as VEGF), a protein that plays a critical role in tumor 
angiogenesis. Bevacizumab inhibits the binding of VEGF to its receptor and thereby inhibits 
angiogenic signals. 
A phase 3 study (Study AVF2107g) 17) was conducted to investigate the efficacy of bevacizumab 
used in combination with IFL therapy (combination chemotherapy with IRI and bolus intravenous 
infusion of 5-FU and LV), which is a first-line treatment of unresectable, advanced/recurrent 
colorectal cancer, by comparing IFL + bevacizumab combination therapy with IFL monotherapy. 
The RR, PFS (median), and OS (median) were 44.8% (p=0.004), 10.6 months (HR = 0.54, 
p<0.001), and 20.3 months (HR=0.66, p<0.001) in the IFL + bevacizumab group, as compared 
with 34.8%, 6.2 months, and 15.6 months in the IFL alone group. These results show the 
superiority of IFL + bevacizumab combination therapy in all endpoints. In addition, Study 
NO16966, 18) in which the combination of bevacizumab and FOLFOX therapy or CAPEOX 
therapy as a first-line treatment was investigated, also demonstrated that the primary endpoint of 
PFS was significantly prolonged in the bevacizumab combination therapy with 
FOLFOX/CAPEOX + bevacizumab group at 9.4 months versus the FOLFOX/CAPEOX alone 
group at 8.0 months (HR=0.83, p=0.0023). Common adverse events in the two studies are listed in 
Table 4.d. 
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Table 4.d Incidence of serious adverse events (≥ grade 3) reported with bevacizumab 
Therapy 
Study AVF2107g  
Study NO16966  
IFL 
+ bevacizumab 
(n=392) 
FOLFOX 
+ bevacizumab 
(n=342) 
CAPEOX 
+ bevacizumab 
(n=353) 
No. (%) 
Venous thromboembolism  
Grade 3: 
35 (8.8) 
Grade 4: 
15 (3.8) 
32 (9.4) 
22 (6.2) 
Gastrointestinal perforation 
8 (2.0) 
1 (0.3) 
3 (0.8) 
Hemorrhage 
Grade 3: 
10 (2.6) 
Grade 4: 
3 (0.8) 
7 (2.0) 
6 (1.7) 
Complications 
due 
to 
delayed 
healing of wound 
5 (8.3) 
9 (2.6) 
3 (0.8) 
With regard to second-line treatment, a randomized controlled study (Study E3200) 19) was 
conducted to investigate the efficacy of FOLFOX4 + bevacizumab combination therapy as 
compared with FOLFOX4 monotherapy in patients who were resistant to IRI + 5-FU combination 
therapy. The OS (median) was 12.9 months in the FOLFOX4 + bevacizumab group, which was 
significantly prolonged in comparison with 10.8 months in the FOLFOX4 alone group (HR=0.75, 
p<0.0011). The PFS (median) was also significantly longer in the FOLFOX4 + bevacizumab 
group, at 7.3 months as compared with 4.7 months in the FOLFOX4 alone group (HR=0.61, 
p<0.0001). In addition, the usefulness of chemotherapy + continued bevacizumab therapy 
(bevacizumab beyond first progression: BBP) as a second-line treatment was investigated in 
patients with unresectable, advanced/recurrent colorectal cancer who had progressive disease 
(hereinafter referred to as PD) after bevacizumab combination chemotherapy (Study ML18147). 
20) The OS (median) was significantly longer in the chemotherapy + BBP group at 11.2 months as 
compared with 9.8 months in the chemotherapy alone group (HR=0.81, p=0.0062), and the PFS 
was also significantly longer in the chemotherapy + BBP group at 5.7 months as compared with 
4.1 months in the chemotherapy alone group (HR=0.68, p<0.0001). BBP did not increase serious 
adverse events. 
Factors for predicting the therapeutic effect of bevacizumab (hereinafter referred to as biomarkers) 
have also been investigated. Study AVAGAST, 21) in which the usefulness of bevacizumab for 
advanced stomach cancer was investigated, reported that serum VEGF-A level and expression of 
neuropilin-1 in tumor tissue were candidates for predictive factors of the therapeutic effect of 
bevacizumab. However, no definite biomarker has been established yet. 
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4.1.6 
RAS (KRAS/NRAS) mutation and panitumumab in 
unresectable, advanced/recurrent colorectal cancer 
In a phase 3 study (Study 20040408) of panitumumab monotherapy that investigated its efficacy 
as a third-line treatment in patients with unresectable, advanced/recurrent colorectal cancer who 
had received standard treatment, an exploratory biomarker analysis was performed. The results 
showed that the presence or absence of mutations in not only KRAS exon 2 but also in KRAS 
exons 3 and 4 or neuroblastoma rat sarcoma (hereinafter referred to as NRAS) exons 2, 3, and 4 
may be predictive factors of the effect of panitumumab. 22) 
Among the patients enrolled in the PRIME Study, 23) those who were determined to have wild-
type KRAS exon 2 tumors by Therascreen® KRAS Mutation Kit were analyzed for the relationship 
between PFS and OS and the presence or absence of mutations in the genes of KRAS exons 3 
(codon 61) and 4 (codons 117, 146), NRAS exons 2 (codons 12, 13), 3 (codon 61), and 4 (codons 
117, 146), and BRAF exon 15 (codon 600) in the tumor. These mutations were analyzed with 
DNA sequencing by the Sanger method and WAVE-based SURVEYOR® Scan Kit. 
In patients with KRAS wild-type and NRAS wild-type colorectal cancer (hereinafter referred to as 
RAS wild type), OS (median) was significantly prolonged by 5.6 months in the FOLFOX + 
panitumumab group at 25.8 months as compared with 20.2 months in the FOLFOX alone group 
(HR= 0.77, two-sided 95% CI: 0.64 to 0.94, p=0.009) (Figure 4.a). In patients with RAS mutation 
(KRAS or NRAS mutation), on the other hand, the median OS was significantly shorter in the 
FOLFOX + panitumumab group at 15.5 months as compared with 18.7 months in the FOLFOX 
alone group (HR=1.21, two-sided 95% CI: 1.01 to 1.45, p=0.04). 
 
Figure 4.a Overall survival in patients with RAS wild-type cancer in the PRIME Study 
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The PEAK Study is a randomized phase 2 study to compare mFOLFOX6 + panitumumab 
combination therapy and mFOLFOX6 + bevacizumab combination therapy as a first-line 
treatment of unresectable, advanced/recurrent colorectal cancer. 24) 
DNA sequencing by the Sanger method and WAVE-based SURVEYOR Scan Kit were used to 
determine whether or not gene mutations existed. Patients with and without gene mutations in 
KRAS exon 2 (codons 12, 13), exon 3 (codons 59, 61), or 4 (codons 117, 146) and NRAS exon 2 
(codons 12, 13), 3 (codons 59, 61), or 4 (codons 117, 146) were grouped into RAS mutation and 
RAS wild type, respectively. Additional analysis was performed for PFS and OS. 
The median of PFS, the primary endpoint, was 10.9 months in the mFOLFOX6 + panitumumab 
group and 10.1 months in the mFOLFOX6 + bevacizumab group (HR=0.87, two-sided 95% CI: 
0.65 to 1.17, p=0.353); these are not significantly different. In patients with RAS wild-type cancer, 
however, the median PFS was 13.0 months in the mFOLFOX6 + panitumumab group and 
9.5 months in the mFOLFOX6 + bevacizumab group (HR=0.65, two-sided 95% CI: 0.44 to 0.96, 
p=0.029), which shows that the PFS was significantly prolonged in the mFOLFOX6 + 
panitumumab group. In RAS-mutant patients, on the other hand, the median PFS was not 
significantly different between the two groups, at 7.8 months for the mFOLFOX6 + panitumumab 
group and 8.9 months for the mFOLFOX6 + bevacizumab group (HR=1.39, two-sided 95% CI: 
0.73 to 2.64, p=0.32). 
The median of OS was 34.2 months (incidence of events: 37%) in the mFOLFOX6 + 
panitumumab group, which is significantly longer than the 24.3 months (55%) in the mFOLFOX6 
+ bevacizumab group (HR=0.62, two-sided 95% CI: 0.44 to 0.89, p= 0.009). In patients with RAS 
wild-type cancer, moreover, it was 41.3 and 28.9 months (HR=0.63, two-sided 95% CI: 0.39 to 
1.02, p=0.058), respectively, which shows that the outcome tended to be more favorable in the 
mFOLFOX6 + panitumumab arm (Figure 4.b). 
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Figure 4.b Overall survival in panitumumab and bevacizumab arms in the PEAK Study 
In conclusion, in terms of both PFS and OS, mFOLFOX6 + panitumumab combination therapy 
has been shown to be superior to mFOLFOX6 + bevacizumab combination therapy as a first-line 
treatment of colorectal cancer with wild-type KRAS (exons 2, 3, and 4) and wild-type NRAS 
(exons 2, 3, and 4). 
In addition to the above studies, several post hoc analyses have shown that that anti-EGFR 
antibody drugs are ineffective in patients with KRAS (exons 3 and 4) and NRAS (exons 2, 3, and 4) 
mutations. 25) 
It has been recognized that evaluation of the presence or absence of RAS (KRAS/NRAS, hereinafter 
referred to as RAS) mutations other than KRAS exon 2 should be added. The Japanese Society of 
Medical Oncology has published “Guidance for measuring RAS (KRAS/NRAS) mutations in 
colorectal cancer patients.” 26) 
 
4.2 
Rationale for the proposed study 
As of November 2014, it is unclear which molecular target drug, bevacizumab or anti-EGFR 
antibody, should be used in first-line treatment of chemotherapy-naïve, unresectable, 
advanced/recurrent colorectal cancer, and several controlled studies are currently ongoing and being 
analyzed. 
The PEAK Study, conducted by Schwartzberg et al., 24) had results similar to those described above: 
for patients with RAS wild type, including KRAS/NRAS wild types besides KRAS exon 2, 
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mFOLFOX6 + panitumumab combination therapy was shown to be superior in both PFS and OS in 
comparison to mFOLFOX6 + bevacizumab combination therapy as a first-line treatment for 
unresectable, advanced/recurrent colorectal cancer. The FIRE-3 Study, conducted by Heinemann et 
al., 27) is a phase 3 study directly comparing FOLFIRI + cetuximab and FOLFIRI + bevacizumab as 
first-line treatment for patients with KRAS exon 2 wild-type, unresectable, advanced/recurrent 
colorectal cancer. In patients with KRAS exon 2 wild-type cancer, the FOLFIRI + cetuximab 
combination group showed statistical significance in prolongation with a median OS 3.7 months 
longer than that in the FOLFIRI + bevacizumab combination group. Further, when limited to 
patients with RAS wild-type cancer through retrospective analysis, the cetuximab combination 
significantly improved the median OS by 7.5 months in comparison to the bevacizumab combination 
group. The CALGB/SWOG 80405 Study is a large-scale, phase 3 study directly comparing 
cetuximab and bevacizumab for combination therapy with mFOLFOX6 or FOLFIRI. In the 
CALGB/SWOG 80405 Study report for the American Society of Clinical Oncology 2014 
meeting, 28) unlike the PEAK Study and FIRE-3 Study, no difference was shown in OS and PFS 
between the EGFR antibody plus chemotherapy group and the bevacizumab plus chemotherapy 
group, even in patients with KRAS wild-type cancer. Further, at the European Society for Medical 
Oncology 2014 meeting, a retrospective analysis result of patients with RAS wild type in the same 
study was described, 29) and the median OS was 32.0 months for the cetuximab combination group 
for all chemotherapy and 31.2 months for the bevacizumab combination group for all chemotherapy; 
thus, no significant difference was shown (HR=0.9, two-sided 95% CI: 0.7 to 1.1, p=0.40). 
FOLFOX was selected for chemotherapy in 70% of the patients participating in the 
CALGB/SWOG80405 study. In the analysis of each chemotherapy in the FOLFOX group, the 
median OS was 32.5 months in the cetuximab combination group and 29.0 months in the 
bevacizumab combination group. This slight difference is not statistically significant (HR=0.86, 
two-sided 95% CI: 0.6 to 1.1, p=0.2).  
From the above results, consensus has not been reached about whether to choose bevacizumab or 
anti-EGFR antibody as a molecular-targeted drug for combination therapy in the first-line treatment 
of RAS wild-type, unresectable, advanced/recurrent colorectal cancer. Also, results from these 
studies (PEAK Study, FIRE-3 Study, and CALGB/SWOG80405 study) were based on results from 
post hoc analyses of prospective studies, and as of November 2014, a prospective comparative study 
limited to RAS wild type has not been conducted. 
With this background, in order to determine the molecular-targeted drug to be used in combination 
with mFOLFOX6 therapy, we considered it necessary to prospectively verify that mFOLFOX6 + 
panitumumab combination therapy prolongs OS as compared with mFOLFOX6 + bevacizumab 
combination therapy for first-line treatment in patients with RAS wild-type, unresectable, 
advanced/recurrent colorectal cancer. Therefore, we planned this study. 
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5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY 
5.1 
Objective 
To verify that mFOLFOX6 + panitumumab combination therapy prolongs OS as compared with 
mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naïve 
patients with RAS wild-type, unresectable, advanced/recurrent colorectal cancer. 
 
5.2 
Definition of endpoints 
5.2.1 
Primary endpoint 
The following item concerning all and left-sided sites: 
Overall survival (OS) 
 
5.2.2 
Secondary endpoints 
The following items concerning all and left-sided sites: 
Efficacy 
Progression-free survival (PFS) 
Response rate (RR) 
Duration of response (DOR) 
Curative resection (complete resection, hereinafter referred to as R0) rate 
Safety 
Percentage of patients with adverse events 
 
5.2.3 
Exploratory endpoint 
 
 
 
 
 
 
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5.3 
Rationale for the endpoints 
5.3.1 
Primary endpoint 
The OS was selected as the primary endpoint because it is considered to be the most important 
efficacy measure in the first-line treatment of unresectable, advanced/recurrent colorectal cancer. 
Given that retrospective analyses and meta-analyses of several large-scale clinical studies in 
recent years showed that treatment sensitivity and prognosis vary according to differences in the 
location of the primary site in unresectable, advanced/recurrent colorectal cancer, it was decided 
to evaluate the endpoint for all and left-sided sites separately. 
 
5.3.2 
Secondary endpoints 
The PFS, RR, and DOR were selected as secondary endpoints because they reflect the antitumor 
efficacy. The percentage of patients treated with R0 resection after chemotherapy was also 
selected as the secondary endpoint because it is suggested that R0 resection following 
chemotherapy may contribute to prolonged survival of patients with unresectable colorectal 
cancer. 
In addition, the percentage of patients with adverse events was selected as a secondary endpoint, 
because safety is also an important factor in treatment selection. 
It was decided to evaluate the secondary endpoints for all and left-sided sites, as will be done for 
the primary endpoint. 
 
5.4 
Additional research 
In an exploratory manner according to the Ethical Guideline for Clinical Research, blood and 
tumor tissue samples will be used for additional research to assess biomarkers that may be 
predicting factors for the therapeutic effect of the tested treatments. Details will be determined in a 
separately prepared protocol. The additional research will be conducted at a study site that has 
been approved by the site director on the basis of approval of the ethics review board, etc. Also, 
among the participants in this study, patients will only participate in the additional research if 
consent has been confirmed with an ICF relevant to the additional research. 
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6.0 
CLINICAL STUDY DESIGN 
6.1 
Clinical study design 
This study is a phase 3, randomized, controlled study to verify that mFOLFOX6 + panitumumab 
combination therapy prolongs OS versus mFOLFOX6 + bevacizumab combination therapy in first-
line treatment of chemotherapy-naïve patients with RAS wild-type, unresectable, advanced/recurrent 
colorectal cancer. Patients who are judged eligible for the study on the basis of the inclusion and 
exclusion criteria will be randomized to either the mFOLFOX6 + panitumumab arm or mFOLFOX6 
+ bevacizumab arm in a 1:1 ratio at the time of registration. See Section “8.0 PROTOCOL 
TREATMENT” for details of treatment. 
For randomization, a minimization method will be performed with the allocation factors of study 
site, age (20 to 64 years/65 to 79 years), and presence/absence of liver metastasis. 
Protocol study of both treatment groups will be started within 14 days (2 weeks) after enrollment.  
Protocol treatment will be continued until the criteria in Section “8.7 Criteria for discontinuation of 
protocol treatment for individual ” are met. Treatment may be performed for inpatients or 
outpatients. 
 
 
Untreated mCRC with RAS wild-type, chemotherapy-naïve patients with RAS wild-type, unresectable, 
advanced/recurrent colorectal cancer; R, registration and randomization with allocation factors of study site, age at 
the time of entry (20 to 64 years/65 to 79 years), and liver metastasis (presence/absence). 
Figure 6.a Outline of study design 
 
 
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6.2 
Rationale for study design 
6.2.1 
Study population 
To verify the superiority of mFOLFOX6 + panitumumab combination therapy over mFOLFOX6 
+ bevacizumab combination therapy in prolonging OS in first-line treatment, chemotherapy-naïve 
patients with unresectable, advanced/recurrent colorectal cancer will be included in the study. The 
patients should also be RAS wild type, because the above-mentioned analysis results in the 
PRIME 23) and PEAK 24) studies suggest that panitumumab may be the most effective in these 
patients. 
KRAS/NRAS tests will be performed with an in vitro diagnostic that has been approved for 
marketing. 
 
6.2.2 
Treatment regimens and planned number of patients 
6.2.2.1 Reason for selecting mFOLFOX6 +bevacizumab combination therapy and 
mFOLFOX6 + panitumumab combination therapy as the treatment 
regimens 
As described in Section 4.1.2, the following regimens are shown in the “Guidelines for Treatment 
of Colorectal Cancer (2014)” as first-line treatments for patients with unresectable, 
advanced/recurrent colorectal cancer. 
1. 
FOLFOX therapy + bevacizumab or CAPEOX therapy + bevacizumab 
2. 
FOLFIRI therapy + bevacizumab 
3. 
FOLFOX therapy + cetuximab or panitumumab 
4. 
FOLFIRI therapy + cetuximab or panitumumab 
5. 
FOLFOXIRI therapy 
6. 
FL or capecitabine + bevacizumab or UFT + LV 
In Japan, FOLFOX-based therapy is more frequently selected as first-line treatment for 
unresectable, advanced/recurrent colorectal cancer 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). On the other hand, the phase 2 PEAK Study 24) suggested that panitumumab may be 
superior to bevacizumab in prolonging OS when used in combination with FOLFOX-based 
chemotherapy for RAS wild-type colorectal cancer. As of November 2014, however, no phase 3 
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study has been conducted to compare the two combination therapies, and this is an important 
clinical issue to be addressed. Therefore, the present study is designed to assess the superiority of 
mFOLFOX6 + panitumumab combination therapy as compared with mFOLFOX6 + bevacizumab 
combination therapy, the most widely used first-line treatment for unresectable, 
advanced/recurrent colorectal cancer for RAS wild type. 
6.2.2.2 Rationale for planned number of patients 
The planned number of randomized patients is set at 400 per group, for a total of 800 patients. The 
rationale is described below. 
Table 6.a shows the OS (median) in clinical studies of mFOLFOX6 + bevacizumab combination 
therapy in chemotherapy-naïve patients with advanced/recurrent colorectal cancer. The OS was 
reported to be between 21.0 and 30.9 months in the NO16966 Study, HORIZON III Study, and 
SOFT Study, and all studies were performed in patients with advanced/recurrent colorectal cancer 
not limited to KRAS wild type. The OS (median) of patients with KRAS wild-type cancer was 24.3 
months in the PEAK Study, which was a randomized controlled phase 2 study of mFOLFOX6 + 
panitumumab combination therapy versus mFOLFOX6 + bevacizumab combination therapy as a 
first-line treatment of unresectable, advanced/recurrent colorectal cancer. Also, in the 
CALGB/SWOG80405 Study, 28) a phase 3 study of chemotherapy + cetuximab combination or 
chemotherapy + bevacizumab combination therapy as a first-line treatment of unresectable, 
advanced/recurrent colorectal cancer, the OS of the FOLFOX group was 26.9 and 29.0 months 
among patients with KRAS and RAS wild-type cancer, respectively. 
Therefore, the OS with mFOLFOX6 + bevacizumab combination therapy was assumed to be 29 
months in the present study in patients with RAS wild-type, unresectable, advanced/recurrent 
colorectal cancer. 
Table 6.a Overall survival (OS) (median) with mFOLFOX6 + bevacizumab combination therapy 
reported so far 
Study name 
Phase 
Number of 
patients 
OS 
(median), 
months 
KRAS 
NO16966 
3  
349  
21.0 
Wild type/variant 
HORIZON III 
3  
713  
21.3 
Wild type/variant 
SOFT 
3  
159  
30.9 
Wild type/variant 
PEAK 
2  
143  
24.3 
Wild type 
PEAK 
2  
82  
28.9 
Wild type (including 
NRAS) 
CALGB/SWOG80405
(FOLFOX group) 
3 
409  
26.9 
Wild type 
CALGB/SWOG80405
(FOLFOX group) 
3  
192  
29.0 
Wild type (including 
NRAS) 
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The median OS among patients with RAS wild-type cancer in the FOLFIRI + cetuximab group and 
FOLFIRI + bevacizumab group was 33.1 and 25.6 months, respectively, in the FIRE-3 Study (phase 
3 study for comparing FOLFIRI + cetuximab with FOLFIRI + bevacizumab as a first-line treatment 
in patients with KRAS wild-type cancer with unresectable, advanced/recurrent colorectal cancer) of 
cetuximab, which has the same mechanism of action as panitumumab. The survival curve for each 
treatment group was almost overlapping up to 18 months, and showed a tendency to diverge from 
then on. The CALGB/SWOG80405 Study also showed differences in the survival curve from the 
middle of the administration period, similar to those seen in the FIRE-3 Study. 
On the basis of the above data, the survival curve in this study is presumed to show group 
differences after 18 months, piecewise exponential distribution will be assumed with a survival rate 
after 18 months of 75%, and the survival rate after 48 months is assumed to be 22% for the 
bevacizumab group and 32% for the panitumumab group.  
In order to verify the OS prolongation with FOLFOX + panitumumab combination therapy 
compared with FOLFOX + bevacizumab combination therapy on the basis of the log-rank test with a 
one-sided significance level of 2.5%, assuming the enrollment period to be 24 months and a constant 
rate of patient registration and enrollment, the follow-up period to be 36 months from the enrollment 
of the last patient, and the drop-out rate to be 5%, a total of 800 patients (400 patients per group) 
were to be enrolled. By accumulating a total of 570 death events, a detection power of approximately 
80% will be ensured. Therefore, a total of 800 patients (400 patients per group) were scheduled to be 
enrolled. 
The number of patients was calculated by assuming a median OS of 29 months in the bevacizumab 
group, but ensuring the scheduled number of events during the follow-up period may become 
difficult when OS is improved in both the bevacizumab group and the panitumumab group. The 
number of patients may be calculated again to ensure the required number of events, depending on 
the level of OS in the two groups reported by periodic monitoring report under blinded conditions. 
[Detection power of the main analysis of changed primary endpoint] (Added in the second version) 
The number of patients with a left-sided site is presumed to be 600 and the number of death events is 
assumed to be 400 when it is assumed that the total number of patients is 760 (800, taking the 5% drop-
out rate into account) and the total number of death events is 570. The main objective of the protocol after 
modification is to verify the OS prolongation by mFOLFOX6 + panitumumab combination therapy in 
comparison with mFOLFOX6 + bevacizumab combination therapy either in all or left-sided sites. The 
following is the detection power when the log-rank test with a one-sided significance level of 1.25% is 
conducted for both all and left-sided sites.  
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For left-sided sites, the HR in mFOLFOX6 + bevacizumab combination therapy and mFOLFOX6 + 
panitumumab combination therapy is presumed to be 0.68, 0.70, 0.72, and 0.74, and the hazard of 
mFOLFOX6 + bevacizumab combination therapy is calculated based on the median survival time of the 
TRICOLORE Study (Table 1).  
For the right side, the median survival time for the right side of the FIRE-3 Study is used (Table 2). 
 
Efficacy of the treatment reported so far by primary tumor (RAS wild type, left side) 
Study 
CRYSTAL 
(phase 3) 
PRIME 
(phase 3) 
CALGB/SWOG 
80405 (phase 3) 
FIRE-3 
(phase 3) 
PEAK 
(phase 2) 
Treatment 
group 
FOLFIRI 
FOLFIRI 
 + Cmab 
FOLFOX 
FOLFOX 
+ Pmab 
FOLFOX/F
OLFIRI + 
Bmab 
FOLFOX/F
OLFIRI + 
Cmab 
FOLFIRI 
+ Bmab 
FOLFIRI 
+ Cmab 
FOLFOX 
+ Pmab 
FOLFOX 
+ Bmab 
No. of 
patients 
138 
142 
159 
169 
152 
173 
149 
157 
53 
54 
OS 
(months, 
median) 
21.7 
28.7 
23.6 
30.3 
32.6 
32.9 
28.0 
38.3 
43.4 
32.0 
HR 
0.65 
0.73 
0.77 
0.63 
0.84 
95% CI 
0.50–0.86 
0.57–0.93 
0.59–0.99 
0.48–0.85 
0.22–3.27 
P value 
0.02 
not reported 
0.04 
0.002 
not reported 
 
Table 1. Median overall survival time of the TRICOLORE Study 
TRICOLORE 
Treatment group 
mFOLFOX6 or CAPEOX 
+ bevacizumab combination therapy 
No. of patients 
243 
OS, median, months 
33.6 
 
Table 2. Median overall survival time of each group of the FIRE-3 Study (RAS wild type, right side) 
 
FIRE-3 
Treatment group 
FOLFIRI 
+ bevacizumab combination 
therapy 
FOLFIRI 
+ cetuximab combination 
therapy 
No. of patients 
50 
38 
OS, median, months 
23.0 
18.3 
 
The log-rank test with a one-sided significance level of 1.25% will be conducted for both all and left-
sided sites. A Monte Carlo simulation was conducted, assuming an enrollment period of 24 months and 
numbers of 800 patients for all and 600 for left-sided sites, allowing for a follow-up period of 36 months 
from enrollment of the last patient, accumulating a total of 570 death events for all and 400 for left-sided 
sites. As the result, the detection powers when “the log-rank test was significant in either all or left-sided 
sites was significant” were as follows (Table 3). 
Table 3. Results of Monte Carlo simulation 
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No. of patients 
Level of 
significance 
HR between the 
two groups in the 
left-sided site 
Detection 
power 
760 patients in all sites (380 
patients/group) 
600 patients in left-sided site 
(300 patients/group) 
One-sided 
1.25%* 
0.68 
91% 
0.70 
86% 
0.72 
79% 
0.74 
71% 
 
*: A significant group difference in either all or left-sided sites will represent a significant difference 
between the mFOLFOX6 + bevacizumab combination therapy and mFOLFOX6 + panitumumab 
combination therapy. 
 
[Level of significance and detection power of main analysis of changed primary endpoint] (Added in the 
third version) 
The protocol was amended (approved by the clinical research steering committee on March 17, 2020) to 
change the main analysis as follows: 
 
Main analysis: 
For the OS concerning left-sided sites, a stratified log-rank test will be performed with stratification 
according to allocation factors other than study site. If the analysis for left-sided sites shows a significant 
intergroup difference, then the stratified log-rank test for all sites will be performed with a hierarchical 
testing procedure. 
 
Significance level for the main analysis:  
The number of death events for left-sided sites for the final analysis planned for 2021 is assumed to be 
420. The significance level for the final main analysis is discussed below. 
 
In the previous (second) version of the protocol, which detailed plans to perform the interim analysis for 
both all sites and left-sided sites, the planned information time at interim analysis and the amount of alpha 
to be spent at interim analysis, as well as the computed planned nominal significance level for the final 
analysis, were as follows: 
 
Nominal significance level for all sites (second version):  
Time of analysis 
Fraction of total events 
Nominal significance level 
(one-sided) 
Interim analysis  
71.2% 
0.00308 
Final analysis 
100.0% 
0.01154* 
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Nominal significance level for left-sided sites (second version):  
Time of analysis 
Fraction of total events 
Nominal significance level 
(one-sided) 
Interim analysis  
70.5% 
0.00293 
Final analysis 
100.0% 
0.01159* 
 
*: The nominal significance level planned for the final analysis is based on the amount of alpha 
to be spent at the interim analysis planned in the second version of the protocol. 
 
With a protocol amendment, the final main analysis was changed to be performed for left-sided sites, and, 
if the analysis shows a significant difference, then the stratified log-rank test for all sites will be 
performed with a hierarchical testing procedure. The nominal significance level for the analysis on left-
sided sites is calculated as follows: 
(0.0125 − 0.00308) + 0.01159 = 0.02101 
Thus, the nominal significance level is set to one-sided 2.101% (corresponding to two-sided 4.202%). 
The rationale for this is as follows: Although the protocol was amended to perform the final main analysis 
only for left-sided sites, the interim analysis was conducted for all sites and left-sided sites. Given that it 
is difficult to explicitly calculate correlation between the test statistic for left-sided sites at final analysis 
and the test statistic for all sites at interim analysis, the conservative range of 0.0125–0.00308 is used. To 
this value, the nominal significance level of 0.01159 that can be spent for left-sided sites is added, and the 
resultant value is employed as the significance level for the final main analysis. 
 
Detection power for the main analysis:  
When the log-rank test for left-sided sites is conducted with a one-sided significance level of 2.101% (two-
sided 4.202%), the detection power is as follows: The HR for the mFOLFOX6 + bevacizumab combination 
therapy group was assumed on the basis of the median survival in the TRICOLORE Study (33.6 months). 
A Monte Carlo simulation was used to calculate the detection power of the log-rank test for 420 death 
events for left-sided sites. 
 
Table 2. Result of Monte Carlo simulation 
No. of patients 
Level of 
significance  
HR between the 
two groups in the 
left-sided site 
Detection 
power 
604 Patients in left-sided site 
One-sided 
2.101% 
0.70 
91% 
0.72 
87% 
0.74 
80% 
0.76 
71% 
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6.3 
Discontinuation of entire clinical study or discontinuation of clinical 
study at a study site 
6.3.1 
Criteria for discontinuation of entire clinical study 
The person presiding over the study, the representative investigator, and Takeda will hold 
discussions, and this study will immediately be discontinued if at least one of the following 
criteria becomes applicable: 
 When new information or other evaluation on the safety or efficacy of protocol treatment 
becomes available that shows a change in the known risk/benefit profile of the concerned 
compound and risks/benefits are no longer tolerable for patient participation in the study 
 When suspension or discontinuation of the clinical study is notified by the independent data 
monitoring committee and/or the steering committee 
 Occurrence of serious violation of the Clinical Research Act or ICH-GCP that endangers 
safety of patients 
 When study-specific criteria for clinical study discontinuation are met (e.g., when the 
clinical study meets predetermined criteria for usefulness and unusefulness) 
 
6.3.2 
Criteria for discontinuation of clinical study at a study site 
A study site may be notified to discontinue the clinical study by the person presiding over the 
study, the representative investigator, or Takeda, if the site (including the investigator) is found to 
be in significant violation of the Clinical Research Act, ICH-GCP, protocol, or contractual 
agreement; is unable to ensure adequate performance of the study; or as otherwise permitted by 
the contractual agreement. 
 
6.3.3 
Procedures of clinical study suspension and discontinuation of 
entire clinical study or study at a study site 
In the event that the person presiding over the study, the representative investigator, Takeda, or 
the Certified Review Board decides to suspend or discontinue the entire clinical study or clinical 
study at a study site, the person presiding over the study, the representative investigator, and 
Takeda will discuss the procedure according to the Clinical Research Act, and the discussion 
results will be notified by the research secretariat office. The procedure will be followed by 
applicable study sites during the course of clinical study suspension or discontinuation. 
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6.4 
Procedures for protocol amendment 
When protocol amendment is required, the person presiding over the study, the representative 
investigator, and Takeda will assess the propriety of the amendment. 
The protocol will be amended only when the following purposes are applicable, and when an 
amendment is made, the contents of the amendment will be inquired of the representative 
investigator, and the research secretariat office will notify the contents to all study site 
investigators. An amendment will not be made if there is only a minor change that does not fall 
under the above items. Then, investigators should confirm the content of the amendment of the 
protocol and submit a letter of agreement to the research secretariat office to prove agreement 
with the protocol amendment. 
 
1. 
Change or addition of objective 
2. 
Change or addition of efficacy, safety evaluation method 
3. 
Addition of test (frequency, items) or change in test method that may increase the burden 
of the patient 
4. 
Dose alteration (including addition of treatment group) 
5. 
Critical change or addition to inclusion/exclusion criteria 
6. 
Change in planned number of patients 
7. 
Change of plan or description of content resulting from occurrence of serious adverse 
event, etc. 
8. 
Following discussion by the person presiding over the study, the representative 
investigator, and Takeda, it is determined that the proposed change is a critical change 
Upon receipt of the above notification, investigators at the study sites must obtain approval from 
the supervisor in accordance with the regulations at each site. 
 
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7.0 
SELECTION OF STUDY PARTICIPANTS AND ENROLLMENT 
Prior to enrollment, it is necessary to confirm all inclusion/exclusion criteria including test results. 
 
7.1 
Inclusion criteria at enrollment 
Patient’s eligibility will be determined on the basis of the following criteria: 
1. Patients who, in the opinion of the investigator* or the subinvestigator, are capable of 
understanding and complying with protocol requirements. 
*: A person who takes part in conducting the study and presides over the study-related 
activities within a study site. 
2. 
Patients who sign and date a written ICF prior to the initiation of any study procedures 
3. 
Patients aged ≥20 and <80 years at the time of informed consent 
4. 
Patients with unresectable adenocarcinoma originating in the large intestine (excluding 
carcinoma of the appendix and anal canal cancer) 
5. 
Patients with lesion(s) that can be evaluated† 
†: It is not required that the lesion be measurable with the Response Evaluation Criteria 
in Solid Tumours (RECIST, version 1.1).  
6. 
Patients who have not received chemotherapy. Patients who experience relapse more 
than 24 weeks (168 days) after the final dose of perioperative adjuvant chemotherapy 
with fluoropyrimidine agents may be enrolled.‡ 
‡: Patients who have received perioperative adjuvant chemotherapy that includes OXA 
cannot be enrolled. 
7. 
Patients classified as KRAS/NRAS wild type§ by KRAS/NRAS testing.** 
§: KRAS/NRAS test will be performed with the in vitro diagnostic that has been 
approved for marketing. 
**: All codons listed below are required to be wild type. If any codon is unmeasured or 
unmeasurable, it will not be defined as 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 
8. 
Patients who satisfy the following criteria for major organ function in tests performed 
within 2 weeks (14 days) prior to enrollment 
(1) Neutrophil count ≥1.5×103/µL 
(2) Platelet count ≥10.0×104/ µL 
(3) Hemoglobin ≥9.0 g/dL 
(4) Total blood bilirubin ≤2.0 mg/dL 
(5) AST ≤100 IU/L (≤ 200 IU/L if liver metastases are present) 
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(6) ALT ≤100IU/L (≤200 IU/L if liver metastases are present) 
(7) Serum creatinine ≤1.5 mg/dL  
(8) PT-INR <1.5 (<3.0 for patients treated with oral warfarin) 
(9) Urine protein: meet at least one of the following 
(i) 
Urine protein (dip stick method) ≤1+ 
(ii) UPC (urine protein creatinine) ratio ≤1.0 
(iii) Measurement of 24-hour urine protein ≤1,000 mg 
9. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) has been 
determined to be 0 to 1.  
10. Life expectancy of ≥3 months (90 days) after enrollment. 
 
7.2 
Exclusion criteria at enrollment 
A patient who meets any of the criteria below will not be included in this study. 
1. 
Patients who have received radiotherapy within 4 weeks (28 days) prior to enrollment, 
except therapy received for pain relief of bone metastasis site 
2. 
Patients with known brain metastasis or strongly suspected of brain metastasis 
3. 
Patients with synchronous cancers or metachronous cancers with a disease-free period 
of ≤5 years (excluding colorectal cancer), excluding mucosal cancers cured or possibly 
cured by regional resection (esophageal, stomach, and cervical cancer; non-melanoma 
skin cancer; bladder cancer, etc.) 
4. 
Patients with 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, are breast-feeding, or test positive for pregnancy 
6. 
Patients with non-healing surgical wound(s) (excluding implanted venous reservoirs) 
7. 
Patients with active hemorrhage requiring blood transfusion 
8. 
Patients with disease requiring systemic steroids for treatment (excluding topical 
steroids) 
9. 
Patient with stent placement in colon 
10. Patients who have received intestinal resection within 4 weeks (28 days) prior to 
enrollment or colostomy within 2 weeks (14 days) prior to enrollment 
11. Patients with history or obvious and extensive computerized tomography (CT) findings 
of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) 
12. Patients with arterial thromboembolism such as unstable angina pectoris, cardiac 
infarction, cerebral hemorrhage, or cerebral infarction, or have had arterial 
thromboembolism within the 24 weeks (168 days) before registration 
13. Patients with serious drug hypersensitivity 
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14. Patients with local or systemic active infection requiring treatment or fever indicating 
infection 
15. Patients with heart failure or serious heart disease of ≥ class II by New York Heart 
Association 
16. Patients with intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea 
(incapacitating symptoms despite adequate treatment) 
17. Patients with poorly controlled hypertension 
18. Patients with poorly controlled diabetes mellitus 
19. Patients with active hepatitis B 
20. Patients with known HIV infection 
21. Patients with peripheral neuropathy (peripheral motor neuropathy and/or peripheral 
sensory neuropathy) of ≥ grade 2 by Common Terminology Criteria for Adverse Events 
(CTCAE, Japanese edition JCOG version 4.03)  
22. Other patients judged by the investigator or subinvestigator to be ineligible for 
enrollment in the study (such as patients who may be coerced to give consent) 
 
7.3 
Procedures for registration and allocation of drugs 
7.3.1 
Procedures for registration and initiation of protocol treatment 
In this study, there are two steps for registration, the preregistration and the formal registration. 
The investigator or subinvestigator will register patients according to the following procedure. 
1. The investigator, subinvestigator, or study collaborator should preregister the patient, who 
has been given written information on informed consent, by entering the identification code 
and date of informed consent discussion into the web-based case registration system 
(https://edmsweb28.eps.co.jp/paradigm_study/).* 
*: A study collaborator may enter data into the web-based case registration system by 
instruction of the investigator or the subinvestigator. 
2. After preregistration, the investigator, subinvestigator, or study collaborator should enter the 
necessary items into the web-based case registration system (formal registration) for a patient 
who has given consent. 
3. After formal registration, eligibility of a prospective participant is judged by the web-based 
case registration system and a protocol study group will be assigned if the patient is eligible. 
4. The investigator, subinvestigator, and study collaborator will check the registration result and 
assigned protocol study group on the web-based case registration system. The registration 
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result and assigned protocol study group will be sent via email from the web-based case 
registration system to the investigator, subinvestigator, and study collaborator. 
5. The investigator or the subinvestigator should start the allocated protocol treatment within 
2 weeks (14 days) of formal registration (including the same day of week as the day of 
enrollment). However, if protocol treatment cannot be initiated within 4 weeks of formal 
registration, or it is predicted that the initiation of protocol will be more than 4 weeks after 
registration, this must be reported to the study office before protocol treatment initiation. See 
the attached Sheet 1 for study office contacts. 
 
7.3.2 
Contacts for enrollment procedure 
See the attached Sheet 1. 
 
7.3.3 
Preparation and storage of allocation procedures 
The statistics representative, or person designated by the statistics representative, should prepare 
the allocation procedures and manage allocation information of patients. The minimization 
method should be used for allocation of protocol treatment using the allocation factors of 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 
independent from the statistics representative or person designated by the statistics representative. 
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8.0 
PROTOCOL TREATMENT 
The protocol treatment, contraindicated drugs/therapies, and recommended supportive care/ 
combination therapies in this study are explained in this section. 
 
8.1 
Definition of protocol treatment 
Even if any of the criteria for suspension or discontinuation of each drug is met, treatment with 
other drugs will be continued unless any of the criteria for discontinuation of protocol treatment is 
met. However, neither OXA, bevacizumab, OXA + panitumumab, nor OXA + bevacizumab 
should be administered alone, and in such a case the protocol treatment will be discontinued. 
 
8.2 
Drugs used in protocol treatment 
The drugs used for this study should be commercial drugs used by the study site. See the latest 
package insert for details and handling of each drug. 
 
8.2.1 
mFOLFOX6 + panitumumab combination therapy 
The treatment regimen shown below should be administered once every 2 weeks (14 days) (with 
one treatment as one course), until any of the criteria specified in Section “8.7 Criteria for 
discontinuation of protocol treatment for individual ” is met. For administration of each drug, see 
Section “8.4 Criteria for administration” and Section “8.5 Criteria for protocol treatment change.” 
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) 
2,400 mg/m2 
civ 46 hr 
Day 1-3 
div, intravenous drip infusion; iv, intravenous infusion; civ, continuous intravenous infusion. 
*: When the dose at one time exceeds 1,000 mg, intravenously administer it over 90 minutes or longer after 
dilution with JP physiological saline to make approximately 150 mL. 
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div: intravenous drip infusion, iv: intravenous infusion, civ: continuous intravenous infusion 
Figure 8.a mFOLFOX6 + panitumumab combination therapy 
 
8.2.2 
mFOLFOX6 + bevacizumab combination therapy 
The treatment regimen shown below should be administered once every 2 weeks (14 days) (with 
one treatment as one course) until any of the criteria specified in Section “8.7 Criteria for 
discontinuation of protocol treatment for individual ” is met. For administration of each drug, see 
Section “8.4 Criteria for administration” and Section “8.5 Criteria for protocol treatment change.” 
Table 8.b Treatment regimen of mFOLFOX6 + bevacizumab combination therapy  
Drug 
Dose 
Method of 
administration 
(recommended) 
Date of 
administration 
Bevacizumab 
5 mg/kg 
div 30–90 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) 
2,400 mg/m2 
civ 46 hr 
Day 1–3 
div, intravenous drip infusion; iv, intravenous infusion; civ, continuous intravenous infusion. 
*: The method of administration specified at each study site will be employed. 
 
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div: intravenous drip infusion, iv: intravenous infusion, civ: continuous intravenous infusion 
Figure 8.b mFOLFOX6 + bevacizumab combination therapy 
 
8.3 
Recommended dose of protocol treatment 
The dose will be calculated based on the body surface area and body weight at the time of study 
entry. At the time of study entry, the data center will announce the body surface area, which is 
calculated by the DuBois & DuBois formula, as well as the dose, which is calculated according to 
the criteria for truncation described below and will serve as the reference value. The dose should 
be recalculated and confirmed at the study site. The calculated dose of each drug at one time may 
be adjusted according to the description below. The dose should be recalculated for 10% change 
in body weight, in principle, but at the discretion of the study site. If more than 10% change in 
body weight is observed further after the recalculation, the same method should be taken. 
Panitumumab or bevacizumab 
: round down in unit of 10 mg 
OXA 
: round down in unit of 10 mg 
l-LV 
: round down in unit of 25 mg 
bolus 5-FU 
: round down in unit of 50 mg 
infusional 5-FU 
: round down in unit of 50 mg 
 
8.4 
Criteria for administration 
In principle, the day (day 15) that is 2 weeks after the day of treatment (day 1) in the previous 
course will be day 1 of the subsequent course. Postponement or acceleration due to holidays is 
allowed. See “Table 9.b Allowance range for protocol treatment and laboratory tests.” 
It should be confirmed that all of the criteria for initiation of protocol treatment (Table 8.c to *: 
See footnote for Table 8.e. 
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Table 8.e) are satisfied on the day of treatment. However, the latest data obtained from 2 days 
before treatment to the day of treatment may be used for blood tests. 
Treatment will be postponed when any of the criteria for each drug is not met, and will be started 
after confirming that the symptom and laboratory data satisfy all of the criteria. 
When treatment is postponed, the date of starting treatment after postponement will be designated 
as day 1 of the course and serve as the reference point for the subsequent schedule. 
When the criteria for administration are not satisfied only for panitumumab or bevacizumab, 
mFOLFOX6 therapy or 5-FU + l-LV therapy will be administered. The subsequent course of 
treatment with panitumumab or bevacizumab will be administered in time with mFOLFOX6 
therapy or 5-FU + l-LV therapy. (In principle, panitumumab monotherapy is not allowed during 
mFOLFOX6 therapy). However, when mFOLFOX6 cannot be continued for any reason and if 
panitumumab monotherapy is considered appropriate according to the judgment of the 
investigator or the subinvestigator, panitumumab monotherapy will be allowed, but bevacizumab 
monotherapy will not be allowed. 
Protocol treatment should be discontinued when the subsequent course of treatment has not been 
started 28 days after it was scheduled to start (on day 43 with the date of starting the previous 
course as day 1). Postponement due to holidays is allowed. 
Table 8.c Criteria for initiation of treatment course 
Item 
Criteria for initiation 
Neutrophil count 
≥1.2×103/μL 
Platelet count 
≥7.5×104/μL 
Total bilirubin 
≤2.0 mg/dL 
AST 
≤100 IU/L  
(≤200 IU/L with liver metastasis) 
ALT 
Serum creatinine 
≤1.5 mg/dL  
Infection 
Absence of fever (≥38 °C) indicating infection 
Nausea, vomiting, diarrhea, stomatitis 
≤ Grade 1 
Initiation of treatment may be postponed at the discretion of the investigator or the 
subinvestigator due to adverse events not listed above. 
 
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Table 8.d Criteria for initiation of treatment with panitumumab 
Item 
Criteria for initiation 
Skin symptom 
(eg, rash acneiform, dry skin, paronychia) 
≤ Grade 2 
infusion reaction (infusion-related reaction)* 
≤ Grade 1 
Dose reduction/suspension is allowed as necessary, at the discretion of the investigator or the 
subinvestigator, because of adverse events not listed above. 
*: See footnote for Table 8.e. 
 
Table 8.e Criteria for initiation of treatment with bevacizumab 
Item 
Criteria for initiation 
Proteinuria 
At least one of the following is satisfied: 
(i) Urine protein (dip stick method) ≤2+ 
(ii) UPC ≤2.0 
(iii) Urine protein ≤ 2,000 mg by measurement of 24-hr urine 
protein 
Thromboembolism 
≤ Grade 2* 
Hemorrhage 
≤ Grade 1 
Dose suspension is allowed as necessary, at the discretion of the investigator or the subinvestigator, 
as a result of adverse events not listed above. 
UPC, urine protein creatinine ratio. 
*: In the event of grade 2 thromboembolism, bevacizumab should be suspended for the first episode. After the start of 
anticoagulation therapy, PT-INR should be confirmed to be within the therapeutic range (≥1.5, <3.0). Bevacizumab 
may be resumed when all of the criteria described below are satisfied in the subsequent course of treatment. From 
the second episode onwards of grade 2 thromboembolism (after the start of anticoagulation therapy), although 
suspension of bevacizumab is not mandatory it may be administered after confirming that PT-INR is within the 
therapeutic range (≥1.5, <3.0) and all of the criteria described below are satisfied. PT-INR should be measured when 
bevacizumab is resumed. After resumption of bevacizumab, PT-INR will be measured as appropriate, but it will not 
be mandatory. 
1. No subjective or objective symptom of thrombosis 
2. No evidence of exacerbation of thrombosis 
3. No serious hemorrhage during treatment with bevacizumab 
4. Clinically low risk of hemorrhage (no tumor invasion to the macrovascular system) 
 
8.5 
Criteria for protocol treatment change 
8.5.1 
Criteria for dose reduction/suspension of mFOLFOX6 
The criteria for dose reduction/suspension and the doses of OXA and 5-FU (bolus/infusional) are 
shown in Table 8.f and Table 8.g, respectively. The dose of l-LV should not be changed. 
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Table 8.f Criteria for dose reduction/suspension of OXA and 5-FU 
Item 
Grade 
Dose adjustment of OXA and 5-FU for next 
course 
Neutropenia, thrombopenia 
4 
Suspend 
both 
OXA 
and 
5-FU 
(bolus/infusional). Upon resumption, confirm 
initiation criteria are satisfied, administer dose 
decreased by 1 level  
 
Grade 3 neutropenia or thrombopenia 
that persists for more than 7 days 
≥3 
Febrile neutropenia, infection, nausea, 
vomiting, diarrhea, fatigue 
≥3  
Sensory nerve disorder* 
≥3  
Suspension of OXA 
2 
Suspension or dose reduction of OXA by 1 
level 
Pulmonary fibrosis (interstitial 
pneumonia) 
≥2  
Discontinue protocol treatment  
Allergic reaction† 
≥3  
Discontinuation of OXA (no resumption) 
Dose reduction/suspension is allowed as necessary, at the discretion of the investigator or the 
subinvestigator, as a result of adverse events not listed above. 
*: OXA may be resumed when nerve disorder has improved after suspension. 
†: If allergic reaction is observed, immediately discontinue administration of OXA. The course may be resumed at the 
discretion of the study site. If it is an allergic reaction of grade 2 and under, careful administration will be allowed 
after appropriate supportive therapy has been given or infusion speed has been decreased, etc., upon administration 
of subsequent course. 
 
Table 8.g Doses of OXA and 5-FU 
Dose reduction 
level 
OXA 
5-FU (iv) 
5-FU (civ) 
Initial dose 
85 mg/m2 
400 mg/m2 
2,400 mg/m2 
−1 
65 mg/m2 
200 mg/m2 
2,000 mg/m2 
−2 
50 mg/m2 
0 mg/m2 
(discontinuation) 
1,600 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 
Criteria for dose reduction/suspension of panitumumab 
The criteria for dose reduction/suspension and the dose of panitumumab are shown in Table 8.h 
and Table 8.i, respectively. 
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Table 8.h Criteria for dose reduction/suspension of panitumumab 
Item 
Grade 
Dose adjustment of panitumumab for next course 
Skin disorder 
≥3 
Dose reduction by 1 level after suspension 
However, treatment is allowed without dose reduction 
when it recovers to grade 2 or less within 6 weeks 
(42 days). 
Hypomagnesemia* 
Pulmonary fibrosis 
(interstitial pneumonia) 
≥2 
Discontinue protocol treatment  
Infusion reaction (reaction 
from injection)†,‡ 
≥3 
Discontinuation (no resumption) 
Dose reduction/suspension is allowed as necessary, at the discretion of the investigator or the 
subinvestigator, as a result of 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 
hypomagnesemia. 
†: Allergic reaction; anaphylactoid reaction; and chills, fever, and dyspnea occurring within 24 hours after the initial 
dose 
‡: If infusion reaction is observed, immediately discontinue administration. The course may be resumed at the 
discretion of the study site. In the event that grade 1 or 2 infusion reaction occurs during infusion, careful 
administration will be allowed after appropriate supportive therapy has been given or infusion speed has been 
decreased by 50%, etc., upon administration of subsequent course. 
 
Table 8.i Dose of panitumumab 
Dose reduction 
level 
Panitumumab 
Initial dose 
6 mg/kg 
−1 
4.8 mg/kg 
−2 
3.6 mg/kg 
−3 
Discontinuation (no resumption) 
 
8.5.3 
Criteria for discontinuation of bevacizumab 
The dose of bevacizumab is fixed at 5 mg/kg and should not be reduced. However, treatment with 
bevacizumab should be discontinued when any of the events shown in Table 8.j is observed. 
Table 8.j Criteria for discontinuation of bevacizumab 
Item 
Grade 
Bevacizumab 
Thromboembolism 
≥3 
Discontinuation (no 
resumption) 
Hemorrhage 
≥3 
Perforation of the digestive tract 
- 
Treatment may be discontinued when the investigator or the subinvestigator decides that treatment 
should be discontinued because of adverse events not listed above 
 
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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 
Criteria for discontinuation of protocol treatment for individual 
patients 
The number of doses is not specified either for the mFOLFOX6 + panitumumab group or for the 
mFOLFOX6 + bevacizumab group. However, protocol treatment 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 or the subinvestigator decides on 
discontinuation of protocol treatment. The investigator or the subinvestigator should record the main 
reason for discontinuation of protocol treatment in the case report form (hereinafter referred to as 
CRF) according to the classification described below. See Section “9.3 Records of patients who 
discontinued before randomization” for patients withdrawn from the study before randomization. 
1. Lack of efficacy (exacerbation) 
When PD is evident in the clinical or imaging evaluation 
2. Adverse event 
Discontinuation of treatment because of an adverse event, in the opinion of the investigator or 
the subinvestigator, or according to the protocol treatment discontinuation criteria.  
However, death during protocol treatment will be classified in Section “4. Death during 
protocol treatment” and not in this item. 
Protocol treatment is postponed because of an adverse event for 44 days or more after the day 
of starting the last course. However, postponement due to holidays is allowed. 
3. Voluntary discontinuation 
A patient wishes to discontinue study participation. The reason for discontinuation should be 
recorded in the CRF when it is clarified. 
Note: Attempts should be made as best as possible to clarify the reason for voluntary 
discontinuation. (Discontinuation due to adverse event or lack of efficacy should not be 
classified as “voluntary discontinuation.”)  
4. Death during protocol treatment 
A patient dies before investigators decide to discontinue protocol treatment. Date of death, 
reason of death (protocol treatment–related, primary disease, others) should be described in 
the CRF. 
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5. When surgery aimed at curative resection (complete resection: R0 resection) of colorectal 
cancer is scheduled 
Note: “When surgery is scheduled” means the day when the surgery date is decided. 
6. Significant deviation from the protocol 
When study continuation may cause intolerable risk to the health of a patient because the 
patient was found not to satisfy the inclusion criteria specified in the protocol after initiation 
of protocol treatment or the protocol has not been observed. 
7. Lost to follow-up 
When patient fails to make visits and cannot be contacted. The attempts that were made to 
contact the patient should be recorded in the source documents. 
8. Discontinuation of entire study 
When discontinuation of the clinical study is decided by the person presiding over the study, 
the representative investigator, Takeda, or the Certified Review Board. See “6.3.1 Criteria for 
discontinuation of entire clinical study” for details. 
9. Pregnancy 
When a female patient is found to be pregnant. 
Note: Study participation should immediately be discontinued when pregnancy becomes 
known. See Section “9.2.14 Pregnancy” for procedures. 
10. Other 
When the investigator or the subinvestigator decides that protocol treatment should be 
discontinued for other reasons. Details should be described in the CRF. 
 
8.8 
Procedures for discontinuation or withdrawal of a patient 
The investigator or the subinvestigator may discontinue a patient’s study participation at any time 
during the study when the patient meets the study termination criteria described in Section 8.7. In 
addition, a patient may discontinue his or her participation without giving a reason at any time 
during the study. Should a patient’s participation be discontinued, the primary reason for 
termination must be recorded in the CRF by the investigator or the subinvestigator. In addition, 
efforts should be made to perform all tests/observations/evaluations scheduled at the time of 
discontinuation. 
 
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8.9 
Contraindicated drugs/therapies 
The drugs and therapies shown below are contraindicated from informed consent until 
discontinuation of protocol treatment. The investigator or the subinvestigator should instruct the 
patients not to use any drugs, including over-the-counter drugs, other than the prescribed drugs 
without prior consultation. 
 Chemotherapy for primary disease other than protocol treatment 
 Hormone therapy for primary disease 
 Immunotherapy for primary disease 
− 
Cellular immunotherapy 
− 
Vaccine therapy 
− 
Cytokine therapy (except for G-CSF) 
− 
Biological response modifiers therapy 
− 
Antibody therapy 
− 
Gene therapy 
 Other antibody therapy 
However, treatment for the pain relief of bone metastasis is permitted 
 Radiotherapy for primary disease  
Treatment for pain relief of a bone metastasis site is allowed 
 Hyperthermia therapy for primary disease 
 Study drug and unapproved drug 
 
8.10 
Recommended supportive care and combination medications 
The supportive care and concomitant medications shown below are recommended during the 
study period (from obtaining consent until discontinuation of protocol treatment). The absence of 
supportive care or concomitant medications does not constitute a protocol deviation. 
 
Neutropenia 
Granulocyte colony stimulating factor (hereinafter referred to as 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 by 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 the subsequent course. Careful administration of 
panitumumab or bevacizumab by slowing the infusion speed may be considered. 
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 
Hypertension 
Measures may be taken to maintain systolic blood pressure of <140 mm Hg and diastolic 
blood pressure of <90 mm Hg. 
 
Pulmonary fibrosis (interstitial pneumonia) 
If pulmonary fibrosis occurs, it should be treated according to the severity (e.g., steroid pulse 
therapy). 
 
Hepatitis B 
Refer to JSH Guidelines for the Management of Hepatitis B virus infection 
(http://www.jsh.or.jp/doc/guidelines/HBV_GL_ver2.201406.pdf) and take appropriate action 
and monitoring. 
 
Others 
Drugs for treatment of adverse events may be coadministered at the discretion of the 
investigator or the subinvestigator. Symptomatic therapies that 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 or the subinvestigator, when any of panitumumab-related adverse 
events listed below is observed. The absence of supportive care does not constitute a protocol 
deviation. 
 
Skin disorder 
− 
Tetracycline antibiotic (e.g., oral minocycline) 
− 
External salicylic acid petrolatum (10%) 
− 
External steroid therapy, e.g., 
Face: hydrocortisone butyrate (0.1%) 
Trunk: difluprednate (0.05%) 
− 
Moisturizer (eg, 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). 
Dermatopathy prevention with humectants, suntan lotions, antibiotics, or external steroid 
preparations may be carried out by methods employed at each study site. 
 
Electrolyte abnormality (e.g., hypomagnesemia, hypocalcemia) 
− 
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. 
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− 
Magnesium supplementation (e.g., 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) as a result of 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 Section “9.1 Study calendar.”) 
 
8.12 
Recommended follow-up therapy 
8.12.1 
Recommended second-line treatment 
 mFOLFOX6 + panitumumab group: Combination of bevacizumab with IRI-based 
chemotherapy is strongly recommended. 
 mFOLFOX6 + bevacizumab group: combination of bevacizumab or anti-EGFR antibody with 
IRI-based chemotherapy is strongly recommended. 
 
8.12.2 
Recommended third-line or subsequent treatment 
All approved drugs (regorafenib, trifluridine/tipiracil hydrochloride, etc.) should be used 
appropriately as much as possible. 
 
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9.0 
PROTOCOL, EVALUATION ITEMS, AND PROCEDURES FOR 
OBSERVATIONS 
9.1 
Study calendar 
The investigator or the subinvestigator should collect data according to “Table 9.a Study 
calendar.” The same investigator or the subinvestigator should perform 
tests/observations/evaluation of patients if possible. For the allowance range of protocol treatment 
and various laboratory tests, see “Table 9.b Allowance range for protocol treatment and laboratory 
tests.” 
 
Table 9.a Study calendar 
Item 
At enrollment 
During 
protocol 
treatment 
Discontinuation 
of protocol 
treatmenta 
Follow-up 
periodb 
Obtaining ICF 
●c 
 
 
 
Patient background 
● 
 
 
 
RAS status 
● 
 
 
 
Clinical findings  
(including adverse events) 
● 
 ●d 
 ● 
 
Height/body weight 
 ●e 
○f 
 
 
ECOG PS 
 ● e 
 ●d 
 ● 
 
Protocol treatment 
 
 ● 
 
 
Laboratory tests 
 
 
 
 
Hematology, serum chemistry, 
urinalysis 
 ● e 
 ●g 
 ● 
 
Immunological tests  
(HBs antigen) 
 ●h 
 
 
 
Tumor markers 
 
 ●i,j 
 ● 
 
Imaging tests 
(thoracoabdominal-pelvic 
CT/MRI) 
 ●k 
 ●i 
○l 
 
Follow-up treatment 
 
 
 
 ● 
Survival survey 
 
 
 
 ● 
●: Mandatory, ○: Perform as necessary 
a: Perform within 28 days of discontinuation or earlier date than start of follow-up treatment. 
b: Perform every 6 months as a guide, with protocol discontinuation date as starting point. 
c: Consent must be obtained before enrollment. Further, consent should be obtained after RAS status has been 
identified. 
d: Perform before administration on treatment day of each course. 
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e: Perform within 2 weeks (14 days) prior to enrollment (including the same day of week as the day of enrollment). 
Results of tests performed before obtaining consent may be used if it is within 2 weeks prior to enrollment. Height 
can be used even if it was measured before 2 weeks prior to enrollment as long as it had been measured at study site. 
f: Measurement is not mandatory during protocol treatment period. Even if measured, it is unnecessary to record in 
the CRF. However, if transition in decrease of body weight is judged to be a clinical problem by the investigator or 
the subinvestigator, it will be an adverse event. 
g: Perform 2 days before each course prior to administration on treatment day. 
h: Test results from up to 1 year before obtaining consent may be used. However, follow JSH Guidelines for the 
Management of hepatitis B virus infection for the measurement of HBs antibody, HBc antibody, and HBv DNA. 
i: Measure once every 8 weeks (56 days) with day 1 of first course as starting point. However, reduce the frequency 
to once every 12 weeks (84 days) when 2 years have passed since initiation of protocol treatment. 
j: If it has been performed within 28 days before treatment day, the test for the first course may be omitted. 
k: Perform within 4 weeks (28 days) before enrollment (including the same day of week as the day of enrollment). 
Results from tests performed before obtaining consent may be used if they are within 4 weeks before enrollment. 
l: If discontinued because of results of imaging tests (PD), imaging test will not be mandatory. 
 
Table 9.b Allowance range for protocol treatment and laboratory tests 
Performed items 
Protocol specification 
Allowance range 
Clinical laboratory test values 
Before administration 
From −2 days to  
before administration 
Protocol treatment 
From treatment day (day 1) of 
previous course to 2 weeks later 
(day 15) 
±3 days 
Tumor markers (at enrollment) 
From 28 days before initial dose 
to treatment day 
Same as protocol specification 
Imaging tests (at enrollment) 
From 28 days before enrollment 
to the enrollment day 
Tumor markers and imaging tests 
(during protocol treatment) 
Protocol treatment ≤2 years: 8 
weeks (56 days) 
±2 weeks (14 days) 
Protocol treatment >2 years: 12 
weeks (84 days) 
 
9.2 
Collection/test/observation items and procedures during the study 
The investigator or the subinvestigator will perform the following as scheduled in Section “9.1 Study 
calendar.” 
 
9.2.1 
Informed consent procedure 
Consent should be obtained from patient before initiation of study procedures. 
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To anonymize the participant, a unique participant ID code will be assigned to each patient at the 
time of obtaining consent. The participant ID code will be used throughout the study period and will 
not be changed. 
The method for obtaining consent is described in Section “7.3 Procedures for registration and 
allocation of drugs.” 
 
9.2.2 
Registration and allocation of protocol treatment 
For procedures for registration and allocation of drugs and preparation and storage of allocation 
procedures, see Section “7.2 Exclusion criteria at enrollment.” 
 
9.2.3 
Patient demographics 
For demographic data of the patient, date of birth (or age at enrollment if date cannot be provided) 
and sex will be checked. Also, the following items concerning the primary disease of colorectal 
cancer will be examined: 
1. Information on primary organ 
2. Solitary/multiple 
3. Primary tumor site (cecum, ascending colon, transverse colon, descending colon, sigmoid 
colon, rectosigmoid, rectum) 
The definitions of primary lesion location (left-sided/right-sided/other) are as shown below.  
 
Left-sided: Single lesion or multiple lesions in the descending colon, sigmoid colon, 
rectosigmoid region, or rectum 
 
Right-sided: Single lesion or multiple lesions in the cecum, ascending colon, or 
transverse colon  
 
Other: Multiple primary lesions in both the right side and the left side. 
4. Information on metastasis 
5. Number of organs with metastasis (0, 1, ≥2)* 
*: Does not include primary tumor/regional lymph node. Other lymph nodes in several sites 
will be counted as one organ. For example, if metastasis is observed in a cervical lymph 
node and a thoracic lymph node, it will be counted as one organ. 
6. Organ with metastasis (liver, lung, peritoneum, lymph node,* bone, adrenal gland, skin, and 
others†) 
*: Does not include primary tumor/regional lymph node. Other lymph nodes in several sites 
will be counted as one organ. For example, if metastasis is observed in a cervical lymph 
node and a thoracic lymph node, it will be counted as one organ. 
†: Name of organ to be recorded in CRF. 
7. History of treatment 
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8. History of surgery in primary tumor site/palliative metastasis site and history of colostomy/ 
bypass surgery 
9. For patients with history of surgery, the date of surgery 
However, endoscopic surgery, which is not considered a history of surgery, should not be 
entered into the CRF 
10. History of radiotherapy (radical irradiation) 
11. For patients with history of radiotherapy, the date of final dose 
However, irradiation for pain relief (palliative irradiation) in a bone metastasis site, which is 
not considered radiotherapy, should not be entered into the CRF 
12. History of preoperative and/or postoperative adjuvant chemotherapy 
For patients with a history of adjuvant chemotherapy, record the type of preoperative and/or 
postoperative adjuvant chemotherapy, date of final treatment, and most recent date of 
relapse 
13. RAS assay 
Histological type will be evaluated on the basis of histological findings in the “Japanese 
Classification of Colorectal Carcinoma.” 
14. Histological type (primary) of sample used in RAS assay 
15. Collection site (primary tumor/metastasis site) of sample used in RAS assay 
16. Type of sample used in RAS assay 
a. Biopsy sample 
b. Surgical sample 
17. Collection date of sample used in RAS assay 
18. Method of RAS assay 
19. Results of RAS assay (wild type/mutant type/not measured or unable to determine) 
The following test results of codons should all be recorded in the CRF 
KRAS 
Exon 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
NRAS 
Exon 
2 
3 
4 
codon 
12, 13 
59, 61 
117, 146 
 
9.2.4 
Concurrent medical condition 
A concurrent medical condition is defined as any symptom or disease present at initiation of 
protocol treatment. Any notable concurrent medical condition will be entered into 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 
concurrent medical condition at the discretion of the investigator or the subinvestigator. 
• 
Notable concurrent medical conditions: hypertension, diabetes mellitus, and others* 
*: When judged by the investigator or the subinvestigator that evaluation in this study may be 
affected. 
 
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9.2.5 
Clinical findings (including adverse events) 
Medical examination will be performed prior to protocol treatment. In particular, the following 
symptoms at the medical examination will be confirmed: 
Allergic reaction, fatigue, rash acneiform, cutaneous dryness, paronychia, infusion reaction 
(infusion-related reaction), anorexia, diarrhea, nausea, vomiting, oral mucositis, hypomagnesemia, 
blood neutrophil count decreased, febrile neutropenia, reduced blood platelet count, peripheral 
sensory neuropathy, thromboembolism, gastrointestinal perforation, interstitial pneumonia. 
The results of medical examinations after initiation of protocol treatment will be compared with 
the results of medical examinations before initiation of protocol treatment to evaluate the 
clinically problematic abnormalities. 
See Section “10.0 Adverse events” for definition of adverse event. 
 
9.2.6 
Height, body weight 
Body weight at enrollment should be measured within 2 weeks (14 days) before enrollment 
(including the same day of the week as the day of enrollment) and recorded in the CRF. Height 
measured at the study site in the past may be used. 
 
9.2.7 
Eastern Cooperative Oncology Group Performance Status  
ECOG PS will be assessed according to “Table 9.c. Eastern Cooperative Oncology Group 
Performance Status” at enrollment or within 2 weeks (14 days) prior to enrollment (including 
same day of the week as the day of enrollment). Before initiation of each course, PS will be 
determined on treatment day before administration. PS at discontinuation will be determined as 
much as possible within 4 weeks (28 days) after discontinuation or before next treatment, 
whichever date is earlier. 
 
Table 9.c Eastern Cooperative Oncology Group Performance Status 
P.S. 
Definition 
0 
Fully active, able to carry on all predisease 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 
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P.S. 
Definition 
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 
 
9.2.8 
Protocol treatment implementation status 
The investigator or the subinvestigator should record the compliance with protocol treatment in 
the CRF as follows: 
• 
When dosage of drug used in protocol treatment is adjusted (Number of 
adjustments/reduction/suspension/discontinuation) 
• 
If drug used in protocol is adjusted, the dosage should be recorded 
 
9.2.9 
Laboratory tests 
Laboratory tests should be conducted at each study site. 
Laboratory tests at enrollment will be conducted within 2 weeks (14 days) prior to enrollment 
(including same day of the week as the day of enrollment). Tests before initiation of each course 
will be conducted before administration on treatment day. Tests at discontinuation will be 
conducted as much as possible within 4 weeks (28 days) after discontinuation or before next 
treatment, whichever date is earlier. 
Test items and notes are listed in Table 9.d to Table 9.f. 
The investigator and the subinvestigator should evaluate and store the reported laboratory test 
results.  
For laboratory test standard values, common standard value (common standard range list, Japan 
Clinical Oncology Group, hereinafter referred to as JCOG) will be used. 
 
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Table 9.d Laboratory tests performed at the time of enrollment 
Hematology 
Serum chemistry 
Tumor marker 
Urinalysis 
Neutrophil count 
Platelet count 
Hemoglobin content 
Immunology 
HBs antigen* 
Total bilirubin 
ALT 
AST 
Creatinine 
PT-INR 
Mg 
Albumin 
Na 
K 
Ca 
None 
One of the 
following: urine 
protein (dipstick 
method), UPC ratio, 
and 24-hour urine 
protein  
*: Test results measured up to 1 year before obtaining consent may be used. However, follow JSH Guidelines for the 
Management of Hepatitis B virus infection for the measurement of HBs antibody, HBc antibody, and HBv DNA. 
 
 
 
Figure 9.a JSH Guidelines for the management of hepatitis B virus infection 
Hepatitis B due to HBv reactivation occurs in some patients who are HBsAg-positive or HBsAg-negative during or 
after intensive chemotherapy for hematological malignancies, and some cases become fulminant; therefore, caution is 
required. In addition, the risk of HBv reactivation should be taken into account in routine chemotherapy for 
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hematological malignancies or solid tumors and in immunosuppressive therapy for autoimmune diseases, such as 
rheumatic diseases and collagen diseases. With conventional chemotherapy and immunosuppressive therapy, the 
frequency of HBv reactivation, onset of hepatitis, and fulminant hepatitis is not clear, and there is not enough 
evidence for guidelines. In addition, the preventive effect of nucleic acid analog administration on fulminant disease 
is not completely guaranteed.  
Notes: 
1. 
HBv carriers and patients with a history of HBv infection should be screened before immunosuppressive 
therapy or chemotherapy. First, HBsAg is measured to determine whether the patient is an HBv carrier. If 
the patient is negative for HBs antigen, then HBc antibody and HBs antibody should be measured to 
confirm whether the patient has a history of infection. The measurement of HBs antigen HBc antibody and 
HBs antibody should be performed by a highly sensitive method. In addition, HBv reactivation has been 
reported in patients who are positive for HBs antibody alone (HBs antigen negative and HBc antibody 
negative). Therefore, it is desirable to take measures in accordance with the Guideline unless the history of 
vaccination is clear. 
2. 
Patients who are HBsAg-positive should be referred to a hepatologist. It is desirable to consult a 
hepatologist when administering nucleic acid analog in all cases. 
3. 
In cases of retreatment without HBc antibody or HBs antibody measurement at the start of initial 
chemotherapy and cases in which immunosuppressive therapy has already been started, the antibody titer 
may have decreased, and close examination by HBv DNA quantitative test, etc., is desirable. 
4. 
Patients with a history of HBv infection will be screened for HBv DNA by real-time polymerase chain 
reaction. 
5. 
                         
a. 
Use of rituximab/steroid, fludarabine-based chemotherapy, and hematopoietic stem cell 
transplantation is associated with a high risk of HBv reactivation in patients with a history of 
infection, and caution should be exercised. Monitor HBv DNA monthly during treatment and for 
at least 12 months after stopping treatment. Long-term monitoring after hematopoietic stem cell 
transplantation is necessary. 
b. 
There is a risk of HBv reactivation, albeit infrequent, when usual chemotherapy and molecular-
targeted drugs with immune effects are used concomitantly. Monitoring of HBv DNA levels 
should be performed approximately every 1 to 3 months, and the interval and duration should 
depend on the type of treatment. Careful measures are desirable for hematological malignancies. 
c. 
Immunosuppressive therapy with corticosteroids, immunosuppressants, or molecular-targeted 
agents with immunosuppressive or immunomodulatory properties may also result in HBv 
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reactivation. Monthly monitoring of HBv DNA levels is recommended after initiation of 
immunosuppressive therapy and for at least 6 months after any change in therapy. After 6 
months, the interval and period will be decided in consideration of the contents of treatment. 
6. 
It is desirable to start administration as soon as possible before the start of immunosuppressive 
therapy/chemotherapy. However, in HBsAg-positive patients with a high viral load, cases of death due to 
fulminant hepatitis have been reported even during prophylactic administration of nucleos(t)ide analogs, 
and it is desirable to reduce the viral load before the start of immunosuppressive therapy/chemotherapy. 
7. 
Administration should be started immediately when HBv DNA is 2.1 log copies/mL or more during or after 
immunosuppressive therapy/chemotherapy. For patients receiving immunosuppressive therapy or 
chemotherapy, it is recommended that immunosuppressants or antineoplastic drugs with 
immunosuppressive effects should not be discontinued immediately and that the patient should be referred 
to a hepatologist for treatment. 
8. 
The use of entecavir as a nucleoside analog is recommended. 
9. 
Termination of nucleoside analog therapy may be considered if the following conditions are met: Patients 
who are positive for HBs antigen at screening meet the criteria for termination of nucleic acid analog 
treatment for chronic hepatitis B. In patients who are positive for HBc antibody or HBs antibody at 
screening, (1) treatment should be continued for at least 12 months after completion of immunosuppressive 
therapy or chemotherapy; (2) ALT (GPT) is normalized during this extension period (except in cases of 
ALT abnormalities other than HBv); and (3) test results for HBv DNA remain negative during this 
extension period. 
10. Patients will be closely monitored, including HBv DNA monitoring, for at least 12 months after the end of 
nucleic acid analog treatment. The method of follow-up is based on the precautions for use of each 
nucleoside analog. Resume treatment as soon as HBv DNA ≥2.1 log copies/mL during follow-up. 
 
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Table 9.e Laboratory tests performed before the start of each course of treatment 
Hematology 
Serum chemistry 
Tumor marker 
Urinalysis 
Neutrophil count* 
Platelet count* 
Hemoglobin content* 
Total bilirubin* 
ALT* 
AST* 
Creatinine* 
PT-INR*,† 
Mg* 
Albumin* 
Na* 
K* 
Ca* 
CEA‡, § 
One of the following: 
urine protein (dipstick 
method), UPC ratio, 
and 24-hour urine 
protein* 
 
*: The test in course 1 may be omitted when the pre-entry test had been performed within 2 days before treatment in 
course 1. The test in course 1 will be performed before administration in course 1 when the pre-entry test had been 
performed more than 2 days before treatment in course 1. 
†: Measurement before the start of each course of treatment is not mandatory. However, in the event of grade 2 
thromboembolism, bevacizumab should be suspended for the first episode. After the start of anticoagulation 
therapy, it should be confirmed that PT-INR is within the therapeutic range (≥1.5, <3.0). Bevacizumab may be 
resumed when all of the criteria described below are satisfied in the subsequent course of treatment. From the 
second episode onward of grade 2 thromboembolism (after the start of anticoagulation therapy), suspension of 
bevacizumab is not mandatory; it may be administered after confirming that PT-INR is within the therapeutic 
range (≥1.5, <3.0) and all of the criteria described below are satisfied. PT-INR should be measured when 
bevacizumab is resumed. After resumption of bevacizumab, PT-INR will be measured as appropriate, but it will 
not be mandatory. 
(1) No subjective or objective symptom of thrombosis 
(2) No evidence of exacerbation of thrombosis 
(3) No serious hemorrhage during treatment with bevacizumab 
(4) Clinically low risk of hemorrhage (no tumor invasion to the macrovascular system) 
‡: If it has been conducted within 28 days before treatment day, it may be omitted. 
§: With day 1 of first course as starting point, measure once every 8 weeks (56 days). However, when 2 years have 
passed since initiation of protocol treatment, once every 12 weeks (84 days). 
 
Table 9.f Laboratory tests performed at the time of discontinuation 
Hematology 
Serum chemistry 
Tumor marker 
Urinalysis 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
PT-INR* 
Mg 
Albumin 
Na 
K 
Ca 
CEA† 
One of the following: 
urine protein (dipstick 
method), UPC ratio, 
and 24-hour urine 
protein 
*: Optional tests  
†: If ≥28 days has not passed since the last measurement, the test can be omitted 
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9.2.10 
Imaging test (thoracoabdominal-pelvic CT/MRI) 
Imaging test will be performed within 4 weeks (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 was performed within 4 weeks (28 days) prior to enrollment.  
Furthermore, the data of measurable lesion should be evaluated with imaging test conducted 
within 2 weeks (14 days) prior to initiation of protocol treatment (including the same day of the 
week as the day of enrollment) preferably. If another imaging test has been conducted newly after 
enrollment but before initial administration, this data should be recorded in the CRF. 
After initiation of protocol treatment, imaging test will be performed every 8 weeks (56 days) with 
protocol treatment initiation date (day 1) of the first course as the starting point. However, when 
2 years have passed since initiation of protocol treatment, it will be performed once every 12 
weeks (84 days) (See “Table 9.a Study calendar”). 
Thoracoabdominal-pelvic CT (in principle, contrast CT with a slice width of 10 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 entered into the CRF. If necessary, a brain MRI/CT and a neck CT may be performed. 
In principle, the same modality should be used for imaging tests during protocol treatment 
throughout the study period. 
The investigator or the subinvestigator should evaluate the test results according to the RECIST 
v1.1 
 and enter the determined results into the CRF. 
Furthermore, for patients withdrawn from the study for any reason other than imaging test results, 
such as clinical PD, imaging test specified at the time of discontinuation should be performed 
within 4 weeks (28 days, including the same day of week as the day of decision). 
 
9.2.11 
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 (in case of 
fractional excision, the last surgery date will be entered), site of surgery, and postoperative 
assessment of residual tumor should be recorded into the CRF. The residual tumor is assessed 
according to the table shown below, and the histological results of resection specimens should be 
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recorded into the CRF as much as possible. On the day the scheduled date of surgery aimed at 
curative resection of colorectal cancer is decided, protocol treatment will be discontinued. 
When surgery aimed at curative resection is performed in more than one session, the number of 
sessions should be entered into the CRF. As for the postoperative determined results of residual 
tumor, data obtained before initiation of subsequent treatment or within 6 months from 
discontinuation of protocol treatment, whichever is earlier, should be entered into the CRF.  
 
Table 9.g Histological changes  
Grade 
Criteria 
Grade 0 (no change) 
Denaturation and necrosis, such as by treatment, is not 
recognized in cancer cells 
Grade 1a (very slight change) 
Less than about one-third of the cancer shows degeneration or 
necrosis 
Grade 1b (slight change) 
More than one-third but less than two-thirds of the cancer shows 
degeneration, necrosis, or melting 
Grade 2 (moderate change) 
More than two-thirds of the cancer is markedly modified by 
necrosis, melting, or disappearance 
Grade 3 (marked change) 
The entire cancer is marked by necrosis, melting, or 
disappearance, or the entire cancer has been replaced by a 
granuloma-like tissue or patchy fibrosis 
 
Table 9.h 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 
*: When radio frequency ablation, microwave coagulation therapy, etc., has been used in combination, classify 
as R2. 
 
9.2.12 
Follow-up treatment 
When follow-up treatment is performed after discontinuation of protocol treatment, the following 
information on follow-up treatment should be collected every 6 months, in principle, after 
discontinuation of protocol treatment. Information on the follow-up treatment should be collected 
until a patient dies or the period of evaluation of the study is terminated. 
• Secondary treatment  
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– Drug name 
– Initiation date, end date 
• Third-line or subsequent treatment 
– Drug name 
– Initiation date 
 
 
9.2.13 
Survival survey 
After discontinuation of protocol treatment, every patient will be followed up to confirm survival 
of patients every 6 months in principle after discontinuation of protocol treatment. The following 
information on survival should be collected. The survey should be continued until the patient dies 
or the period of study evaluation is terminated. 
• 
Survival survey date 
• 
Date of death or last confirmed date of survival 
− 
If deceased, the reason of death (death from primary disease/other) 
 
9.2.14 
Pregnancy 
When it becomes apparent that a female participant is pregnant, with consent from the patient, the 
investigator or the subinvestigator should notify the primary care physician (obstetrician and 
gynecologist, etc.) that the patient was participating in a clinical study at the time she became 
pregnant and provide details of protocol treatment. 
For every female patient allocated in the panitumumab group and reported to have become 
pregnant, the investigator or subinvestigator should follow the patient up to delivery, including 
result of premature delivery, with consent from the patient, and report to the research secretariat 
office using the specified follow-up form. Evaluation after delivery will also be conducted. 
 
9.3 
Records of patients who discontinued before randomization 
Every patient who signed the ICF and then dropped out before randomization should be registered 
in the web-based registration center, and a CRF should be prepared for them. 
The following items are to be described in the CRF. 
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• 
Date of consent obtained 
• 
Date of birth (the age at enrollment) 
• 
Sex 
• 
Eligibility 
• 
Reason for discontinuation 
For patients who drop out of the study before randomization, the main reason for drop-out should 
be entered into the CRF according to the following categories: 
– 
Not satisfying at least one of the inclusion criteria or meeting any of the 
exclusion criteria 
– 
Serious deviation from the protocol 
– 
Lost to follow-up 
– 
Voluntary discontinuation <specify the reason> 
– 
Discontinuation of the entire study 
– 
Others <specify the reason> 
The participant ID code of a patient withdrawn from the study before randomization should not be 
reused. 
 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Adverse events 
Adverse events are any unfavorable medical events encountered in a patient 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 medical practice 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation of protocol treatment (mFOLFOX6 + bevacizumab or 
mFOLFOX6 + panitumumab combination treatment) or concomitant drugs under use, or 
adjustment in dosage 
• 
Considered unfavorable by the investigator or the subinvestigator 
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. If an adverse event could not be expressed by a diagnosis name, the sign or 
symptom will be the adverse event. 
Laboratory test values and ECG findings: 
Abnormal laboratory values and ECG findings are recorded as adverse events when the 
investigator or the subinvestigator judges the course to be clinically problematic (in other words, 
when certain action or medical practice is required, or the investigator or the subinvestigator 
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judges the change to have exceeded the normal physiological variation range of the patient). 
Retest and/or continued monitoring of abnormality are not considered medical practice. Also, 
repeated or additional conduct of noninvasive test for verification, evaluation, and monitoring of 
abnormality are not considered medical practice. 
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 medical condition is aggravated, the aggravation will be determined as an adverse 
event and the investigator or the subinvestigator should record in the CRF that the adverse event is 
an aggravation of the concurrent disease (e.g., “aggravation of hypertension,” etc.). 
When a patient 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 patient 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 or the subinvestigator should record in a way that will make the reported adverse 
event name be recognized as a change from baseline (e.g., aggravation of XX). 
Change of severity of adverse events: 
When the severity of an adverse event has changed, the event should be recorded once at the 
highest degree of severity (grade based on the CTCAE [Japanese edition JCOG version 4.03]), 
and should be recorded in each protocol treatment course. 
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 that resulted 
from previously planned surgery is reported as an adverse event. 
Nonurgent surgery or treatment: 
Nonurgent surgery or treatment that does not induce a change in the condition of a patient 
(cosmetic surgery, etc.) is not considered an adverse event. However, it should be recorded in the 
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source documents. Complications due to a nonurgent 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, if a clinical progression of pre-
existing cancer (including new metastasis) is confirmed via imaging, it will be determined as a 
serious adverse event if the severity satisfies any of the criteria specified in Section 10.1.3. 
Panitumumab overdose: 
When overdose of panitumumab becomes apparent, it should be recorded in the CRF. If an 
adverse event occurs with overdose, it should be recorded as an adverse event in the adverse event 
column of the CRF. 
Furthermore, the overdose of panitumumab is defined as follows. 
1. 
Received administration exceeding approved dosage (6 mg/kg) of panitumumab 
2. 
Received next administration within 10 days of previous administration 
 
10.1.3 
Serious adverse events 
Of all the unfavorable medical events that developed with administration of drugs (irrespective of 
dose), a serious adverse event is an event that: 
1. Results in death during protocol treatment,* including all deaths irrespective of a causal 
relationship with protocol treatment 
*: Period from initiation of protocol treatment up to 4 weeks (28 days) after discontinuation 
of protocol treatment or initiation of next 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 
†: From 29 days after discontinuation of protocol treatment or from initiation of next 
treatment 
3. Is life-threatening 
The term “life-threatening” refers to an event in which the patient 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 more severe. 
4. Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization described below is not considered a serious adverse event: 
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(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. Serious adverse events also include other medically important events that cause a risk to 
the patient, even if not immediately life-threatening and not resulting in death or 
hospitalization, or that require action or treatment to prevent the results in items 1 to 6 
above 
10.1.4 
Special interest adverse event 
Adverse events listed in “Table 10.a Takeda medically significant adverse event list” will be handled 
as “special interest adverse event” irrespective of severity determined by the investigator or the 
subinvestigator. Further, any adverse events listed in Table 10.a that have been determined as serious 
by the investigator or the subinvestigator will be handled as serious adverse event. 
Table 10.a Takeda medically significant adverse event list 
Acute respiratory failure/acute respiratory 
distress syndrome 
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 events is classified into five grades (grades 1–5) as follows based on the 
Common Terminology Criteria for Adverse Events (hereafter referred to as CTCAE, Japanese 
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edition JCOG version 4.03), of National Cancer Institute, USA. Furthermore, the grade for 
adverse events not listed in CTCAE will be classified according to the following criteria. 
 
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 noninvasive 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 
 “;” stands for “or.” 
*: Activities of daily living except for self-care activities include meal preparation, shopping for daily 
necessities and clothing, making phone calls, 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 (mFOLFOX6 + bevacizumab or mFOLFOX6 + 
panitumumab combination therapy) and adverse events, and causal relationship between adverse 
events in the mFOLFOX6 + panitumumab group and panitumumab (information on causal 
relationship with panitumumab will be collected only when causal relationship is “related” with 
protocol treatment) 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 (including clinical course after 
discontinuation). Possibly due to protocol treatment (chemotherapy, panitumumab, 
or bevacizumab) although other factors such as underlying disease, complications, 
concomitant drugs/treatment are also presumed. 
Furthermore, for the panitumumab group, an adverse event possibly due to 
panitumumab. 
Not 
related 
An adverse event with no chronological correlation with protocol treatment 
(chemotherapy, panitumumab, or bevacizumab). Very likely due to other factors 
such as underlying disease, complications, and concomitant drugs/treatment. 
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10.1.7 
Action taken for protocol treatment 
As for action concerning protocol treatment, when protocol treatment is discontinued as an action 
against the concerned adverse event, it will be defined as “discontinuation.” 
 
10.1.8 
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 
• 
Laboratory values improved but have not returned to normal or baseline 
• 
The patient died from a cause other than the adverse event concerned while the 
event was resolving 
Not recovered 
• 
No change in symptoms, findings, or laboratory data 
• 
The symptoms, findings, or laboratory data on the final day of observable period 
were aggravated in comparison with the date of onset 
• 
Irreversible congenital anomaly 
• 
The patient died and the concerned adverse event was not a direct cause of death 
but the concerned adverse event remained not recovered  
Recovered with 
sequelae 
• 
Disability that 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 
• 
Outcome of an adverse event that was not determined (judged, presumed) a direct 
cause of death observed in the same patient is not considered as death 
Unknown 
• 
Follow-up specified in the protocol after the date of onset was not possible due to 
change of hospitals or relocation, etc. 
 
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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 4 
weeks (28 days) after discontinuation of protocol treatment or initiation of next treatment, 
whichever date is earlier. In addition, a causal relationship with protocol treatment cannot be ruled 
out for adverse events collected later than 4 weeks (28 days) after discontinuation of protocol 
treatment or initiation of next treatment.  
10.2.1.2 Reporting of adverse events 
At each visit with the patient, the investigator or the subinvestigator should confirm whether the 
onset of subjective symptoms is present or not. Onset of any adverse event that developed after 
the previous visit should be checked by asking the patient a question such as, “How has your 
condition been since the last visit?” 
The investigator or the subinvestigator should follow up all participants who developed adverse 
events, irrespective of a causal relationship with protocol treatment, until disappearance of 
symptoms or abnormal laboratory values and return of clinically problematic abnormal laboratory 
values to the value before administration of study drug or, if not, until observed changes can be 
sufficiently explained for other events (persistent/irreversible adverse event, etc.). 
All adverse events should be entered into the CRF: the name of the adverse event, severity, 
seriousness, causal relationship with protocol treatment (unrelated or related). Further, if a patient 
in the panitumumab group has causal relationship “related” to protocol treatment, causal 
relationship with panitumumab (unrelated or related) should be recorded. Also, for the last course, 
action taken and outcome concerning protocol treatment should be recorded. 
Follow-up period of adverse events is until recovery of an adverse event or the investigator or the 
subinvestigator judges that further follow-up would be unnecessary. 
 
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: 
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When the investigator or the subinvestigator judges that a serious adverse event has occurred, on 
the basis of reporting by a patient, etc., or results of various tests, imaging findings, or definitive 
diagnosis, etc., it should immediately be reported to the supervisor at the study site. 
The investigator or the subinvestigator should also report to the research secretariat office (see the 
attached Sheet 1 for contact information) within 72 hours of recognition of the onset of an event. 
The investigator should also submit a report on diseases associated with the drug to the research 
secretariat office within 10 calendar days. 
Furthermore, the content below, which is to be reported to the research secretariat office within 
72 hours, is mandatory, and other items should be reported as much as possible. 
• 
Name of the adverse event (including known/unknown events*) 
• 
Brief description of the adverse event and the reason why it was determined to be serious 
• 
Study title 
• 
Participant ID code 
• 
Name of study site 
• 
Name of investigator or subinvestigator 
• 
Name of protocol treatment being conducted 
• 
Determined causal relationship  
*: The investigator or subinvestigator will determine whether adverse events are known or 
unknown according to the latest package insert of the drug used in the protocol treatment. 
The representative investigator receiving a report from the research secretariat office will hear the 
opinions of the Certified Review Board, and also provide information to the investigator at each 
study site through the research secretariat office according to the Clinical Research Act. The 
investigator will provide information to the supervisor at the study site as necessary. When 
receiving a report of an unknown serious adverse event, Takeda will add the following item to the 
report from the investigator and disseminate them to the independent monitoring committee. 
 
10.2.3 
Follow-up of serious adverse events 
The investigator or the subinvestigator 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 or the subinvestigator should submit a report specifying details of the change to 
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the supervisor at the study site and the research secretariat office. When requested by the research 
secretariat office or the Certified Review Board, related data of the study site (e.g., ECG, 
laboratory test values, summary of discharge report, result of autopsy, etc.) should be provided. 
 
10.2.4 
Reporting of additional information concerning adverse events 
If the representative investigator and Takeda request provision of additional information 
concerning adverse events for reporting to regulatory authorities, the investigator or the 
subinvestigator should confirm the necessary additional information and enter it in the EDC 
system or submit a report within the period specified by the representative investigator and 
Takeda. 
 
10.2.5 
Reporting of serious adverse events, etc., to regulatory 
authorities 
Takeda should report, according to regulations, unexpected serious adverse drug reactions and 
other serious adverse events that are subject to emergency reporting to regulatory authorities. 
From the time point of first acknowledging the event or receiving additional information, Takeda 
or research secretariat office should comply with regulatory required time frame for reporting, and 
make an emergency report concerning unexpected serious adverse drug reactions and expected 
serious adverse drug reactions to regulatory authorities. Also, Takeda should in the same way 
make an emergency report of other critical safety information that may have a major effect on the 
study drug risk-benefit, continuation of study drug administration, and continuation of this clinical 
study. 
 
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11.0 
COMMITTEES ESTABLISHED FOR 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 the person presiding over the study, the 
representative investigator, the research steering committee members, the statistics representative, 
and Takeda. Takeda or its designee will act as the secretariat. The research steering committee 
will not be informed of the content of treatment allocation throughout the study period. 
Details of management of the research steering committee will be specified in a separately 
prepared procedure manual. Research steering committee members are listed in Section 1.2. 
 
11.2 
Independent data monitoring committee 
The independent data monitoring committee (hereinafter referred to as IDMC) will be established 
according to the ICH E6 (1.25), and Takeda or its designee will serve as the secretariat of the 
IDMC. 
The objective of IDMC is to evaluate the progress of this clinical study, safety data, and endpoints 
of clinical efficacy on a regular basis and propose continuation, alteration, or discontinuation of 
this study to Takeda. 
The IDMC will prepare an IDMC advisory report on continuation/discontinuation of the study and 
a change of the study plan according to the efficacy analysis results as well as the safety analysis 
results for reference, which will be submitted to Takeda. The person presiding over the study, the 
representative investigator, and Takeda will hold discussions and determine whether to continue, 
discontinue, or change the study based on the results. 
Takeda will prepare the IDMC procedures (IDMC charter) specifying details such as the 
objective, roles, and responsibilities of the IDMC and management procedures. IDMC members 
are listed in attached Sheet 1. 
 
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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 with MedDRA.  
 
12.1 
Case report form 
The investigator or the subinvestigator should prepare the case report form (CRF) for all patients 
who have given consent. 
Takeda or its designee should provide study sites with access authorization to the electronic data 
capture (hereinafter referred to as EDC). Takeda or its designee should provide the investigator, 
subinvestigators, and study collaborators with training for utilization of EDC. The CRF will be 
used to report the information collected during the study period to Takeda. The CRF will be 
prepared in Japanese. Data will be directly entered in preparing the CRF. However, written CRFs 
will be collected when the sixth or a subsequent line of treatment is performed in the collection in 
Section “9.2.12 Follow-up treatment.” 
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, the person who made the change or correction, the date 
of change or correction, and the reason for the change or correction. 
The investigator or its designee should ensure the accuracy and completeness of the CRF and 
provide an electronic signature on the relevant page of the case report form. The investigator bears 
full responsibility for the accuracy and reliability of all data entered into the CRF. 
The data below will be directly recorded into the CRF: 
• 
Seriousness, severity, and causal relationship of adverse event with protocol treatment 
– 
Further, for the panitumumab group, causal relationship with panitumumab 
When the investigator or the subinvestigator makes a change or correction in the data entered into 
the CRF after fixation of the clinical database, a record (data clarification form) of change or 
correction in the CRF, provided by Takeda, 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 their 
name, or affix a seal, and date it. 
The monitor should confirm that the CRF has been prepared appropriately. The monitor should 
have access to the medical records of study participants and in-house records to ensure the 
accuracy of the CRF as necessary. The completed CRF is the property of Takeda, and the 
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investigator, subinvestigator, or study collaborator should not disclose the information to a third 
party without written permission from Takeda. 
12.2 
Time limit for data input into the electronic data capture 
The research secretariat office or monitor should request the investigator, subinvestigator, or study 
collaborator to promptly enter EDC during the period from enrollment of the patient to the end of 
the follow-up. 
It is recommended that, after consent has been obtained from the patient, the EDC should be 
entered 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 it should be entered as soon 
as possible. 
1. 
At enrollment: within 2 weeks (14 days) after enrollment 
2. 
During protocol treatment: within 2 weeks (14 days) after initiation of each course of 
protocol treatment 
3. 
At discontinuation of protocol treatment: within 4 weeks (28 days) after discontinuation of 
protocol treatment 
4. 
Imaging test results: within 2 weeks (14 days) after evaluation of efficacy 
5. 
Follow-up period: within 2 weeks (14 days) after request for follow-up 
6. 
Inquiry about data input items of EDC: within 2 weeks (14 days) from inquiry 
 
12.3 
Storage of records 
The investigator should store the following materials, including those specified in Section 14.1, 
and study-specific documents to be used by the person designated by the representative 
investigator for investigation and audit. The materials include a list of patient screenings, medical 
records, signed and dated original consent forms, and a record of change and correction of the 
CRF (copy or electronic copy) containing the audit trail. Also, the investigator should store the 
essential documents for 5 years after completion of the study. However, when the representative 
investigator and Takeda require a longer storage period, the investigator will discuss the period 
and methods of storage with the representative investigator and Takeda. 
Further, the investigator will store the essential documents until the representative investigator or 
Takeda notifies that storage is no longer necessary. 
 
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13.0 
STATISTICAL ANALYSIS METHODS 
The statistics representative or his/her designee (a person belonging to an institution independent 
from Takeda; analysis personnel) will conduct analysis. Takeda will not be involved in analysis. 
 
13.1 
Statistical and analytical plans 
The analysis personnel should start preparing the statistical analysis plan (SAP) (first version) by 
the time of interim analysis and establish the SAP before conducting the final analysis. The SAP 
should be finalized before data fixation of the final analysis. Detailed definition of endpoints and 
analysis methods should be specified in the SAP to deal with all the purposes of the study. 
Data review should be performed before data fixation. Data review is performed to evaluate the 
accuracy and completeness of the study data, patient 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 the main efficacy analysis set, and is defined as “randomized patients who received at least 
one dose of protocol treatment and satisfied main enrollment criteria.” Detailed definition of 
analysis sets is separately specified in the SAP. 
The analysis personnel should finalize the definition of analysis sets and appropriateness of 
analytical handling rules of the participant data in the analysis sets before data fixation, in 
discussion with the statistics representative. 
 
13.1.2 
Analysis of demographic and other baseline characteristics 
Descriptive summary should be provided for demographic and other baseline characteristics for 
each treatment group for all and for left-sided sites. 
 
13.1.3 
Efficacy analysis 
13.1.3.1 Primary endpoint and analysis method 
 [Primary endpoint] 
Overall survival (OS) 
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OS is the period from the day of randomization (day 1) until death by all causes. For surviving 
patients, the period is terminated on the final day of confirming survival or data cut-off date, 
whichever occurs earlier. 
 [Main analysis] 
The following analysis will be performed using the full analysis set. 
For the OS concerning left-sided sites, a stratified log-rank test will be performed with stratification 
according to allocation factors other than study site. The significance levels used for this analysis are 
described in Section “13.1.3.5 Level of significance, confidence coefficient.” 
Show the survival curve by the Kaplan-Meier method until occurrence of an event for each group 
and calculate the quantile of survival period, point estimation of survival rate at a given time point 
and its confidence interval, and the confidence interval corresponding to the level of significance 
at the time of analysis for each treatment group. For reference, the 95% confidence interval (two-
sided) will be calculated.  
Also, calculate the intergroup HR and its confidence interval (two-sided) with a stratified Cox 
model with allocation factors other than sites as the stratum, and the confidence interval 
corresponding to the level of significance at the time of analysis. For reference, the 95% 
confidence interval (two-sided) will also be calculated and the log-rank test and Cox model 
calculation without stratification will also be conducted. 
This analysis will use a hierarchical testing procedure in which only if the analysis for left-sided 
sites shows a significant intergroup difference, the same analysis for all sites will be performed. 
Thus, if the analysis for left-sided sites shows a significant intergroup difference, then the same 
analysis for all sites will be performed. 
 [Adjustment by covariate] 
For the full analysis set, if deviation is observed in an important covariate, apply the Cox model 
and adjust confounding element and calculate HR and 95% confidence interval (two-sided) 
between treatment groups. 
13.1.3.2 Secondary endpoints and analysis method 
 [Secondary endpoints] 
Progression-free survival (PFS) 
PFS is the period from the day of randomization (day 1) until the day of documented PD or the 
day of death due to all causes, whichever comes earlier. For surviving patients without 
documented PD, the period will be cut off on the final day when no progression is confirmed 
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(final day of confirming PFS). Confirmation of progression-free status by imaging test or sample 
test is not mandatory, and clinical confirmation by outpatient medical examination, etc., will be 
allowed. Contact only by telephone will not be allowed. If information on aggression and 
progression-free status is received from medical institutions to which the patient is transferred or 
referred, a medical examination information form stating rationale for diagnosis must be obtained 
and retained. In this case also, contact only by telephone will not be allowed. For surviving 
patients without documented PD for whom curative resection is indicated during protocol 
treatment, the period will be cut off on the final day when specified preoperative diagnostic 
imaging reveals no PD (final day of confirming PFS). 
 [Analysis method] 
The analyses below will be performed in patients with evaluable lesion in the full analysis set of 
all and of left-sided sites. 
Show the survival curve up to the onset of an event by Kaplan-Meier method by treatment group, 
and calculate point estimation of survival rate and its 95% confidence interval (two-sided) by 
treatment group at quantile of survival period and the specified time point. The stratified log-rank 
test will be applied to the analysis with allocation factors other than study sites as the stratum, and 
the intergroup HR and its 95% confidence interval (two-sided) will be calculated with the 
stratified Cox model with allocation factors other than study sites as the stratum. For reference, 
the log-rank test and the Cox model calculation without stratification will also be conducted. 
 
Response rate (RR) 
Percentage of patients whose best overall response is either CR or PR 
 [Analysis method] 
For patients with evaluable lesion in the full analysis set, perform frequency tabulation in each 
treatment group for all and for left-sided sites, respectively, to calculate the point estimation value 
and 95% confidence interval (two-sided). Apply the Cochran-Mantel-Haenszel test by using the 
allocation factors other than study sites as a stratum and calculate the point estimation value of 
intergroup difference (mFOLFOX6 + panitumumab group minus the mFOLFOX6 + bevacizumab 
group) and its 95% confidence interval (two-sided). 
 
Duration of response (DOR) 
DOR is the period from the day when either CR or PR is first confirmed until the day of 
documented PD or the day of death due to all causes, whichever occurs earlier. For surviving 
patients without documented PD, the period will be cut off on the final day when specified 
diagnostic imaging reveals no PD (final day of confirming PFS). For surviving patients without 
documented PD for whom curative resection is indicated during protocol treatment, the period 
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will be cut off on the final day when specified preoperative diagnostic imaging reveals no PD 
(final day of confirming PFS). 
 [Analysis method] 
Show the Kaplan-Meier survival curve until the onset of event by treatment group for the patients 
who showed response among the full analysis set of all and of left-sided sites, respectively, and 
calculate the point estimation value of survival rate and its 95% confidence interval (two-sided) 
for each treatment group at the quantile of survival period and specified time points. 
 
Percentage of curative resection 
Percentage of patients treated with curative resection (complete resection: R0 resection) 
 [Analysis method] 
Perform frequency tabulation for each group in the full analysis set to calculate the point 
estimation value and 95% confidence interval (two-sided) of all and of left-sided sites, and 
calculate the point estimation value and 95% confidence interval (two-sided) of intergroup 
difference (mFOLFOX6 + panitumumab group minus the mFOLFOX6 + bevacizumab group). 
13.1.3.3 Exploratory endpoints 
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13.1.3.4 Data conversion method and handling of missing data 
Details are separately determined in the SAP. 
13.1.3.5 Level of significance, confidence coefficient 
Primary endpoint: 
 
Level of significance:  
2.101% (two-sided 4.202%) for left-sided sites 
2.5% (two-sided 5.0%) for all sites 
 
Confidence coefficient:  
95.798% (two-sided) for left-sided sites* 
95% (two-sided) for all sites* 
*; Errors were found at the time of finalization of the statistical analysis plan and were corrected at 
the time of revision to the clinical study protocol (5th edition) 
Secondary endpoints and other efficacy endpoints: 
The significance level is not determined. Refer to the significance level: 5% (two-sided). 
13.1.4 
Subgroup Analyses 
 
 
 
13.1.5 
Safety analysis 
Perform the following analyses in the safety population. 
13.1.5.1 Treatment-emergent adverse events 
Treatment-emergent adverse events (TEAEs) are adverse events that developed during the protocol 
treatment period after initiation of protocol treatment. 
Perform the following TEAE analyses for each treatment group. Code TEAEs with MedDRA and 
summarize by preferred term and system organ class (SOC). 
 
Frequency tabulation of all TEAEs 
 
Frequency tabulation of TEAEs for which the causal relationship with protocol treatment was 
“related” 
 
Frequency tabulation of all TEAEs by severity 
 
Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
 
Frequency tabulation of TEAEs for which action taken for protocol treatment was 
“discontinuation” 
 
Frequency tabulation of serious TEAEs 
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13.2 
Criteria for interim analysis and premature discontinuation 
The purpose of interim analysis is to determine whether or not to continue the prespecified follow-
up period of mFOLFOX6 + panitumumab combination therapy in a comprehensive manner in 
terms of efficacy and safety as compared with mFOLFOX6 + bevacizumab combination therapy. 
In relation to the number of events observed, interim analysis during enrollment period will not be 
conducted. 
One interim analysis is planned for OS in this study to evaluate the efficacy for all and left-sided 
sites, respectively, when approximately 70% of the overall targeted number of events are observed 
(399 events are expected for all sites and 280 events are expected for left-sided sites).  
To maintain the type 1 error of the entire study within 2.5%, significance level of interim and final 
analyses will be calculated by using O’Brien-Fleming type alpha-spending function, and a 
significance level of 1.25% will be used for both all and left-sided sites. 
The analysis personnel will prepare an interim analysis plan that determines details of interim 
analysis prior to interim analysis. 
 
13.3 
Determination of the planned number of participants 
See Section “6.2.2.2 Rationale for planned number of patients.” 
 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of study sites 
The monitor will perform periodic monitoring of study sites to confirm that this 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. 
Details of procedures for monitoring will be determined in the separately prepared procedures.  
 
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 on the basis of the data collected by EDC. 
The results of central monitoring will be evaluated by the research steering committee and 
feedback will be given to study sites as 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. Source documents are the original documents, data, and records. The 
investigator and the supervisor at the study site will ensure that the monitor and the Certified 
Review Board have access to the source documents. 
The monitor will access the records, including the list of patient screenings, medical records, and 
signed and dated original consent forms, to confirm that this study is appropriately conducted in 
compliance with the protocol and to confirm consistency between the CRF and the related source 
documents. The investigator, the subinvestigator, and other personnel involved in the study will 
ensure sufficient time to facilitate monitoring procedures during visits to the study site. 
Prior to site visit monitoring, study sites are randomly selected to perform source document 
verification for the enrolled patients. 
The frequency and procedures of study site visit monitoring should follow the separately prepared 
procedure manual. 
 
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14.1.3 
Deviations from the Clinical Research Act, ICH-GCP, and 
protocol (non-compliance) 
The investigator or the subinvestigator should record all deviations from the Clinical Research 
Act, ICH-GCP, and protocol. 
When acknowledging that the Clinical Research Act, ICH-GCP, and protocol are not met 
(hereinafter referred to as “non-compliance”), the investigator or subinvestigator should 
immediately report it to the supervisor at the study site and notify the research secretariat office. 
They should provide information on non-compliance to the investigator at each study site and the 
supervisor at the study site through the research secretariat office. 
The representative investigator receiving a report from the research secretariat office will hear the 
opinions of the Certified Review Board according to the Clinical Research Act when he/she 
determines it to be serious non-compliance. 
 
14.2 
Quality assurance 
The auditor and the Certified Review Board will audit the study site when necessary. In such a 
case, the auditor designated by the representative investigator and Takeda should contact the study 
site in advance to determine the date of the audit. The auditor may request a visit to other sites that 
will be used during the study. The investigator and the supervisor at the study site should ensure 
that the auditor has access to study-related source documents. 
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15.0 
ETHICAL CONDUCT OF CLINICAL STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
the Clinical Research Act, and the ICH-GCP. The investigator at each site will conduct this study 
according to the regulatory requirements 
 
 
 
 
15.1 
Application to the Certified Review Board 
Through the conduct of this clinical study, approval by the Certified Review Board and 
permission for the conduct of the study by the supervisor in each study site should be obtained 
according to the clinical study protocol and using the written information for patients. 
 
15.2 
Conflict of interests 
This study will be conducted with support from a sponsor. 
Prior to conduct of the study, the investigator should appropriately manage, according to the 
Clinical Research Act, that this study has no conflict of interests (hereinafter referred to as COI) in 
companies involved in protocol treatment. 
 
15.3 
Written information and patient’s consent 
The ICF contains specific requirements of the Declaration of Helsinki, Ethical Guideline for 
Clinical Research and the ICH-GCP, and all applicable laws and regulations. The ICF specifies 
the use of personal information and medical information of participants in this study (both in and 
outside Japan) and disclosure of that information to a third party. The written explanation explains 
in detail the general idea and purpose of the study and its possible risks and benefits. The ICF also 
clarifies the conditions for study participation and states the fact that patients can discontinue 
study participation at any time without giving reasons and without loss of benefits in treatment. In 
principle, the items below are described: 
1. Clinical study and ICF 
2. Disease and medical condition 
3. Method of treatment for disease 
4. Name of study and explanation that approval has been obtained from the director of study 
site for conducting the study 
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5. Name of research steering committee chairman, study site, and investigator 
6. Objective of study and meaning 
7. Method of study (including purpose of use of samples/information collected from patient) 
and study duration 
8. The estimated number of patients participating in the study 
9. The reason for being selected as participant 
10. Burden for the patient and foreseeable risk and benefits 
11. Consent for participation 
12. Even if consent for carrying out or continuing the study has been given, this can be 
withdrawn at any time 
13. Explanation that the patient can disagree on or withdraw consent for carrying out or 
continuing the study without loss of benefits 
14. Method of information disclosure 
15. Explanation that, upon request, the patient can obtain and have access to material 
concerning protocol and method of study and on the method of obtainment and access 
within the scope where protection of personal information of other patients and the 
assurance of originality of the study is not hindered 
16. Handling of personal information (including method of anonymity) 
17. Method of storage and destruction of sample/information 
18. Status related to funding of study, etc.; study site–related conflict of interest and personal 
benefits related to the study, etc.; and study staff–related conflict of interest 
19. Intellectual property rights 
20. Possibility that the data will be used for future studies 
21. Correspondence to inquiries from patients and persons concerned 
22. Expenses 
23. Items on other methods of treatment 
24. Correspondence to health care provided after study has been conducted 
25. Compensation for injuries related to the study and what injuries are covered 
26. Issues to be followed 
27. Notification of new information and study discontinuation 
28. Explanation that participant’s privacy will be preserved and monitoring personnel, audit 
personnel, and ethics review committee members will only have access to information or 
samples related to participants within the scope of necessity 
29. Explanation that informed consent cannot be obtained from anyone but the patient  
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The investigator is responsible for preparation, content, and the site committee such as ethics 
review committee approval of the ICF. The ICF should be approved by the site committee, such as 
the ethics review committee, before use. 
The ICF should be written in a language easily understood by patients. The investigator or the 
subinvestigator is responsible for providing detailed explanation of the ICF to patients. 
Information should be provided orally and in writing as much as possible by the method deemed 
appropriate by the site committee such as the ethics review committee. 
The investigator or the subinvestigator should ensure that the patients have (1) an opportunity to 
inquire about the study and (2) sufficient time to determine study participation. When a patient 
decides to participate in the study, the patient should sign or write name/affix seal and date the 
consent form prior to study participation. The investigator and the subinvestigator should request 
the patient to sign or write name/affix seal using a legal name and not a nickname with black or 
blue ballpoint pen. The investigator or the subinvestigator should also sign or write name/affix 
seal and date the consent form prior to patient participation. Further, if study collaborator has 
made complementary explanations, the collaborator should also sign or write name/affix seal and 
date the consent form. 
The investigator or the subinvestigator should store the original consent form that was signed or 
contains name/affixed seal. The investigator or the subinvestigator should document in the 
patient’s medical record the date when the patient signed or wrote name/affixed seal on the 
consent form. A copy of the consent form with signature or name typed with seal affixed should 
be provided to the patient. 
If the ICF is revised, the investigator or the subinvestigator should repeat the same procedures 
taken for obtaining the initial consent. The date of obtaining new consent should be recorded in 
the patient’s medical record, and a copy of the revised consent form should be provided to the 
patient. 
 
15.4 
Patient confidentiality 
The person engaged in this clinical study or the person who has been engaged in this clinical study 
should comply with the principles of protection of the patient’s right against invasion of privacy. 
The participant ID code in this study is used to connect the clinical study database and related 
study documents of Takeda with the source data of patients. The limited information of patients 
such as sex, age, and date of birth may be used within the scope of all applicable laws and 
regulations for identification of patients and confirmation of accuracy of participant ID code. 
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In compliance with the Clinical Research Act and the ICH-GCP, the investigator should provide 
monitoring and audit personnel with 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 the monitor, auditor, and the Certified Review Board. The 
investigator or the subinvestigator should obtain approval from patient concerning access to the 
original medical records by a monitor when obtaining consent from a patient (see Section 15.3). 
When providing a copy of source documents to the representative investigator and Takeda, the 
investigator or the subinvestigator should delete the information leading to identification of an 
individual (name and address of the patient, other personal information not recorded in the CRF of 
the patient). 
 
15.5 
Contacts for inquiries from patients and concerned people 
The investigator should establish a contact service to respond to inquiries concerning this study 
from patients or concerned people. Details of the contacts for inquiries will be described in the 
ICF. 
 
15.6 
Advantages and disadvantages to participants 
15.6.1 
Advantage to participants 
This study is performed as part of normal medical practice, and no advantages are expected by 
participating in this study. 
 
15.6.2 
Disadvantage to participants 
This study is performed as part of normal medical practice, and no disadvantage is expected by 
participating in this study. 
 
15.7 
Attribution of study results and access rights 
15.7.1 
Attribution of study results 
The study results and data obtained from this study belong to Takeda. The intellectual property 
rights regarding the pharmaceutical products manufactured and/or distributed by Takeda also 
belong to Takeda. Data generated from this study may be made available for secondary use (e.g., 
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meta-analysis) without any link to personally identifying information, only after discussion among 
and approval by the person presiding over the study, the research representative, and the research 
steering committee. 
 
15.7.2 Data access rights 
Access rights for all data and information generated from this study will be given to personnel 
approved by Takeda. 
 
15.8 
Reporting of results, publication, disclosure, and clinical study 
registration policy 
15.8.1 
Reporting of results, publication, and disclosure 
The investigator should report to the supervisor of the study site a written summary of results of 
this study, and provide Takeda with all the results and data obtained from this study. Only Takeda 
may disclose the study information to other investigators or subinvestigators during the study 
period except for a case required by laws and regulations. 
During the study period and after the end of study, Takeda or its designee should promptly 
summarize the results and present it through medical journals, academic conferences, etc. 
Takeda may publish the data and information obtained from this study (including the data and 
information provided by the investigator) on the basis of the agreement with the personnel 
presiding over the study and the representative investigator. 
The investigator or the subinvestigator should obtain the prior written approval from Takeda when 
publishing the information obtained in this study at an academic conference, etc. 
Takeda should report to the supervisor of the study site that final publication of the study result 
has been made. 
 
15.8.2 
Clinical study registration 
The representative investigator and Takeda will ensure timely publication of information about the 
clinical study and registration of all clinical research in patients under way all over the world, at 
least to the ClinicalTrials.gov and public website (JAPIC) to comply with the applicable 
laws/regulations and guidelines. The city and country where a study is performed and the patient 
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recruitment status should be registered, as well as the contact information of Takeda, to enable 
general access. 
The representative investigator will perform registration in the database established by the 
Ministry of Health, Labour and Welfare (jRCT: Japan Registry of Clinical Trials) according to the 
Clinical Research Act after approval by the Certified Review Board. 
 
15.8.3 
Clinical trial results disclosure 
Takeda will post the results of the clinical study on ClinicalTrials.gov and JAPIC as specified by 
the applicable laws and/or regulations, irrespective of results. 
The representative investigator will perform registration in the database established by the 
Ministry of Health, Labour and Welfare (jRCT: Japan Registry of Clinical Trials) according to the 
Clinical Research Act after reporting to the Certified Review Board. 
 
15.8.4 
Method of storage and destruction of material/information 
concerning clinical study 
The investigator should appropriately retain the material/information related to this study for at 
least 5 years from completion of the study. 
 
15.9 
Insurance and compensation for injury 
The patients 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) guidelines for the treatment 
of colorectal cancer 2014. Kanehara & CO., LTD; 2014. 
3. 
Moertel CG. N Engl J Med. 1994;330(16):1136–42. 
4. 
Saltz LB, et al; Irinotecan Study Group. N Engl J Med. 2000;343(13):905–14. 
5. 
Douillard JY, et al. Lancet. 2000;355(9209):1041–7. 
6. 
de Gramont A, et al. J Clin Oncol. 2000;18(16):2938–47. 
7. 
Rothenberg ML, et al. J Clin Oncol. 2003;21(11):2059–69. 
8. 
Goldberg RM, et al. J Clin Oncol. 2004;22(1):23–30. 
9. 
Tournigand C, et al. J Clin Oncol. 2004;22(2):229–37. 
10. Clinical Practice Guidelines in Oncology: Colon Cancer version 3. National Comprehensive 
Cancer Network; 2013. 
11. Pharmaceutical interview form. Panitumumab (genetical recombination) injection, latest 
version. 
12. Van Cutsem E, et al. J Clin Oncol. 2007;25(13):1658–64. 
13. Douillard JY, et al. J Clin Oncol. 2010;28(31):4697–705. 
14. Peeters M, et al. J Clin Oncol. 2010;28(31):06-4713. 
15. Muro K, et al. Jpn J Clin Oncol. 2009;39(5):321–6. 
16. Boku N, et al. Jpn J Clin Oncol. 2014;44(3):214–23. 
17. Hurwitz H, et al. N Engl J Med. 2004;350(23):2335–42. 
18. Cassidy J, et al. Br J Cancer. 2011;105(1):58–64. 
19. Giantonio BJ, et al. J Clin Oncol. 2007;25(12):1539–44. 
20. Bennouna J, et al. Lancet Oncol. 2013;14(1):29–37. 
21. Van Cutsem E, et al. J Clin Oncol. 2012;30(17):2119–27. 
22. Peeters M, et al. Clin Cancer Res. 2013;19(7):1902–12. 
23. Douillard JY, et al. N Engl J Med. 2013;369(11):1023–34. 
24. Schwartzberg LS, et al. J Clin Oncol. 2014 Jul 20;32(21):2240–7. 
25. Sorich MJ, et al. Ann Oncol. 2015 Jan;26(1):13–21.  
26. Japanese Society of Medical Oncology. Guidance for measuring RAS (KRAS/NRAS) 
mutations in colorectal cancer patients, ver.2. Japanese Society of Medical Oncology; April 
2012. 
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Panitumumab-3001 
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27. Heinemann V, et al. Lancet Oncol. 2014;15:1065–75. 
28. Venook AP, et al. J Clin Oncol. 2014;32:5s(suppl; abstr LBA3). 
29. Lenz H, et al. Ann Oncol. 2014;25(suppl 4):v1. 
30. Schmoll HJ, et al. J Clin Oncol. 2012;30(29):3588–95. 
31. Daisuke Takahari, et al. J Clin Oncol. 2013;31(suppl; abstr 3519). 
32. Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences 
Research (Decision by Director of Health Science Division No. 0331001 dated March 31, 
2008) partially amended on June 26, 2018. 
33. Management of Conflict of Interest in Clinical Trials in the Clinical Research Act 
(Notification by Director of Research and Development Division, Health, Labour and 
Welfare, Ministry of Health, Labour and Welfare No. 0302-1 dated March 2, 2018). 
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SAP_001.pdf: 
 
 
Title: A phase 3, randomized, controlled study of mFOLFOX6 + bevacizumab 
combination therapy versus mFOLFOX6 + panitumumab combination therapy in 
chemotherapy-naïve patients with RAS (KRAS/NRAS) wild-type, unresectable, 
advanced/recurrent colorectal cancer 
 
NCT Number: NCT02394795 
Statistical analysis plan Approve Date: 03-Feb-2022 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue 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). 
 


Statistical Analysis Plan Ver. 1.0 
 
 
Phase III Randomized Controlled Efficacy and Safety Study of 
mFOLFOX6 + Bevacizumab versus mFOLFOX6 + Panitumumab 
in Patients with Chemotherapy-Naïve Unresectable Advanced 
Recurrent Colorectal Cancer with Wild-Type RAS (KRAS/NRAS) 
(PARADIGM study) 
 
 PAnitumumab and RAS, DIagnostically-useful Gene Mutation for mCRC 
 
Statistical Analysis Plan 
Ver. 1.0 
Study Protocol Number: Panitumumab-3001 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan Ver. 1.0 
Table of Contents 
1.
Objectives ..................................................................................................................................... 1 
2.
Rationale for Target Sample Size .................................................................................................. 1 
3.
Analysis Populations ..................................................................................................................... 5 
3.1. 
Full Analysis Set (FAS) ......................................................................................................... 5 
3.2. 
Safety Analysis Set (SAS)..................................................................................................... 5 
3.3. 
Efficacy Analysis Population ................................................................................................ 5 
4.
Disposition of Subjects ................................................................................................................. 6 
4.1. 
Analysis Variables ................................................................................................................. 6 
4.2. 
Analysis Populations ............................................................................................................. 6 
4.3. 
Analysis Methods .................................................................................................................. 6 
5.
Demographic and Other Baseline Characteristics ......................................................................... 7 
5.1. 
Analysis Variables ................................................................................................................. 7 
5.2. 
Analysis Populations ............................................................................................................. 8 
5.3. 
Analysis Methods .................................................................................................................. 8 
6.
Efficacy Results ............................................................................................................................ 8 
6.1. 
Analysis Variables ................................................................................................................. 8 
6.2. 
Analysis Populations ............................................................................................................. 9 
6.3. 
Analysis Methods .................................................................................................................. 9 
7.
Subgroup Analyses...................................................................................................................... 12 
8.
Safety Analyses ........................................................................................................................... 13 
8.1. 
Analysis Variables ............................................................................................................... 13 
8.2. 
Analysis Populations ........................................................................................................... 13 
8.3. 
Analysis Methods ................................................................................................................ 13 
9.
General Specification .................................................................................................................. 14 
10. Data Handling ............................................................................................................................. 14 
11. Interim analysis ........................................................................................................................... 14 
12. Software ...................................................................................................................................... 14 
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Statistical Analysis Plan Ver. 1.0 
In the FIRE-3 study of cetuximab (which has the same mechanism of action as panitumumab), a 
phase III study of FOLFIRI + cetuximab versus FOLFIRI + bevacizumab as first-line therapy for 
unresectable advanced recurrent colorectal cancer with wild-type KRAS, the median OS in patients 
with wild-type RAS was 33.1 and 25.6 months in the FOLFIRI + cetuximab group and the FOLFIRI 
+ bevacizumab group, respectively. Nonetheless, the survival curves of these treatment groups were 
mostly similar until Month 18, and varied afterward. In the CALGB/SWOG80405 study, the survival 
curves also varied at a later stage, as in FIRE-3.
In the current study, if varied survival curves in the treatment groups are assumed from Month 18, as 
in the above discussion, the survival rates would be 75% in both treatment groups at Month 18 and 
22% and 32% in the bevacizumab group and the panitumumab group, respectively, at Month 48, 
with the expectation of partially exponential distribution. Assuming that 800 subjects (400 subjects 
in each group) are enrolled at a constant rate for 24 months and followed for 36 months after the last 
subject enrollment, that 5% of subjects drop out, and a total of 570 events of death are accumulated, 
prolonged OS with FOLFOX + panitumumab versus FOLFOX + bevacizumab would be 
demonstrated with a power of approximately 80% in a log-rank test at a one-sided significance level 
of 0.025. Therefore, the planned number of subjects to be enrolled was 800 in total (400 in each 
group).
The sample size calculation was based on the assumption of median OS of 29 months in the 
bevacizumab group. Therefore, if OS is prolonged in the study overall, the target number of events 
may not be accumulated as planned in the study. Hence, it may be possible to recalculate the sample 
size in order to ensure the necessary number of events, depending on OS results in both treatment 
groups in periodic blinded monitoring reports.
[Revision of the main analysis of the primary endpoint, and powers after the revision] (Added in 
Version 2)
It is also assumed that 600 of 760 total subjects (assuming a 5% dropout rate of the original 800 
subjects) will have left-sided disease, and that 400 death events will occur in left-sided subjects out 
of the target number of 570 events of death in subjects overall. In the revised study protocol, the 
primary objective is to demonstrate prolonged OS with mFOLFOX6 + panitumumab versus 
mFOLFOX6 + bevacizumab in at least one of the treatment groups, either subjects overall subjects 
or left-sided subjects. The powers for log-rank tests at a one-sided significance level of 0.0125 in 
each group of subjects overall and left-sided subjects are discussed below (Table 3), assuming 
hazard ratios of 0.68, 0.70, 0.72, and 0.74 in the mFOLFOX6 + bevacizumab group and the 
mFOLFOX6 + panitumumab group in left-sided subjects. In addition, the hazard ratio in the 
mFOLFOX6 + bevacizumab group was calculated based on the hazard ratio of the median survival 
in the TRICOLORE study (Table 1).
For right-sided subjects, the median survival in patients with right-side disease in the FIRE-3 study
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Statistical Analysis Plan Ver. 1.0 
was used (Table 2). 
Efficacy by Primary Lesion Location in Previous Reports (Left-Sided Disease with Wild-Type RAS) 
Study 
CRYSTAL 
(Phase III) 
PRIME 
(Phase III) 
CALGB/SWOG 
80405 (Phase III) 
FIRE-3 
(Phase III) 
PEAK 
(Phase II) 
Treatment 
group 
FOLFIRI
FOLFIRI 
+Cmab
FOLFOX 
FOLFOX 
+Pmab 
FOLFOX/FOL
FIRI+Bmab 
FOLFOX/FOL
FIRI+Cmab 
FOLFIRI 
+Bmab
FOLFIRI 
+Cmab
FOLFOX 
+Pmab 
FOLFOX 
+Bmab
Number of 
subjects 
138 
142 
159 
169 
152 
173 
149 
157 
53 
54 
OS 
(median in 
month) 
21.7 
28.7 
23.6 
30.3 
32.6 
32.9 
28.0 
38.3 
43.4 
32.0 
HR 
0.65 
0.73 
0.77 
0.63 
0.84 
95% CI 
0.50-0.86 
0.57-0.93 
0.59-0.99 
0.48-0.85 
0.22-3.27 
P-Value
0.02 
not reported 
0.04 
0.002 
not reported 
Table 1.  OS based on Median Survival in Study TRICOLORE 
TRICOLORE 
Treatment group 
mFOLFOX6 or CapeOX + 
bevacizumab 
Number of subjects 
243 
OS 
(median in month) 
33.6 
Table 2. OS based on Median Survival in Treatment Groups in Study FIRE-3 (Right-Side Disease with 
Wild-Type RAS) 
FIRE-3 
Treatment group 
FOLFIRI + bevacizumab 
FOLFIRI + cetuximab 
Number of subjects 
50 
38 
OS 
(median in month) 
23.0 
18.3 
In subjects overall and left-sided subjects separately, a log-rank test will be performed at a one-sided 
significance level of 0.0125. A Monte Carlo simulation was performed, assuming that subjects are 
enrolled for 24 months and followed for 36 months after the last subject enrollment, and that 570 and 
400 death events are accumulated in 800 subjects overall and 600 left-sided subjects, respectively. 
Based on these assumptions, a significant difference should be demonstrated in a log-rank test in at 
least one group, either subjects overall or left-sided subjects, at the following powers (Table 3). 
Table 3.  Results of Monte Carlo Simulation 
Number of subjects 
Significance 
level 
Between-group HR 
in left-sided subjects 
Power 
760 (380/group) for overall subjects 
600 (300/group) for left-sided 
subjects 
One-sided 
0.0125* 
0.68 
91% 
0.70 
86% 
0.72 
79% 
0.74 
71% 
* A significant difference between the mFOLFOX6 + bevacizumab group and the mFOLFOX6 +
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Statistical Analysis Plan Ver. 1.0 
panitumumab group will be demonstrated when a significant difference between these groups is 
demonstrated in either subjects overall or left-sided subjects. 
[Significance levels and powers of the main analysis of the primary endpoint] (Added in Version 3) 
The main analysis was revised as follows. 
Main analysis:  
For overall survival (OS) in left-sided subjects, a stratified log-rank test will be performed, where the 
stratification factors include all stratification factors other than study site. When the analysis in left-
sided subjects demonstrates a significant difference between treatment groups, the stratified log-rank 
test will proceed with overall subjects as a hierarchical procedure. 
Significance level of the main analysis:  
Assuming that 420 death events have been accumulated in left-sided subjects at the time of the final 
analysis planned in 2021, the significance level in the final main analysis will be as discussed below. 
The previous study protocol (version 2) planned to have interim analyses in both overall subjects and 
left-sided subjects. The information time and alpha used at the interim analyses as well as the 
resultant nominal significance levels planned for the final analyses were as follows. 
Nominal Significance Level for Overall Subjects (Protocol Version 2):  
Analysis 
Percentage of events 
Nominal significance level 
(one-sided) 
Interim analysis 
71.2% 
0.00308 
Final analysis 
100.0% 
0.01154* 
Nominal Significance Level for Left-Sided Subjects (Protocol Version 2): 
Analysis 
Percentage of events 
Nominal significance level 
(one-sided) 
Interim analysis 
70.5% 
0.00293 
Final analysis 
100.0% 
0.01159* 
*: The nominal significance level planned for the final analyses in study protocol version 2, which 
was based on alpha used in the interim analysis in study protocol version 2. 
In the revised study protocol, the final main analysis was changed to be performed in a hierarchical 
manner. A stratified log-rank test will be performed first in left-sided subjects and subsequently in 
subjects overall only when a significant difference was demonstrated. The nominal significance level 
of analysis in left-sided subjects is; 
(0.0125 − 0.00308) + 0.01159 = 0.02101 
That is, the nominal significance level will be 0.02101 (one-sided; equivalent to two-sided 0.04202). 
The rationale is as follows. In the revised study protocol, the final main analysis was changed to be 
 
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Statistical Analysis Plan Ver. 1.0 
performed in left-sided subjects only. Nonetheless, the interim analysis had already been performed 
in both subjects overall and left-sided subjects. Because it might be impracticable to explicitly 
calculate the correlation between the test statistics in left-sided subjects in the final analysis and the 
test statistics in overall subjects in the interim analysis, the value of 0.0125 − 0.00308 was adopted, 
despite it being a conservative value. To that value, the nominal significance level of 0.01159, which 
may be used in left-sided subjects, was added, yielding the significance level of the final main 
analysis. 
Powers of main analysis: 
The powers for log-rank tests at a one-sided significance level of 0.02101 (two-sided 0.04202) in left-
sided subjects are discussed below. Assuming hazard ratios based on the median survival (33.6 
months) in the mFOLFOX6 + bevacizumab group in the TRICOLORE study and 420 death events in 
left-sided subjects, a Monte Carlo simulation was performed to obtain the power for each log-rank test. 
Table 2. Results of Monte Carlo Simulation 
Number of subjects 
Significance 
level 
Between-group HR 
in left-sided 
subjects 
Power 
604 for left-sided subjects 
One-sided 
0.02101% 
0.70 
91% 
0.72 
87% 
0.74 
80% 
0.76 
71% 
3.
Analysis Populations
The analysis populations are defined below.
3.1. 
Full Analysis Set (FAS) 
The FAS will include enrolled subjects who were randomized, received at least one dose of the 
protocol treatment, and met the major eligibility criteria. 
3.2. 
Safety Analysis Set (SAS) 
The SAS will include all enrolled subjects who initiated the protocol treatment. 
3.3. 
Efficacy Analysis Population 
The efficacy analysis population is the FAS. 
Additionally, the following two populations are defined for analysis of disposition of subjects, 
although not defined in the study protocol. 
1)
Consented subjects
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Statistical Analysis Plan Ver. 1.0 
This will include all subjects who gave informed consent. 
2)
All enrolled subjects
This will include all consented subjects who were actually enrolled in this study.
4.
Disposition of Subjects
4.1. 
Analysis Variables
1)
Disposition of subjects
2)
Protocol deviations
3)
Reason for protocol treatment discontinuation
4)
Extent of exposure to the protocol treatment
4.2. 
Analysis Populations 
Among the analysis variables in Section 4.1, analyses of variable 1 will be performed in consented 
subjects, analyses of variables 2 and 3 will be performed in all enrolled subjects, and analyses of 
variable 4 will be performed in the SAS. 
4.3. 
Analysis Methods 
1)
Disposition of subjects
Disposition of subjects will be tabulated and presented in figures.
2)
Protocol deviations
Protocol deviation in subjects will be tabulated.
3)
Reason for protocol treatment discontinuation
Reasons for protocol treatment discontinuation in the study will be tabulated by reason.
4)
Extent of exposure to the protocol treatment
For extent of exposure to the protocol treatment in the study, summary statistics of duration of
treatment and number of treatment courses will be calculated for the protocol treatment overall
and for each drug. Frequencies and proportions (%) of subjects who had dose reduction, dose
interruption, or drug discontinuation will be calculated in each treatment group.
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Statistical Analysis Plan Ver. 1.0 
5.2. 
Analysis Populations 
Analyses will be performed in the efficacy analysis population and the safety analysis population. 
5.3. 
Analysis Methods 
1)
Subjects’ Characteristics
The above-mentioned variables of subject characteristics will be summarized with descriptive
statistics. Minimums, medians, maximums, first quartiles, third quartiles, interquartile ranges,
means, and standard deviations will be calculated for continuous variables, and frequencies and
proportions will be calculated for categorical variables. In analyses to make summaries in the
subsequent sections, variables will be analyzed descriptively in the same manner. For subject
characteristics, analyses will be performed by primary lesion location (i.e., for subjects overall,
left-sided subjects, and right-sided subjects) in each treatment group. The definitions of primary
lesion location (left-sided/right-side/other) are as shown below.

Left-sided: Single lesion or multiple lesions in the descending colon, sigmoid colon,
rectosigmoid region, or rectum

Right-sided: Single lesion or multiple lesions in the cecum, ascending colon, or transverse
colon

Other: Multiple primary lesions in both the right side and the left side.
6.
Efficacy Results
6.1. 
Analysis Variables
1)
Primary endpoint
Overall survival (OS)
2)
Secondary endpoints
(1)
Progression-free survival (PFS)
(2)
Response rate (RR)
(3)
Duration of response (DOR)
(4)
Proportion of subjects with curative resection
3)
Exploratory endpoints
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Statistical Analysis Plan Ver. 1.0 
6.2. 
Analysis Populations 
All analyses will be performed in the efficacy analysis population. However, analyses may be 
performed in the safety analysis population if specified separately. 
6.3. 
Analysis Methods 
1)
Primary endpoint
OS is defined as the time from the date of randomization (Day 1) until the date of death from
any cause. Survival subjects will be censored at the last confirmed date of survival or the date
of data cutoff, whichever is earlier.
For overall survival (OS) in left-sided subjects, a stratified log-rank test will be performed,
where the stratification factors include all stratification factors other than study site. Kaplan-
Meier curves of event-free survival will be presented for each treatment group. For survival
time, quartiles will be calculated for each treatment group. For survival rates in Months 12, 24,
36, 48, and 60, point estimates will be calculated for each treatment group along with the
confidence intervals (determined by the Greenwood formula; the same shall apply hereafter)
and the confidence intervals at the significance level chosen for the analysis. Two-sided 95%
confidence intervals will be calculated for reference. Moreover, a Cox model stratified using all
stratification factors other than study site will be used to calculate between-group hazard ratios
along with two-sided confidence intervals and the confidence intervals at the significance level
chosen for the analysis. Two-sided 95% confidence intervals will be calculated for reference.
Apart from the above, an unstratified log-rank test and an unstratified Cox model analysis will
be performed for reference. When a significant difference is observed between treatment groups
in any analysis in left-sided subjects, the analysis will proceed with overall subjects as a
hierarchical procedure. That is, when a significant difference is demonstrated between treatment
groups in any analysis in left-sided subjects, the same analysis will be performed for subjects
overall. In these analyses, significance levels and confidence coefficients will be as follows.
[Significance level] 
0.02101 (two-sided, 4.202%) for left-sided subjects 
0.025 (two-sided, 0.05) for overall subjects 
[Confidence coefficient] 
95.798% (two-sided) for left-sided subjects 
95% (two-sided) for overall subjects 
If non-normal distribution is indicated for any major covariates, a Cox model to correct the 
confounding will be used to calculate between-group hazard ratios along with the two-sided 
95% confidence intervals. 
 
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Statistical Analysis Plan Ver. 1.0 
2)
Secondary endpoints
Analyses (1) to (4) below will be performed in both subjects overall and left-sided subjects.
(1)
Progression-free survival (PFS)
PFS is defined as the time from the date of randomization (Day 1) until the date of progression
of disease (PD) assessment or the date of death from any cause, whichever is earlier. Survival
subjects without PD assessment will be censored on the last confirmed date of no clinical
progression (the last confirmed date of progression-free survival). (The absence of progression
may be confirmed clinically in an outpatient setting and not necessarily confirmed by imaging
or sample analysis. It is not allowed to confirm a subject’s status simply via telephone. For
subjects for whom the presence or absence of progression was confirmed in another hospital to
which the subject had been transferred or referred, the written medical information with
rationale for the diagnosis will be obtained and retained. In this case also, it is not allowed to
confirm a subject’s status simply via telephone). Survival subjects without PD assessment, who
became eligible for curative resection during the protocol treatment, will be censored on the last
date of no PD as confirmed by predefined preoperative imaging (the last confirmed date of
progression-free survival).
Kaplan-Meier curves of progression (event)-free survival will be presented for each treatment
group. For survival time, quartiles will be calculated for each treatment group. For progression-
free survival rates in Months 12, 24, 36, 48, and 60, point estimates will be calculated for each
treatment group along with two-sided 95% confidence intervals. A stratified log-rank test will
be performed, where the stratification factors include all stratification factors other than study
site. Moreover, a stratified Cox model, where the stratification factors include all stratification
factors other than study site, will be used to calculate between-group hazard ratios along with
two-sided 95% confidence intervals. Apart from the above, an unstratified log-rank test and an
unstratified Cox model analysis will be performed for reference.
(2)
Response rate (RR)
Response rate (RR) is defined as the proportion of subjects with CR or PR as best overall
response.
For subjects in the FAS with an evaluable lesion, frequency analyses will be performed to
calculate point estimates along with two-sided 95% confidence intervals for each treatment
group. Moreover, a Cochran-Mantel-Haenszel test will be performed, where the stratification
factors include all stratification factors other than study site. For between-group differences
(Group P - Group B), point estimates along with two-sided 95% confidence intervals will be
calculated.
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Statistical Analysis Plan Ver. 1.0 
(3)
Duration of response (DOR)
Duration of response (DOR) is defined as the time from the date of first confirmed complete
response (CR) or partial response (PR) until the date of PD assessment or death from any cause,
whichever is earlier. Survival subjects without PD assessment will be censored on the last date
of no PD as confirmed by predefined imaging (the last confirmed date of progression-free
survival). Survival subjects without PD assessment, who became eligible for curative resection
during the protocol treatment, will be censored on the last date of no PD as confirmed by
predefined preoperative imaging (the last confirmed date of progression-free survival).
For subjects with response in the FAS, Kaplan-Meier curves of event-free survival will be
presented for each treatment group. For survival time, quartiles will be calculated for each
treatment group. For survival rates until Months 12, 24, 36, 48, and 60, point estimates will be
calculated for each treatment group along with two-sided 95% confidence intervals.
(4)
Proportion of subjects with curative resection
This is defined as the proportion of subjects who had curative resection (complete resection =
R0 resection).
For each treatment group, frequency analysis will be performed to calculate point estimates
along with two-sided 95% confidence intervals. For between-group differences
(Group P - Group B), point estimates along with two-sided 95% confidence intervals will be
calculated.
3)
Exploratory Endpoints
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Statistical Analysis Plan Ver. 1.0 
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Statistical Analysis Plan Ver. 1.0 
 
  
 
 
 
 
 
 
 
 
8.
Safety Analyses
8.1. 
Analysis Variables
1)
Adverse events
8.2. 
Analysis Populations 
Safety analyses will be performed in the safety analysis population. 
8.3. 
Analysis Methods 
1)
Treatment-Emergent Adverse Events (TEAEs)
A TEAE is defined as an adverse event that occurred after the first dose of the protocol
treatment and during the protocol treatment.
For each treatment group, the numbers of subjects with TEAEs, the numbers of TEAEs, and the
incidences of TEAEs will be calculated by event and by severity. Adverse events will be coded
using the system organ classes (SOCs) and preferred terms (PTs) of the MedDRA for analyses.
In calculating the numbers of subjects with TEAEs, a subject who had the same event more
than once will be counted as 1 subject in the applicable category or term. In calculating the
numbers of TEAEs, an event that occurred in the same subject more than once will be counted
as 1 event in the applicable category or term for every time it occurred. In calculating severity, a
subject who had the same event more than once will be counted as 1 subject in the severest
category. The MedDRA version used will be the latest version available at the time of database
lock. The above analyses will be performed for the following variables.

TEAEs related to any drug of the protocol treatment

TEAEs leading to discontinuation of the protocol treatment

Serious TEAEs related to the protocol treatment
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Statistical Analysis Plan Ver. 1.0 
9.
General Specification
1)
Significance levels in testing will be 0.05 (two-sided) in principle. For confidence intervals, two-
sided 95% confidence intervals will be calculated unless otherwise specified.
2)
In listing, units and digits used will be those as recorded. In tabulation, the number of digits will
be as specified below. Proportions (%) will be given to the first decimal place.

Minimum and maximum: Reference number of digits

Mean, median, first quartiles, third quartiles, and interquartile ranges: Reference number of
digits + 1 digit

Standard deviation and confidence interval: Reference number of digits + 2 digits
The reference numbers of digits are those defined for or reported (shown) in case report forms.
Nonetheless, some values, including confidence intervals of hazard ratios, may be shown with an
appropriate number of digits.
3)
The following formulae will be applied in calculating year, month, week, and day.
1 year = 365.25 days
1 month = 30.4375 days
1 week = 7 days
10. Data Handling
1)
Missing Data
No imputation of missing data will be performed in principle.
2)
Quantitation Limit
Laboratory values reported as “quantitation limit” will be deemed values of the quantitation limits
for analyses.
11. Interim analysis
An interim analysis is planned in this study, as detailed in the study protocol and in the interim
analysis plan.
12. Software
Analyses will be performed and figures will be created using the following software.
1)
Microsoft Office Excel 2016 or later
2)
SAS version 9.3 or later, or R version 3.6.2 or later
End of the document 
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