Clinical trial NCT02613221
Conditions: Colorectal Cancer
Keywords: Metastatic colorectal cancer, Panitumumab, TAS-102
Sponsor: Takeda
Start date: 2015-12-07; Completion date: 2018-03-30
Enrollment: 56 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the combination of panitumumab and Triflridine/Tipiracil (FTD/TPI; TAS-102) in patients with RAS wild-type metastatic colorectal cancer (CRC) refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines, irinotecan and angiogenesis inhibitors).

Detailed description:
The purpose of this study is to evaluate the combination of panitumumab and TAS-102 in patients with RAS wild-type metastatic colorectal cancer (CRC) refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines, irinotecan and angiogenesis inhibitors).

Patients who are judged eligible for the study based on the inclusion and exclusion criteria will be received panitumumab (6 mg/kg) every 2 weeks and TAS-102 (35 mg/m² given orally twice a day in a 28-day) in 2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period.

A maximum of 58 participants will be enrolled.

Arms: arm 1: Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Interventions: intervention 1: Panitumumab + TAS-102
Intervention descriptions: intervention 1: panitumumab + TAS-102 combination therapy

Protocol documents:
Prot_001.pdf: 
 
 
Title: A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 
for 
patients 
with 
RAS 
(KRAS, 
NRAS) 
wild-type, 
unresectable, 
advanced/recurrent colorectal cancer 
 
NCT Number: NCT02613221 
Protocol Approve Date: 29-Sep-2017 
 
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). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


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PROTOCOL 
 
 
A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 for patients with RAS (KRAS, NRAS) wild-type, unresectable, 
advanced/recurrent colorectal cancer 
 
APOLLON study 
A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 for patients with RAS wild-type metastatic colorectal cancer refractory to 
standard chemotherapy 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Panitumumab-1501 
Version 
Second Edition 
Product name 
Panitumumab 
Creation date 
September 29, 2017 
 
 


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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 applicable institutional review committee 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 Principals 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science 
and Technology and the Ministry of Health, Labour and Welfare, December 22, 2014). 
• 
International Conference on Harmonisation E6 Good Clinical Practice (hereinafter referred to 
as “GCP”) (including ICH-GCP). 
• All applicable laws and regulations, including, without limitation, data privacy laws, conflict 
of interest guidelines. 
 
1.2 
Clinical Study Administrative Structure 
This study will be conducted under the following administrative structure. 
Clinical research steering committee 
Research steering committee chairman: 
Research steering committee members: 
Data Monitoring Committee (hereinafter referred to as DMC) 
DMC chairman: 
 
PPD
PPD
PPD


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DMC members: 
Statistics Representative: 
 
 
Also, terms used in this protocol will be defined as follows: 
Study site: 
A corporation an administrative organization or a sole proprietor conducting the study, except for 
sites performing only a part of the study related activities on consignment such as sample/ 
information storage and statistic processing. 
Joint research institution: 
An institution jointly conducting the study based on the protocol, and will include institutions that 
will additionally obtain sample/ information from study subjects and providing them to other 
study sites. 
Study staff: 
Investigators and other staff personnel conducting the study (including activities performed in 
institutions that collect and provide samples/ information), except for personnel who only 
provides existing samples/information besides study site or partially engage in the study related 
activity on consignment. 
Investigator: 
A personnel taking part in conducting the study and presides over the study related activities 
within the belonging study site. 
Study site director: 
Director of a corporation, an administrative organization or a sole proprietor conducting the study 
Study subjects: 
A person who is applicable to either of the following: 
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 
PPD
PPD


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1.3 
Contacts for protocol inquiries 
Study office: 
 
E-mail: 
 
Tel: 
 
[Reception hours] 
 
1.4 
Contacts for enrollment procedure 
Case enrollment center: 
 
 E-mail:
 
[E-mail receipt confirmation] 
 Tel: 
 
[Reception hours] 
 
1.5 
Sponsor 
Takeda Pharmaceutical Company Limited, 
Strategic Medical Research Planning, Global Medical Affairs Department, Japan Oncology Business 
Unit 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS 
1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY MANAGEMENT 
INFORMATION ..................................................................................................................... 3 
1.1 
Clinical Study Principals .................................................................................................. 3 
1.2 
Clinical Study Administrative Structure ........................................................................... 3 
1.3 
Contacts for protocol inquiries ......................................................................................... 5 
1.4 
Contacts for enrollment procedure ................................................................................... 5 
1.5 
Sponsor ............................................................................................................................. 5 
2.0 
STUDY SUMMARY ............................................................................................................ 13 
3.0 
LIST OF ABBREVIATIONS ............................................................................................... 22 
4.0 
INTRODUCTION ................................................................................................................. 24 
4.1 
Background..................................................................................................................... 24 
4.1.1 
Etiology of colon cancer .......................................................................................... 24 
4.1.2 
Standard treatment for colon cancer ........................................................................ 24 
4.1.3 
Efficacy and safety of panitumumab in patients with unresectable, 
advanced/recurrent colorectal cancer....................................................................... 26 
4.1.4 
Efficacy and safety of TAS-102 for unresectable, advanced/recurrent colorectal 
cancer ....................................................................................................................... 30 
4.1.5 
RAS (KRAS/NRAS) mutation and panitumumab in unresectable, advanced/recurrent 
colorectal cancer ...................................................................................................... 32 
4.2 
Rationale for the proposed study .................................................................................... 33 
5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY ............................................................ 38 
5.1 
Objective......................................................................................................................... 38 
5.2 
Definition of endpoints ................................................................................................... 38 
5.2.1 
Definition of endpoints for phase I part ................................................................... 38 
5.2.2 
Definition of endpoints for phase II part ................................................................. 38 
5.3 
Rationale for the endpoints ............................................................................................. 39 
5.3.1 
Primary endpoint ..................................................................................................... 39 
5.3.2 
Secondary endpoints ................................................................................................ 39 
6.0 
CLINICAL STUDY DESIGN .............................................................................................. 40 
6.1 
Clinical study design ...................................................................................................... 40 
6.2 
Rationale for study design .............................................................................................. 41 


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6.2.1 
Study population ...................................................................................................... 41 
6.2.2 
Treatment regimens and planned number of subjects .............................................. 42 
6.3 
Discontinuation of entire clinical study or discontinuation of clinical study at a study 
site .................................................................................................................................. 45 
6.3.1 
Criteria for discontinuation of entire clinical study ................................................. 45 
6.3.2 
Criteria for discontinuation of clinical study at a study site .................................... 45 
6.3.3 
Procedures of clinical study suspension and discontinuation of entire clinical study 
or study at a study site ............................................................................................. 45 
6.4 
Procedures for protocol amendment ............................................................................... 45 
7.0 
SELECTION OF STUDY SUBJECTS AND ENROLLMENT ........................................... 47 
7.1 
Inclusion criteria at enrollment ....................................................................................... 47 
7.2 
Exclusion criteria at enrollment ...................................................................................... 48 
7.3 
Procedures for registration and protocol treatment ......................................................... 49 
7.3.1 
Procedures for registration and initiation of protocol treatment .............................. 49 
7.3.2 
Contacts for enrollment procedure .......................................................................... 50 
8.0 
PROTOCOL TREATMENT ................................................................................................. 51 
8.1 
Definition of protocol treatment ..................................................................................... 51 
8.2 
Treatment regimen .......................................................................................................... 51 
8.3 
Recommended dose of protocol treatment ..................................................................... 52 
8.4 
Criteria for administration .............................................................................................. 53 
8.5 
Criteria for protocol treatment change ............................................................................ 56 
8.5.1 
Criteria for suspension/dose reduction of panitumumab ......................................... 56 
8.5.2 
Criteria for suspension/dose reduction of TAS-102 ................................................ 57 
8.6 
Criteria for dose increase of protocol treatment ............................................................. 59 
8.7 
Criteria for discontinuation of protocol treatment for each subject ................................ 59 
8.8 
Procedures for Discontinuation or Withdrawal of a Subject .......................................... 60 
8.9 
DLT ................................................................................................................................ 61 
8.9.1 
DLT Evaluation Period ............................................................................................ 61 
8.9.2 
Subjects Included in the DLT Evaluation ................................................................ 61 
8.9.3 
DLT Criteria ............................................................................................................ 61 
8.10 
Replacement/Addition of Subjects ................................................................................. 62 


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8.11 
Contraindicated drugs/therapies ..................................................................................... 62 
8.12 
Recommended supportive care and combination medications ....................................... 63 
8.13 
Recommended follow-up therapy................................................................................... 64 
9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR OBSERVATIONS..... 65 
9.1 
Study calendar ................................................................................................................ 65 
9.2 
Collection/test/observation items and procedures during the clinical study ................... 68 
9.2.1 
Informed consent procedure .................................................................................... 68 
9.2.2 
Enrollment and protocol treatment .......................................................................... 69 
9.2.3 
Subject demographics .............................................................................................. 69 
9.2.4 
Concurrent medical condition .................................................................................. 70 
9.2.5 
Clinical findings ...................................................................................................... 70 
9.2.6 
Body weight, height ................................................................................................. 70 
9.2.7 
Eastern Cooperative Oncology Group Performance Status (ECOG) Performance 
Status ....................................................................................................................... 71 
9.2.8 
Compliance .............................................................................................................. 71 
9.2.9 
Clinical laboratory tests ........................................................................................... 71 
9.2.10 Imaging test (thoracoabdominal-pelvic CT/MRI) ................................................... 74 
9.2.11 Follow-up treatment................................................................................................. 76 
9.2.12 Survival survey ........................................................................................................ 76 
9.2.13 Pregnancy ................................................................................................................ 76 
9.3 
Records of subjects who discontinued before enrollment .............................................. 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 
10.1.3 Serious adverse events ............................................................................................. 80 
10.1.4 Special interest adverse event for sponsor ............................................................... 81 
10.1.5 Severity of adverse events ....................................................................................... 81 
10.1.6 Causality of adverse events ..................................................................................... 82 
10.1.7 Date of onset of adverse events ............................................................................... 83 
10.1.8 Action taken for protocol treatment ......................................................................... 83 


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10.1.9 Outcome................................................................................................................... 84 
10.2 
Procedures ...................................................................................................................... 84 
10.2.1 Collection and reporting of adverse events .............................................................. 84 
10.2.2 Collection and reporting of serious adverse events ................................................. 85 
10.2.3 Follow-up of serious adverse events ........................................................................ 86 
10.2.4 Reporting of additional information concerning adverse events ............................. 86 
10.2.5 Dissemination of unknown serious adverse event to joint research institutions ...... 86 
10.2.6 Reporting of serious adverse events, etc., to ethics review committee, etc., and 
regulatory authorities ............................................................................................... 87 
11.0 
COMMIITTEES ESTABLISHED FOR THIS STUDY ....................................................... 88 
11.1 
Research steering committee .......................................................................................... 88 
11.2 
Data monitoring committee ............................................................................................ 88 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ................................................ 89 
12.1 
Case report form ............................................................................................................. 89 
12.2 
Time limit for data input into the EDC ........................................................................... 90 
12.3 
Storage of records ........................................................................................................... 90 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................................. 91 
13.1 
Statistical and analytical plans ........................................................................................ 91 
13.2 
Statistical analysis of the phase I part of the study ......................................................... 91 
13.2.1 Analysis set .............................................................................................................. 91 
13.2.2 Analysis of demographic and other baseline characteristics ................................... 91 
13.2.3 Safety analysis ......................................................................................................... 91 
13.3 
Statistical analysis of the phase II part of the study ........................................................ 92 
13.3.1 Analysis sets ............................................................................................................ 92 
13.3.2 Analysis of demographic and other baseline characteristics ................................... 92 
13.3.3 Efficacy analysis ...................................................................................................... 92 
13.3.4 Safety analysis ......................................................................................................... 95 
13.4 
Criteria for interim analysis and premature discontinuation........................................... 97 
13.5 
Determination of the planned number of subjects .......................................................... 97 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 98 
14.1 
Monitoring of study sites ................................................................................................ 98 


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14.1.1 Central monitoring ................................................................................................... 98 
14.1.2 Site visit monitoring ................................................................................................ 98 
14.1.3 Deviations from Ethical Guideline for Clinical Research, ICH-GCP, and Protocol 99 
14.2 
Quality assurance ............................................................................................................ 99 
15.0 
ETHICAL CONDUCT OF CLINICAL STUDY ................................................................ 100 
15.1 
Approval by the study site committee such as the ethics review committee ................ 100 
15.2 
Conflict of interests ...................................................................................................... 100 
15.3 
Written information and subject’s consent ................................................................... 101 
15.4 
Subject confidentiality .................................................................................................. 103 
15.5 
Contacts for inquiries from subjects and concerned people ......................................... 103 
15.6 
Advantages and disadvantages to subjects ................................................................... 104 
15.6.1 Advantage to subjects ............................................................................................ 104 
15.6.2 Disadvantage to subjects........................................................................................ 104 
15.7 
Attribution of study results and access rights ............................................................... 104 
15.7.1 Attribution of study results .................................................................................... 104 
15.7.2 Data access rights .................................................................................................. 104 
15.8 
Reporting of results, Publication, disclosure, and clinical study registration policy .... 104 
15.8.1 Reporting of results, publication and disclosure .................................................... 104 
15.8.2 Clinical study registration ...................................................................................... 105 
15.8.3 Clinical trial results disclosure ............................................................................... 105 
15.8.4 Method of storage and destruction of material/information concerning clinical study105 
15.9 
Insurance and compensation for injury ......................................................................... 106 
16.0 
REFERENCES .................................................................................................................... 107 
LIST OF IN-TEXT TABLES 
Table 4.a Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study ......... 27 
Table 4.b Common adverse events (≥ 20%) noted in a Japanese phase II clinical study of 
Panitumumab monotherapy.............................................................................................. 28 
Table 4.c Common adverse events in specified drug use surveillance in Japan ................................. 29 
Table 4.d Common adverse events (occurrence 10%) noted in Japanese clinical study..................... 31 
Table 4.e Common adverse events (occurrence 10%) noted in the phase III global clinical study .... 32 
Table 4.f Comparison of rate of adverse events .................................................................................. 36 


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Table 4.g Comparison of rate of adverse events ................................................................................. 36 
Table 8a Treatment regimen of combination therapy with panitumumab + TAS-102 ....................... 51 
Table 8.b TAS-102 dosage.................................................................................................................. 52 
Table 8.c TAS-102 dosage when dose is adjusted .............................................................................. 53 
Table 8.d. Criteria for initiation of treatment with panitumumab ....................................................... 56 
Table 8.e Criteria for initiation of treatment with TAS-102 ............................................................... 56 
Table 8.f Criteria for suspension/dose reduction of panitumumab ..................................................... 57 
Table 8.g Doses of panitumumab ....................................................................................................... 57 
Table 8.h Criteria for suspension of TAS-102 .................................................................................... 58 
Table 8.i Criteria for dose reduction of TAS-102 ............................................................................... 58 
Table 8.j Doses of TAS-102 ............................................................................................................... 58 
Table 9.a Study calendar (phase I part of the study) ........................................................................... 66 
Table 9.b Study calendar (phase II part of the study) ......................................................................... 67 
Table 9.c Allowance range for protocol treatment and laboratory tests.............................................. 68 
Table 9.d Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) .......................... 71 
Table 9.e Laboratory tests performed at the time of enrollment ......................................................... 72 
Table 9.f Clinical laboratory tests performed during the protocol treatment period ........................... 74 
Table 9.g Laboratory tests performed at the time of discontinuation ................................................. 74 
Table 10.a Takeda Medically Significant AE List .............................................................................. 81 
Table 10.b CTCAE (Japanese edition JCOG version 4.03) Grade ..................................................... 82 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a Anti-tumor effect from combination use of FTD and panitumumab in KRAS wild-type 
colorectal cancer cell strain (SW48 and LIM1215, both are KRAS/BRAF wild type) ..... 34 
Figure 6.a Outline of study design ...................................................................................................... 40 
Figure 6.b ASPECCT study Progression-free survival ....................................................................... 44 
Figure 8.a Combination therapy with panitumumab and TAS-102 .................................................... 52 
Figure 9.a JSH Guidelines for the Management of Hepatitis B virus infection .................................. 72 
 
LIST OF APPENDICES 
Appendix A 
Evaluation according to RECIST ver 1.1 .............................................................. 110 


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Appendix B 
Responsibilities of the investigator ........................................................................ 115 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Test product: 
Panitumumab 
Study title: 
A phase I/II study for the safety and efficacy of Panitumumab in combination with TAS-102 for patients 
with RAS (KRAS, NRAS) wild-type unresectable, advanced/recurrent colorectal cancer 
APOLLON study (A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 for patients with RAS wild-type metastatic colorectal cancer refractory to standard 
chemotherapy) 
Protocol number: Panitumumab-1501 
Clinical study design: 
This phase I/II study is a multi-center, open-label single-arm study that consists of a phase I part (dose 
de-escalation) which will assess the tolerability, safety and Recommended Dose (hereinafter referred to as 
RD) of Panitumumab in combination with TAS-102 as primary objective, and a phase II part which will 
assess the efficacy and safety of Panitumumab in combination with TAS-102 as primary objective in 
patients with RAS wild-type unresectable, advanced/recurrent colorectal cancer. In the phase I part, the 
subjects will be included sequentially into Cohort 1 and 2, 3 subjects each with the same dosage and 
administration. In the phase II part, 46 subjects will be included additionally for RD confirmed in the 
phase I part. 
 


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In the phase I part, each cohort will be conducted with 3 subjects, the sponsor will assess tolerability of 
the dosage and administration based on the incidence of Dose Limiting Toxicity (hereinafter referred to as 
DLT) during the assessment period and determine whether or not to move on to the next cohort (opinion 
from the Data Monitoring Committee [hereinafter referred to as DMC] will be confirmed appropriately 
upon determination). Therefore, in Cohort 1, if occurrence of DLT is ≤ 2 subjects out of 3, the dosage and 
administration will be determined tolerable and will move on to Cohort 2. However, if DLT is observed 
in 2 subjects during DLT assessment period in Cohort 1, subjects will be included one at a time in Cohort 
2 in consideration for safety to assess DLT. Similarly 3 subjects will be included in Cohort 2 and DLT 
will be assessed in a total of 6 subjects of Cohort 1 and 2 at most. If DLT is observed in 3 subjects 
included in Cohort 1, or DLT is observed in 3 subjects from a total of 6 subjects of Cohort 1 and 2, the 
sponsor will promptly request to postpone new enrollment of subjects to each site and after consultation 
with the Research Steering Committee and DMC on the continuation of the study, will determine whether 
or not to continue the study. 
If study is to be continued, taking in account of the adverse event that occurred, either panitumumab or 
TAS-102 or both drugs will be reduced one step and re-conducting the phase I part similarly will be 
considered. If DLT is observed in 3 subjects after reducing 1 step of panitumumab or TAS-102 or both 
drugs, the study will be discontinued. 
If DLT is observed in ≤ 2 subjects from a total of 6 subjects of Cohort 1 and 2, the sponsor will 
comprehensively assess with the Research Steering Committee based on the safety data of the phase I 
part, and after confirming the opinion of DMC, will determine the transit to phase II part. 
In the phase II part, in addition to the 6 subjects who received RD dose in the phase I part, a target of 46 
subjects are to be accumulated (a total of 52 subjects). 
Objective: 
Phase I part 
Assess RD (Recommended Dose) of panitumumab in combination with TAS-102 in patients with RAS 
wild-type unresectable, advanced/recurrent colorectal cancer 
Phase II part 
Assess efficacy and safety of panitumumab in combination with TAS-102 in patients with RAS wild-type 
unresectable, advanced/recurrent colorectal cancer 
Study population: patients with RAS wild-type unresectable, advanced/recurrent colorectal cancer 
refractory or intolerant to fluropyrimidines, oxaliplatin, irinotecan and angiogenesis inhibitors 
(bevacizumab, aflibercept, ramycirumab, etc.) 
Planned number of subjects: 
A maximum of 58 subjects 


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Dose limiting toxicity (DLT) definition 
In this study, DLT will be assessed based on the adverse events observed in 6 subjects at maximum 
enrolled in phase I part. DLT will be defined as follows [definition and grade will be based on Common 
Terminology Criteria for Adverse Events (CTCAE) ver4.03]. Further, DLT will be assessed from Day 1 
of course 1 of protocol treatment, and if DLT does not occur by Day 1 of course 2, it will be handled as 
no occurrence of DLT in the subject.  Adverse events that can clearly be denied of causal relationship 
with the protocol treatment will not be assessed as DLT.  If serious adverse event or unexpected adverse 
event occurs which causal relationship with the protocol treatment cannot be denied other than the 
following, it may be determined as to whether or not to handle it as DLT in consultation with the 
Investigator, the Research Steering Committee and the sponsor. 
1. 
Persistent Grade 4 neutropenia for more than 7 days under maximum supportive therapy 
2. 
Febrile neutropenia 
3. 
Blood platelete decreased of Grade 3 requiring platelet transfusion or blood platelete decreased of 
Grade 4 
4. 
If start of second course is delayed for more than 14 days due to adverse event related to protocol 
treatment 
5. 
Grade 3 or higher non-hematologic toxicity that is clinically problematic however the following will 
not be applicable as DLT. 
-Grade 3 gastrointestinal symptoms that can be controlled with supportive care (appropriate use of 
antiemetics, antidiarrheals, etc.) 
-Grade 3 or higher electrolyte abnormalities that are not deemed clinically problematic 
Duration of treatment (as a guide): 
6 months 
Period of evaluation: 
12 months 
Inclusion criteria at enrollment: 
1. 
In the opinion of the investigator* or the subinvestigator, the patient is capable of understanding and 
complying with protocol requirements. 
*: A personnel taking part in conducting the study and presides over the study related activities 
within the belonging study site. 
2. 
A patient who can sign and date a written, informed consent form prior to the study enrollment. 
3. 
Patients aged ≥ 20 to < 75 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 who have measurable lesion (refer to Appendix A) according to Response Evaluation 


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Criteria in Solid Tumors (hereinafter referred to as RECIST) ver 1.1 
6. 
Patients with metastatic colorectal cancer refractory or intolerant* to chemotherapy including 
fluropyrimidines, oxaliplatin, irinotecan and angiogenesis inhibitors (bevacizumab, aflibercept, 
ramycirumab, etc.) 
*: Refractory or intolerant if applicable to any of the following 
1) If recurrence is observed during supportive chemotherapy before or after surgery or from imaging 
diagnosis within 6 months of completion. 
2) If imaging or clinical progression is observed during or within 3 months from the last 
administration of chemotherapy for advanced cancer  
3) When it is determined that resumption is not possible due to intolerable adverse event (serious 
allergic reaction, accumulative neuropathy, etc.) 
7. 
Patients classified as KRAS/NRAS wild-type** by KRAS/NRAS testing*. 
*: KRAS/NRAS test will be performed using 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 may receive oral administration 
9. 
Patients who satisfy the following criteria for the major organ function in tests performed within two 
weeks (14 days) prior to enrollment. 
(1) Neutrophil count 1.5 × 103/L 
(2) Platelet count 10.0 × 104/L 
(3) Hemoglobin 8.0 g/dL 
(4) Total blood bilirubin 1.5 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 
10. Eastern Cooperative Oncology Group (hereinafter referred to as ECOG) performance status (P.S.) 
has been determined as 0-1. 
11. Life expectancy of 3 months (90 days) after enrollment. 


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Exclusion criteria at enrollment: 
1. 
Patients who have treatment history of anti-EGFR antibody drugs (cetuximab, panitumumab), 
regorafenib and TAS-102 
2. 
Patients who have received radiotherapy and chemotherapy for primary disease as previous 
treatment and ≥ 2 weeks (14 days) have not passed since the last treatment at scheduled start day of 
treatment. However, excluding therapy received for pain relief of bone metastasis site 
3. 
Patients with known brain metastasis or strongly suspected of brain metastasis 
4. 
Patients with synchronous cancers or metachronous cancers with a disease-free period of 5 years 
(excluding colorectal cancer) However, excluding mucosal cancers cured or be possibly cured by 
regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder 
cancer, etc.) 
5. 
Patients with body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, 
etc.) 
6. 
Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant 
or breast-feeding, or test positive for pregnancy 
7. 
Patients who have received other study drugs and ≥ 4 weeks (28 days) have not passed since at 
scheduled start day of treatment. 
8. 
Patients with disease requiring systemic steroids for treatment (excluding topical steroids) 
9. 
Patients with history or obvious and extensive computerized tomography (CT) findings of interstitial 
pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) 
10. Patients with serious concurrent medical condition (intestinal paralysis, gastrointestinal obstruction, 
intestinal obstruction, uncontrollable diarrhoea, diabetes mellitus being treated with continuous use 
of insulin or that is difficult to control, renal failure, hepatic failure, psychiatric disorder, 
cerebrovascular disorder, gastrointestinal ulceration requiring blood transfusion) 
11. Patients with serious drug hypersensitivity (excluding allergic reaction to oxaliplatin) 
12. Patients with local or systemic active infection requiring treatment, or fever indicating infection 
13. Patients with heart failure or serious heart disease of class II by New York Heart Association 
(NYHA). 
14. Patients with active hepatitis B 
15. Patients with known HIV infection 
16. Patients who have adverse event from previous treatment that has not recovered to at least Grade 1 
(Grade 2 for peripheral sensory neuropathy) by CTCAE, Japanese edition JCOG version v4.03) 
(excluding hemoglobin content) 
17. Patients with known BRAF mutation. 
18. 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) 
Primary endpoint for phase I part:  
Primary endpoint: 


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Incidence of DLT in panitumumab treatment in combination with TAS-102 
Endpoints for phase II part: 
(Regarding efficacy and other endpoints, subjects who have received RD in the phase I part will also be 
included) 
Primary endpoint: 
Efficacy 
Progression-free survival rate at 6 months (PFS rate) 
Secondary endpoints: 
Safety 
Percentage of subjects with adverse events 
Efficacy 
Overall survival (OS) 
Progression-free survival (PFS) 
Response rate (RR) 
Duration of response (DOR) 
Disease control rate (DCR) 
Time to treatment failure (TTF) 
Additional endpoints: 
Follow-up therapy and its rate 
Statistical method: 
In the phase I part, incidence of DLT will be assessed in DLT assessment study population. 
The primary objective for phase II part is to explore the additional effect on PFS rate in panitumumab 
monotherapy when TAS-102 is used in combination with PFS rate at 6 months as primary endpoint. 
PFS rate at 6 months is the crude rate of subjects who survived or were not determined as progressive at 6 
months from the day of enrollment. Based on the observed PFS rate at 6 months from the day of 
enrollment, binomial test will be conducted on the null hypothesis “value will be determined invalid at 
PFS rate ≤ 29%”. Significant level will be 5% (one-sided) in main analysis. For interval estimation, 
accurate 90% confidence interval (two-sided) based on binomial distribution will be used. 
PFS is the period from the day of enrollment until the day of documented progression or the day of death 
due to all causes whichever comes earlier. Kaplan-Meier method will be used to illustrate progression 
free curve and quantile point and its 95% confidence interval (two-sided) of PFS will be calculated. 
Rationale for planned number of subjects: 
In the phase I part for the assessment of tolerability, 6 to 12 subjects were included according to the 


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“Guidelines for clinical evaluation methods of anti-cancer drugs” (PFSB/ELD notification No. 1101001, 
01/Nov/2005). 
Also, in the phase II part as efficacy will be assessed on PFS rate at 6 months as primary endpoint, 
according to the above guideline and precedent overseas clinical trial results, number of subjects were set 
as to confirm the expected PFS rate to overwhelm the PFS rate threshold. 
In the panitumumab monotherapy vs. best supportive care (BSC) as third-line treatment control trial in 
patients with unresectable, advanced/recurrent colorectal cancer (trial 20020408), the PFS median, the 
primary endpoint, were 8.0 weeks for the panitumumab group and 7.3 weeks for the BSC group. In 
retrospectively conducted KRAS wild-type population and KRAS/NRAS wild-type population, PFS 
median were 12.3 weeks and 14.1 weeks respectively in the panitumumab group. On the other hand, in 
the panitumumab monotherapy vs. cetuximab monotherapy control study (ASPECCT study) in patients 
with KRAS wild-type unresectable, advanced/recurrent colorectal cancer that became resistant to 
fluoropyrimidine agents, OXA, and IRI, the secondary endpoint PFS were 4.1 months for panitumumab 
and 4.4 months for cetuximab and showed no difference (hazard ratio [HR], 1.00; two-sided 95% 
confidence interval [CI], 0.88–1.14). Further, PFS rate at 6 months was 33% (two-sided 95% CI, 29% to 
37%) for the panitumumab group. 
 
On the other hand, for TAS-102, in the domestic phase II study in previously treated subjects with 
unresectable, advanced/recurrent colorectal cancer refractory or intolerant to fluoropyrimidine agents, 
OXA, and IRI and has treatment history of 2 regimens of standard chemotherapy, the secondary endpoint 
PFS median assessed by the Investigator were 1.0 months in the placebo group but significantly 
prolonged to 2.7 months in the TAS-102 group (HR = 0.35, two-sided 95% CI 0.25 to 0.50, p<0.0001). 
As increased anti-tumor effect can be expected by using TAS-102 in combination with panitumumab 
treatment which is the standard treatment for patients with unresectable, advanced/recurrent colorectal 
cancer, the PFS rate at 6 months in this study was assumed to be 48% and this was set as the expected 
PFS rate at 6 month in panitumumab arm is: 33% (95% CI: 29% - 37%) 


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value for the panitumumab treatment in combination with TAS-102 therapy in patients with RAS 
wild-type unresectable, advanced/recurrent colorectal cancer. Also, for the threshold where further testing 
for panitumumab treatment in combination with TAS-102 may be considered not necessary, it was 
assumed to be 29% from the CI lower limit of the PFS rate at 6 months in the ASPECCT study. 
For the main analysis, based on the observed PFS rate at 6 months from start of treatment, binomial test 
will be conducted on the null hypothesis “the true PFS rate at 6 months from start of treatment will be not 
more than the PFS threshold rate where value is determined invalid”. With the PFS threshold rate at 29%, 
PFS expected rate at 48% at 6 months from start of treatment, and one-sided significant level at 5.0%, 
power at 80%, the necessary number of subjects will be 47. Taking into consideration of ineligible or 
discontinued subjects at approximately 10%, the target number of subjects was set to 52 (including 
subjects that received RD in the phase I part). 
Study period: 
Total study period: November 2015 to March 2018 (29 months) 
Enrollment period: November 2015 to March 2017 (17 months) 
Follow-up period: 12 months after completion of enrollment 
 


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3.0 
LIST OF ABBREVIATIONS 
List of 
Abbreviations 
Unabbreviated expression 
5-FU 
fluorouracil 
ALT 
ALanine aminoTransferase 
AST 
ASpartate aminoTransferase 
BSC 
Best Supportive Care 
COI 
Conflict of Interest 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for 
Adverse Events 
DCR 
Disease Control Rate 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
FTD 
Trifluridine 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
HBs 
Hepatitis B surface 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on 
Harmonization 
IRI 
IRInotecan 
JCOG 
Japan Clinical Oncology Group 
KRAS 
Kirsten rat Sarcoma-2 virus 
l-LV 
Levofolinate calcium 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
MTD 
Maximum Tolerated Dose 
NRAS 
Neuroblastoma Rat Sarcoma 
NYHA 
New York Heart Association 
OS 
Overall Survival 
OXA 
OXAliplatin 


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List of 
Abbreviations 
Unabbreviated expression 
Unequivocal 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PR 
Partial Response 
P.S. 
Serformance Status 
RAS 
RAt Sarcoma 
RD 
Recommended Dose 
RECIST 
Response Evaluation Criteria In Solid 
Tumors 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOP 
Standard Operating Procedures 
TPI 
Tipiracil hydrochloride 
TEAE 
Treatment-Emergent Adverse Event 
TTF 
Time to Treatment Failure 
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 2014,” 1) and “Site-specific Cancer Prevalence” in 2010 in Japan, 
colon cancer was the third most prevalent cancer in men (14.5%) and the second in women (15.1%). 
According to “Site-specific Cancer Deaths (2013),” in men, lung cancer was the leading cause of 
cancer death (accounting for 24.0% of cancer deaths), followed by gastric cancer (14.7%) and 
hepatic cancer (9.1%); colorectal cancer (colon cancer and rectal cancer combined) accounted for 
11.9% of cancer deaths which exceeded the death rate of hepatic cancer, representing that colorectal 
cancer is the third leading cause of cancer death. In women, lung cancer (14.0%) was also the 
leading cause of cancer death, followed by gastric cancer (11.3%) and colon cancer (10.0%); deaths 
from colorectal cancer (colon cancer and rectal cancer combined) accounted for 14.9% of cancer 
deaths, representing that colorectal cancer is the first leading cause of cancer death. 
 
4.1.2 Standard treatment for colon cancer 
The “Guidelines for Treatment of Colorectal Cancer (2014)”2) classify the standard treatment of 
colorectal cancer according to staging as follows: endoscopic resection for Stage 0, in which the 
lesion is limited in the mucosa; Surgical resection for Stage I to III with postoperative adjuvant 
chemotherapy for Stage II which is at high risk or 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 treatment 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 or bevacizumab or CapeOX (XELOX) therapy + bevacizumab*1 
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 (XELOX) therapy: combination chemotherapy with capecitabine and OXA 
2. 
FOLFIRI therapy + bevacizumab*1 
FOLFIRI therapy: combination chemotherapy with 5-FU, l-LV and irinotecan (hereinafter 
referred to as IRI) 
3. 
FOLFOX therapy + cetuximab*1, 2 or panitumumab*1, 2 
4. 
FOLFIRI therapy + cetuximab*1, 2 or panitumumab*1, 2 


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5. 
FOLFOXIRI therapy FOLFOXIRI therapy: combination chemotherapy with OXA, IRI, 5-FU 
and l-LV 
6. 
FL*3 or Capecitabine+ bevacizumab*1 or UFT + l-LV 
UFT: combination preparation of tegafur and uracil 
*1:  Combination with molecular-targeted drugs such as bevacizumab or anti-epidermal 
growth factor receptor (hereinafter referred to as EGFR) antibody is recommended, but if 
it is not an indication mono-chemotherapy will be conducted. 
*2:  Indication only for KRAS wild-type 
*3:  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 of patients who have received an OXA-based regimen as a first-line treatment, while 
OXA-based regimens are recommended for patients who have received an IRI-based regimen. This 
principle also applies to molecular-targeted drugs concomitantly used for second-line treatment. For 
KRAS wild-type colorectal cancer, bevacizumab is recommended as a second-line treatment of 
patients who have received an anti-EGFR antibody as a first-line treatment, while switching to an 
anti-EGFR antibody or continued use of bevacizumab is an option as a second-line treatment of 
patients who have received bevacizumab as a first-line treatment. Regimens that can be used for 
second-line treatment are as follows. 
1. 
If subject becomes resistant to regimen including OXA 
1) FOLFIRI ± bevacizumab or IRI alone or IRI + S-1 (IRIS) 
2) FOLFIRI (or IRI alone) + cetuximab or panitumumab (KRAS wild-type) 
2. 
If subject becomes resistant to regimen including IRI 
1) FOLFOX or CapeOX (XELOX) ± bevacizumab 
3. 
If patient becomes resistant to regimen including fluropyrimidines, OXA, IRI 
1) IRI + cetuximab or panitumumab (KRAS wild-type) 
2) Cetuximab or panitumumab monotherapy (KRAS wild-type) 
For third-line treatment and onwards, IRI + cetuximab or panitumumab combination therapy (KRAS 
wild-type) and cetuximab or panitumumab monotherapy (KRAS wild-type), and regorafenib 
monotherapy, TAS-102 monotherapy or symptomatic therapies are currently recommended. 


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4.1.3 Efficacy and safety of panitumumab in patients with unresectable, 
advanced/recurrent colorectal cancer 
4.1.3.1 Panitumumab 
EGFR is a member of the ErbB family of transmembrane receptor tyrosine kinases constantly 
expressed in epithelial-derived tissues, has been shown to be overexpressed in various types of solid 
tumors. Colorectal cancer is characterized by high EGFR expression, and the EGFR signaling 
pathway has been shown to play in the pathogenesis and progression of tumors. Binding of 
epidermal growth factor (hereinafter referred to as EGF), the major ligand of EGFR, to EGFR is 
considered to induce auto-phosphorylation of EGFR and activation of various signaling pathways, 
resulting in induction of cellular proliferation, inhibition of apoptosis, and increased production of 
inflammatory cytokines and angiogenesis factors. Panitumumab is a human IgG2 monoclonal 
antibody that binds to EGFR with specificity and high affinity, and inhibits the proliferation of tumor 
cells by competitively inhibiting the binding of the ligand to EGFR3). 
4.1.3.2 Clinical study results for panitumumab in the U.S. and Europe 
As a clinical trial of panitumumab monotherapy for colorectal cancer, a phase III study was 
conducted to compare best supportive care (hereinafter referred to as BSC) vs. BSC + panitumumab 
therapy in patients with unresectable, recurrent/advanced, EGFR-positive colorectal cancer that 
became resistant to fluoropyrimidine agents, OXA, and IRI (BSC group, 232 patients; BSC + 
panitumumab group, 231 patients)4). The median of the primary endpoint of progression free 
survival (hereinafter referred to as PFS) with BSC alone at 7.3 weeks, whereas with BSC + 
panitumumab therapy at 8weeks, significantly longer than that of BSC, showed 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 primarily due to the fact 
that 173 subjects (75%) in the BSC group received follow-up therapy with panitumumab. Also, a 
phase III randomized control study comparing cetuximab monotherapy and panitumumab 
monotherapy in patients with KRAS wild-type unresectable, recurrent/advanced colorectal cancer 
(anti-EGFR antibody untreated) after they became resistant to fluoropyrimidine agents, OXA, and 
IRI has been reported (ASPECCT study).17) In this study, the median of OS which is the primary 
endpoint was 10.4 months for the panitumumab group (499 subjects) compared to 10.0 months for 
cetuximab group (500 subjects) and this indicated that panitumumab is non-inferior to cetuximab 
(HR = 0.97, two-sided 95% CI 0.84 to 1.11) PFS which is the secondary endpoint were 4.1 months 
for panitumumab group and 4.4 months for cetuximab group and showed no difference (HR = 1.00, 
two-sided 95% CI 0.88 to 1.14). 


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With regard to clinical study of combination of chemotherapy and panitumumab, a phase III clinical 
study (PRIME Study) has been reported, in which FOLFOX4 monotherapy vs. FOLFOX4 therapy + 
panitumumab (given at a dose of 6 mg/kg every 2 weeks) as a first-line treatment was compared in a 
total of 1,183 patients (593 in monotherapy group, 590 in panitumumab group)5). The primary 
endpoint of median PFS in KRAS wild-type patients was 9.6 months and significantly longer in the 
FOLFOX4 + panitumumab group as compared with 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, diarrhoea, and hypomagnesaemia 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 2 
patients (Table 4.a). 
Table 4.a Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study 
Adverse event 
FOLFOX4 + panitumumab 
(n = 322) 
FOLFOX4 alone 
(n = 327) 
n 
% 
n 
% 
Any adverse drug 
reaction 
270 
84 
227 
69 
Leukopenia 
136 
42 
134 
41 
Skin disorder 
116 
36 
7 
2 
Diarrhoea 
59 
18 
29 
9 
Nerve disorder 
52 
16 
51 
16 
Hypokalaemia 
32 
10 
15 
5 
Malaise 
30 
9 
10 
3 
Stomatitis 
28 
9 
2 
< 1 
Hypomagnesaemia 
20 
8 
1 
< 1 
Paronychia 
11 
3 
0 
0 
Pulmonary embolism 
9 
3 
5 
2 
Febrile neutropenia 
8 
2 
7 
2 
infusion reaction 
2 
< 1 
- 
- 
 
With regard to second-line treatment, a phase III clinical study (Study 20050181) has been 
conducted, in which FOLFIRI monotherapy vs. FOLFIRI therapy + panitumumab (given at a dose 
of 6 mg/kg every 2 weeks) was compared6). The primary endpoints were PFS and OS in KRAS 
wild-type patients. In KRAS wild-type patients, 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, the OS median were 12.5 months in the 
FOLFIRI alone group and 14.5 months in the FOLFIRI + panitumumab group (HR = 0.85, 
two-sided 95% CI 0.70 to 1.04, p=0.12) and showed no significant difference. The response rate 


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(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 diarrhoea and hypomagnesaemia 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 Study5) and Study 200501816) described above, in which the presence/absence of 
KRAS 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. 
4.1.3.3 Clinical study results for panitumumab in Japan 
In a Japanese phase I clinical study of panitumumab, panitumumab was administered at the same 
dosing regimens with which the drug was confirmed to be safe and effective in overseas studies; i.e., 
a dose of 2.5 mg/kg once weekly, 6 mg/kg once every 2 weeks, and 9 mg/kg once every 3 weeks. 
Each of these dosing regimens was evaluated in 6 patients, and tolerance was ratified in overseas 
clinical trial. 
In a Japanese phase II clinical study of panitumumab monotherapy, 7) 52 patients with previously 
treated, unresectable colorectal cancer were enrolled. In this study, the 6 mg/kg biweekly regimen of 
panitumumab, which was the recommended dosing regimen in the overseas phase III clinical study, 
was well tolerated, and the incidence of adverse events was similar to that observed in the U.S. and 
Europe (Table 4.b). In addition, 7 patients (13.5%) had partial response (hereinafter referred to as 
PR), and this Japanese study yielded an RR of 13.5% (two-sided 95% CI: 5.6 to 25.8),a time to 
treatment failure of 11.4 weeks (two-sided 95% CI: 8.4 to 15.0), a 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 U.S and Europe. 
On the basis of the above results, panitumumab was approved in April 2010 for the treatment of 
unresectable, advanced/recurrent colorectal cancer in Japan as well. 
Table 4.b Common adverse events (≥ 20%) noted in a Japanese phase II clinical study of 
Panitumumab monotherapy 
Adverse event 
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 


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Adverse event 
Panitumumab Monotherapy (n = 52) 
Any Grade 
Grade 3 or higher 
n 
% 
n 
% 
Acne 
42 
81 
1 
2 
Dry skin 
32 
62 
0 
 
Skin rash 
24 
46 
1 
2 
Pruritus 
17 
33 
0 
 
Paronychia 
17 
33 
1 
2 
Hypomagnesaemia 
17 
33 
0 
0 
Malaise 
13 
25 
0 
0 
Stomatitis 
12 
23 
0 
0 
Anorexia 
11 
21 
1 
2 
 
4.1.3.4 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, 8) the median of treatment period (first day of treatment to the final day of treatment) for 
the 3,085 patients who were subject to safety evaluation was 113 days (range: 1 to 559 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), 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. 
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) 
Any Grade 
Grade 3 or 
higher 
Any Grade 
Grade 3 or 
higher 
Intensively investigated 
item 
n 
% 
n 
% 
n 
% 
n 
% 
Skin & subcutaneous tissue 
disorders (SOC) 
918 
73.2 
118 
9.4 
1446 
79.0 
274 
15.0 
Paronychia 
272 
21.7 
33 
2.6 
459 
25.1 
99 
5.4 
Interstitial lung disease* 
16 
1.3 
- 
- 
23 
1.3 
- 
- 
Infusion reaction 
17 
1.4 
1 
0.1 
30 
1.6 
5 
0.3 
Hypomagnesaemia 
257 
20.5 
61 
4.9 
263 
14.4 
62 
3.4 
Hypocalcaemia 
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 


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4.1.4 Efficacy and safety of TAS-102 for unresectable, advanced/recurrent 
colorectal cancer 
4.1.4.1 TAS-102 
TAS-102 is a new nucleoside anticancer agent formulated with trifluridine (FTD) and tipiracil (TPI) 
prepared at a molar ratio of 1 : 0.5. FTD is an anticancer active ingredient of TAS-102 and TPI is an 
inhibitor specific to thymidine phosphorylase (TPase) which is a FTD decomposing enzyme.9) FTD 
will show anti-tumor effect when administered orally and taken in by DNA, while on the other hand, 
FTD will be metabolized promptly through first-pass effect of oral administration. Therefore, in 
order to have FTD taken in by DNA efficiently, it is necessary to inhibit TPase that engages in 
metabolizing FTD and it is necessary to administer FTD in combination with TPI. In the non-clinical 
study, in a nude mouse subcutaneously implanted with human tumor-derived cell line, as the FTD 
amount taken in DNA and tumor proliferation inhibitory effect had correlated it was presumed that 
tumor proliferation inhibitory effect of TAS-102 is based on FTD and tumor proliferation inhibitory 
effect shows effectiveness when FTD is taken in by DNA. Also, when FTD alone is orally given to 
monkies, FTD could hardly be observed in blood, whereas in combination with TPI that inhibits 
TPase which is a FTD decomposing enzyme, FTD blood concentration was maintained. 
4.1.4.2 Clinical study results for TAS-102 
In Japan, after the phase I study in patients with solid tumors (J001 study) had been conducted, a 
phase II control study (J003 study) with OS as primary endpoint and PFS, DCR, etc. as secondary 
endpoints and the objective of assessing the superiority of TAS-102 group over placebo group in 
patients (number of safety assessed subjects: TAS-102 group 113, placebo group 57, efficacy 
assessed: TAS-102 group 112, placebo group 57) that have received previous treatment of 2 
regimens including fluoropyrimidine agents, OXA, and IRI and with refractory or intolerant, 
unresectable, advanced/recurrent colorectal cancer was conducted. 10) TAS-102 was given 35 
mg/m2/dose orally twice daily for 5 consecutive days, followed by 2 days of washout and after this 
was repeated twice, 14 days washout was implemented. As a result, OS prolongation was observed 
in the TAS-102 group compared to the placebo group. In the TAS-102 group, the OS median was 
9.0 months, and by independent diagnostic imaging organization PFS median was 2.0 months, DCR 
was 43.8% (49/112 subjects).Common adverse events (occurrence 10%) noted in Japanese clinical 
study in 119* subjects are shown in Table 4.d. 
*: 6 subjects who were given the same dosage and regimen as the J003 study in the Japanese phase I 
study (J001 study) were added to the 113 subjects of the Japanese phase II study (J003 study) 


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Table 4.d Common adverse events (occurrence 10%) noted in Japanese clinical study 
Adverse event 
Any Grades 
(n = 119) 
Grade 3 or 
higher 
(n = 119) 
n 
% 
n 
% 
Hematocrit decreased 
34 
28.6 
1 
0.8 
Haemoglobin decreased 
76 
63.9 
22 
18.5 
Lymphocyte count 
decreased 
40 
33.6 
13 
10.9 
Neutrophil count decreased 
87 
73.1 
61 
51.3 
Platelet count decreased 
49 
41.2 
5 
4.2 
Red blood cell count 
decreased 
38 
31.9 
1 
0.8 
White blood cell count 
decreased 
91 
76.5 
36 
30.3 
Diarrhoea 
40 
33.6 
6 
5.0 
Nausea 
75 
63.0 
3 
2.5 
Stomatitis 
18 
15.1 
- 
- 
Vomiting 
34 
28.6 
3 
2.5 
Fatigue 
63 
52.9 
7 
5.9 
Blood albumin decreased 
13 
10.9 
- 
- 
Blood bilirubin increased 
23 
19.3 
1 
0.8 
Weight decreased 
14 
11.8 
- 
- 
Protein urine present 
14 
11.8 
- 
- 
Decreased appetite 
66 
55.5 
3 
2.5 
On the other hand, a phase III global study (RECOURSE study) with OS as primary endpoint and 
PFS, DCR, etc. as secondary endpoints and the objective of assessing the superiority of TAS-102 
over placebo in patients (number of safety assessed subjects: TAS-102 group 533, placebo group 
265, efficacy assessed: TAS-102 group 534, placebo group 266) that have received previous 
chemotherapy of 2 regimens and with refractory or intolerant to fluoropyrimidine agents, IRI,OXA, 
bevacizumab and anti-EGF-R antibody agents (KRAS wild-type), unresectable, advanced/recurrent 
colorectal cancer, was conducted.11) As a result, OS significantly prolonged in the TAS-102 group 
compared to placebo group. In the TAS-102 group, the OS median was 7.1 months, and by 
independent diagnostic imaging organization PFS median was 2.0 months, DCR was 44% (221/502 
subjects). 
Common adverse events (occurrence 10%) noted in the phase III global clinical study in 533 
subjects are shown in Table 4.e. 


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Table 4.e Common adverse events (occurrence 10%) noted in the phase III global clinical study 
Adverse event 
Any Grades 
(n = 533) 
Grade 3 or 
higher 
(n = 533) 
n 
% 
n 
% 
Aneamia 
168 
31.5 
65 
12.2 
Neutropenias 
153 
28.7 
107 
20.1 
Neutrophil count decreased 
145 
27.2 
83 
15.6 
White blood cell count 
decreased 
140 
26.3 
52 
9.8 
Platelet count decreased 
77 
14.4 
13 
2.4 
Diarrhoea 
126 
23.6 
12 
2.3 
Nausea 
210 
394 
5 
0.9 
Asthenia 
58 
10.9 
9 
1.7 
Fatigue 
132 
24.8 
11 
2.1 
Decreased appetite 
141 
26.5 
9 
1.7 
Regarding combination of TAS-102 and antibody drugs, a phase I/II study in combination with 
bevacizumab was conducted in Japan. 12) Patients with colorectal cancer refractory/intolerant to 
anticancer agent therapies including 5-FU, OXA, IRI, and anti VEGF inhibitors (bevacizumab, etc.), 
anti EGFR antibody agents (in cases of RAS wild-type) and has no treatment history of regorafenib 
and TAS-102, and DLT was not observed in the phase I part (6 subjects), RD was determined at 35 
mg/m2 of TAS-102 given twice daily and 5 mg/day of bevacizumab. For efficacy, 21 subjects (total 
from phase I part and phase II part) were analyzed and PFS at week 16 was 42.9%. Also, from the 
assessment by the attending physician PFS median was 24.1 weeks, DCR was 72%. Neutropenia as 
drug related adverse event (Grade 3: 56%, Grade 4: 12%), leukopenia (Grade 3: 40%), febrile 
neutropenia (Grade 3: 16%) were many but no study related deaths. In 17 subjects (68%) start of 
treatment was delayed, in 6 subjects (24%) dose reduction of TAS-102 was necessary, many of the 
causes were neutrophenia. Therefore, tolerance and efficacy has been observed in combination 
therapy with TAS-102 and bevacizumab for unresectable, advanced/recurrent colorectal cancer after 
becoming refractory to standard treatment. 
4.1.5 RAS (KRAS/NRAS) mutation and panitumumab in unresectable, 
advanced/recurrent colorectal cancer 
In a phase III randomized control study (Study 200404084)) of panitumumab monotherapy that 
investigated its efficacy as a third-line treatment in patients with unresectable, advanced/recurrent 
colorectal cancer after receiving standard treatment, the enrolled subjects were analyzed for the 
relationship of 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) in the 


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tumor using 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), the PFS median was 14.1 weeks and significantly prolonged by 7.1 weeks in the 
panitumumab combination group as compared with 7.0 weeks in the BSC group (HR = 0.36, two 
sided 95% CI 0.25 to 0.52, p<0.001). On the other hand, in patients with RAS mutation (KRAS or 
NRAS mutation), the median PFS was 7.3 weeks in the BSC group as compared with 7.4 weeks in 
the panitumumab combination group and did not show significant difference. (HR = 0.97, two sided 
95% CI 0.73 to 1.29). 13) 
Among the patients enrolled in the PRIME study, were analyzed for the relationship of the presence 
or absence of mutations in the genes of KRAS exons 2, 3, 4, NRAS exons 2, 3, 4, and BRAF exon 15 
(codon 600) with PFS and OS. 5) In patients with RAS wild-type, the OS median was 25.8 months 
and significantly prolonged by 5.6 month in the FOLFOX4 + panitumumab group as compared with 
20.2 months in the FOLFOX4 alone group (HR = 0.77, two sided 95% CI 0.64 to 0.94, p = 0.009). 
On the other hand, in patients with RAS mutation, the OS median was 15.5 months and significantly 
shorter in the FOLFOX4 + panitumumab group as compared with 18.7 months in the FOLFOX4 
alone group (HR = 1.21, two sided 95% CI 1.01 to 1.45, p = 0.04). 14) 
Also, in addition to the above studies, patients with KRAS (exons 3 and 4) and NRAS (exons 2, 3 and 
4) mutations other than KRAS exon 2 showing ineffectiveness to anti-EGFR antibody drugs in 
several post hoc analysis has been reported, 15)and for patients determined as having wild-types and 
currently measuring KRAS exon 2 only, it has been recognized that presence/absence of other RAS 
(KRAS/NRAS, hereinafter referred to as RAS) mutations should be added, and “Guidance for 
measuring RAS (KRAS/NRAS) mutations in colorectal cancer patients” 16) has been published from 
Japanese Society of Medical Oncology. 
 
4.2 
Rationale for the proposed study 
For the treatment of KRAS wild-type, unresectable, advanced/recurrent colorectal cancer it is 
recommended to use molecular target drugs of either anti-VEGF antibody agents or anti-EGFR 
antibody agents in combination with FOLFOX or FOLFIRI treatment. OXA combination treatment 
+ anti-VEGF antibody agent for first-line treatment, and if IRI + anti-VEGF antibody agent is used 
in second-line treatment, anti-EGFR antibody agents alone based on the results from 20020408 
study4) or ASPECCT study17), or IRI + anti-EGFR antibody agents based on results from BOND 
study18) or GERCOR study19), etc. for third-line treatment is used often. 
Combination therapy with anti-EGFR antibody agents and chemotherapy has shown that it also has 
antitumor effect in patients that have become resistant to chemotherapy. In the BOND study in 


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which cetuximab alone group and cetuximab + IRI combination group were compared in patients 
with colorectal cancer that have become resistant to IRI, in spite of the fact that the patient group had 
already been IRI resistant, it has been reported that cetuximab + IRI combination group had superior 
antitumor effect and PFS (for RR, cetuximab + IRI combination group was 22.9% [two-sided 95% 
CI 17.5 to 29.1%], IRI group was 10.8% [two-sided 95% CI 5.7 to 18.1%], P=0.007; for PFS, 
cetuximab + IRI combination group was 4.1 months, IRI group was 1.5 months, P<0.001 by the 
log-rank test). 18) Also in the phase II GERCOR study19) where panitumumab and IRI combination 
therapy was used in patients with colorectal cancer refractory to standard treatment, in spite of the 
fact that it included patients that had already become IRI resistant, anti-tumor effect was observed 
with combination use of panitumumab and IRI, and indicated that panitumumab and IRI 
combination therapy was a superior treatment than that of panitumumab monotherapy (PFS median 
in KRAS wild-type was 6.3 months, 95% CI 3.7 to 8.7). 
As indicated in Section 4.1.4.2, regarding combination use of TAS-102 and antibody agents, 
tolerance and efficacy has been observed with TAS-102 and bevacizumab combination therapy in 
patients with unresectable, advanced/recurrent colorectal cancer after being refractory to standard 
treatment. For combination use of panitumumab and TAS-102, currently there is no clinical data that 
would confirm its efficacy, while in non-clinical studies in vitro tests show anti-tumor effect 
increases by combination use of FTD which is the active component of TAS-102 and panitumumab 
compared to using them alone in KRAS wild-type colorectal cancer cell strain (Figure 4.a, in-house 
data). 
 
Figure 4.a Anti-tumor effect from combination use of FTD and panitumumab in KRAS wild-type 
colorectal cancer cell strain (SW48 and LIM1215, both are KRAS/BRAF wild type) 
In a colorectal cancer cell strain trans planted mouse model, it was indicated that a higher anti-tumor 
effect may be obtained with combination use of panitumumab and TAS-102 compared to preparing 
them alone, and also weight decrease, etc. or increase of other toxicities have not been observed. 20) 
Although the mechanism of action is not known for this combination use effect, from the in vitro test 
lo g  F T D  c o n c .[M ]
%  o f C o n tro l
-9
-8
-7
-6
-5
-4
0
5 0
1 0 0
1 5 0
SW48
LIM1215
パニツムマブ
7.81 ng/mL
コントロール
パニツムマブ
31.3 ng/mL
パニツムマブ
125 ng/mL
パニツムマブ
500 ng/mL
パニツムマブ
コントロール
パニツムマブ
パニツムマブ
パニツムマブ
0.78 ng/mL
3.13 ng/mL
12.5 ng/mL
50.0 ng/mL
-8
FTDの濃度[log M]
% of Control
150 
100 
50 
0 
-7
-6
-5
-4
-3
FTDの濃度[log M]
% of Control
150 
100 
50 
-8
0 
-7
-6
-5
-4
-9
FTD concentration 
FTD concentration 
Control 
Panitumumab 
Panitumumab 
Panitumumab 
Panitumumab 
Control 
Panitumumab 
Panitumumab 
Panitumumab 
Panitumumab 


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using colorectal cancer cell strain, FTD which is an active component of TAS-102 activates the 
phosphorylation of EGFR and AKT or MAPK protein that is located downstream from EGFR, and 
also erlotinib which is a tyrosine kinases inhibitor showed synergy effect of inhabitation of cell 
proliferation by simultaneous action with FTD and also indicated that erlotinib down regulates 
phosphorylation of AKT or MAPK protein by FTD.21) From these reasons, it was considered that a 
higher effect may be expected from combination use of TAS-102 and panitumumab compared to 
using them alone. 
As mentioned earlier, for third-line treatment for colorectal cancer with treatment history of 
FOLFOX therapy or FOLFIRI therapy, taking in account of the results, etc. of the 20020408 study4) 
in which treatment with panitumumab alone and BSC were compared, the ASPECCT study17) in 
which panitumumab monotherapy and cetuximab monotherapy were compared, the NCIC CTG 
CO.17 study22) in which treatment with cetuximab alone and BSC were compared, the BOND 
study18) in which treatment groups of cetuximab alone and cetuximab and IRI combination use were 
compared and the GERCOR study19) in which effect of combination use of IRI + panitumumab was 
assessed, treatment with either cetuximab or panitumumab alone or combination use of IRI + 
cetuximab or IRI + panitumumab are recommended by the “Guidelines for Treatment of Colorectal 
Cancer (2014)”.2) Actually, for subjects who did not show serious adverse event in IRI among 
patients with treatment history with fluropyrimidines, IRI, OXA, it is expected that IRI + anti-EGFR 
antibody combination therapy will be a treatment option, although it has not been proven that IRI + 
anti-EGFR antibody combination therapy has longer survival period compared to cetuximab or 
panitumumab monotherapy. If panitumumab + TAS-102 combination therapy has higher 
effectiveness than anti-EGFR antibody monotherapy and similar effect as IRI + anti-EGFR antibody 
in the same patient group, there will be major benefits for the patient such as avoidance of adverse 
event in IRI. 
Comparison of adverse events in treatments with TAS-102 alone and panitumumab alone is shown 
in the table below. Adverse events for TAS-102 are from Japanese phase II study and for 
panitumumab are from Specified drug use surveillance results (all patients surveillance) in Japan, 
incidence of ≥ 10% has been extracted and presented Table 4.f and Table 4.g. As adverse events in 
both drugs do not hardly overlap besides stomatitis, and adverse events besides stomatitis from 
TAS-102 were all ≤ Grade 2, both drugs are considered usable in combination fairly safely. 


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Table 4.f Comparison of rate of adverse events 
in panitumumab alone among common adverse events (incident ≥ 10%) in treatments with TAS-102 
Common adverse events in 
TAS-102 
(incident ≥ 10%) 
TAS-102 
(n = 119) 
Panitumumab alone 
(n = 1254) 
n 
% 
n 
% 
Hematocrit decreased 
34 
28.6 
- 
- 
Haemoglobin decreased 
76 
63.9 
1 
0.1 
Lymphocyte count decreased 
40 
33.6 
0 
0 
Neutrophil count decreased 
87 
73.1 
0 
0 
Platelet count decreased 
49 
41.2 
4 
0.3 
Red blood cell count decreased 
38 
31.9 
- 
- 
White blood cell count decreased 
91 
76.5 
5 
0.4 
Diarrhoea 
40 
33.6 
24 
1.9 
Nausea 
75 
63.0 
9 
0.7 
Stomatitis 
18 
15.1 
123 
9.8 
Vomiting 
34 
28.6 
4 
0.3 
Fatigue 
63 
52.9 
9 
0.7 
Blood albumin decreased 
13 
10.9 
0 
0 
Blood bilirubin increased 
23 
19.3 
1 
0.1 
Weight decreased 
14 
11.8 
1 
0.1 
Protein urine present 
14 
11.8 
2 
0.2 
Decreased appetite 
66 
55.5 
25 
2.0 
Table 4.g Comparison of rate of adverse events 
in TAS-102 among common adverse events (incident ≥ 10%) in treatment with panitumumab alone 
Common adverse events in 
panitumumab alone 
(incident ≥ 10%) 
Panitumumab alone 
(n = 1254) 
TAS-102 
(n = 119) 
n 
% 
n 
% 
Paronychia 
272 
21.7 
1 
0.8 
Hypomagnesaemia 
223 
17.8 
- 
- 
Dermatitis acneiform 
619 
49.4 
- 
- 
Dry skin 
265 
21.1 
1 
0.8 
From the above, this study was planned as it was determined that assessment of recommended dose, 
efficacy and safety of panitumumab in combination with TAS-102 was necessary in RAS wild-type, 
unresectable, advanced/recurrent colorectal cancer. For combination therapy, panitumumab and 
TAS-102 were used as alone treatment and combined. Therefore, panitumumab will be given at a 
dose of 6 mg/kg every 2 weeks, TAS-102 will be given 35 mg/m2/dose for 5 consecutive days orally 
followed by 2 days of washout and after repeating this twice, 14 days of washout will be 
implemented and if safety is confirmed in the phase I part, the dosage and administration will be the 


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recommended dose for the combination therapy and the same dosage and administration will be 
adopted in the phase II part. If it is determined intolerable in the phase I part, continuation of study 
will be considered and dose reduction will be assessed when necessary. 


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5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY 
5.1 
Objective 
Phase I part 
To assess the recommended dose (RD) of panitumumab in combination with TAS-102 in patients 
with RAS wild-type, unresectable, advanced/recurrent colorectal cancer. 
Phase II part 
To assess the efficacy and safety of panitumumab in combination with TAS-102 in RAS wild-type, 
unresectable, advanced/recurrent colorectal cancer. 
 
5.2 
Definition of endpoints 
5.2.1 Definition of endpoints for phase I part 
Primary endpoint: 
Incidence of DLT in panitumumab treatment in combination with TAS-102 
 
5.2.2 Definition of endpoints for phase II part 
(Including subjects who received RD in phase I part) 
Primary endpoint: 
Efficacy 
Progression-free survival rate at 6 months (PFS rate) 
Secondary endpoints: 
Safety 
Percentage of subjects with adverse events 
Efficacy 
Overall survival (OS) 
Progression-free survival (PFS) 
Response rate (RR) 
Duration of response (DOR) 
Disease control rate (DCR) 
Time to treatment failure (TTF) 
Additional endpoints: 


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Follow-up therapy and its rate 
 
5.3 
Rationale for the endpoints 
5.3.1 Primary endpoint 
In the phase I part, incidence of DLT was set as primary endpoint to assess the tolerability and safety 
of panitumumab in combination with TAS-102 in patients with unresectable, advanced/recurrent 
colorectal cancer and determine RD. 
In the phase II part, PFS rate at 6 months was set as primary endpoint as an important criteria in 
assessing the efficacy of combination use of TAS-102 with panitumumab monotherapy in patients 
with unresectable, advanced/recurrent colorectal cancer. 
 
5.3.2 Secondary endpoints 
The OS, PFS, RR, DOR, DCR, and TTF were selected as the secondary endpoint, because they 
reflect the anti-tumor efficacy. In addition, adverse events were selected as the secondary endpoint, 
because safety is also an important factor in treatment selection in phase II part. 


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6.0 
CLINICAL STUDY DESIGN 
6.1 
Clinical study design 
This phase I/II study is a multi-center, open-label single-arm study that consists of a phase I part 
(dose de-escalation) which will assess the tolerability and RD of Panitumumab in combination with 
TAS-102 as primary objective, and a phase II part which will assess the efficacy and safety of 
Panitumumab in combination with TAS-102 as primary objective in patients with RAS wild-type 
unresectable, advanced/recurrent colorectal cancer. In the phase I part, the subjects will be included 
sequentially into Cohort 1 and 2, 3 subjects each with the same dosage and administration. In the 
phase II part, 46 subjects will be included additionally for RD confirmed in the phase I part. 
 
 
Figure 6.a Outline of study design 
In the phase I part, each cohort will be conducted with 3 subjects, the sponsor will assess tolerability 
of the dosage and administration based on the incidence of Dose Limiting Toxicity (hereinafter 
referred to as DLT) during the assessment period and determine whether or not to move on to the 
next cohort (opinion from the Data Monitoring Committee [hereinafter referred to as DMC] will be 
confirmed appropriately upon determination). Therefore, in Cohort 1, if occurrence of DLT is ≤ 2 
subjects out of 3, the dosage and administration will be determined tolerable and will move on to 
Cohort 2. However, if DLT is observed in 2 subjects during DLT assessment period in Cohort 1, 
subjects will be included one at a time in Cohort 2 in consideration for safety to assess DLT. 


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Similarly 3 subjects will be included in Cohort 2 and DLT will be assessed in a total of 6 subjects of 
Cohort 1 and 2 at most. If DLT is observed in 3 subjects included in Cohort 1, or DLT is observed in 
3 subjects from a total of 6 subjects of Cohort 1 and 2, the sponsor will promptly request to postpone 
new enrollment of subjects to each site and after consultation with the Research Steering Committee 
and DMC on the continuation of the study, will determine whether or not to continue the study. 
If study is to be continued, taking in account of the adverse event that occurred, either panitumumab 
or TAS-102 or both drugs will be reduced one step and re-conducting the phase I part similarly will 
be considered. If DLT is observed in 3 subjects after reducing 1 step of panitumumab or TAS-102 or 
both drugs, the study will be discontinued. 
If DLT is observed in ≤ 2 subjects from a total of 6 subjects of Cohort 1 and 2, the sponsor will 
comprehensively assess with the Research Steering Committee based on the safety data of the phase 
I part, and after confirming the opinion of DMC, will determine the transit to phase II part. 
In the phase II part, in addition to the 6 subjects who received RD dose in the phase I part, a target of 
46 subjects are to be accumulated (a total of 52 subjects). 
 
6.2 
Rationale for study design 
6.2.1 Study population 
Survival period for unresectable, advanced/recurrent colorectal cancer patients is approximately two 
and a half years and still prognostic is poor. Although systemic chemotherapy is used for 
unresectable cases as first-line treatment, recovery is difficult and PFS after initial chemotherapy is 
about one year, second-line chemotherapy PFS is about half a year, and in most cases third-line, 
fourth-line treatment is necessary. Therefore, this became the object of this clinical research as 
development of appropriate treatment for unresectable cases that have become refractory/intolerant 
to existing chemotherapy is an important issue. The patients should also be RAS wild-type, because 
the above mentioned analysis results in the PRIME study5) suggest that panitumumab may be the 
most effective in these patients. 
KRAS/NRAS test will be performed using the in vitro diagnostic that has been approved for 
marketing. 
 


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6.2.2 Treatment regimens and planned number of subjects 
6.2.2.1 Reasons for selecting panitumumab + TAS-102 combination therapy as the 
treatment regimen 
As described in Section 4.1.2, the following regimens using FOLFOX and FOLFIRI treatment and 
methods to use bevacizumab, panitumumab and cetuximab in combination, are shown in the 
Guidelines for Treatment of Colorectal Cancer (2014)2) as the first-line treatment and second-line 
treatment for patients with unresectable, advanced/recurrent colorectal cancer. 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. Further, if it becomes refractory or 
intolerant to these first-line treatment, FOLFIRI+ bevacizumab is used widely as second-line 
treatment (in-house document). Furthermore, if it becomes refractory or intolerant to these 
second-line treatments, the following regimens are for third-line treatment and onwards. 
1. 
Panitumumab monotherapy or cetuximab monotherapy 
2. 
IRI + panitumumab combination therapy or IRI + cetuximab combination therapy 
3. 
Regorafenib monotherapy 
4. 
TAS-102 monotherapy 
5. 
Symptomatic therapies 
On the other hand, from the results of  the  randomized, double blinded, placebo controlled 
comparative study (Japanese phase II control study) in which unresectable, advanced/recurrent 
colorectal cancer that have received previous treatment of 2 regimens including fluoropyrimidine 
agents, OXA, and IRI and became refractory or intolerant was assessed, and it was reported that 
overall survival prolonged significantly compared to placebo administration and TAS-102 obtained 
approval in March 2014 for “unresectable, advanced/recurrent colorectal cancer (restricted to where 
standard treatment is difficult)” as indication. Also, from the results of the phase III global study 
(RECOURSE study11)) in which colorectal cancer patients had no change to standard therapy, it was 
reported that overall survival prolonged significantly compared to placebo and TAS-102 has become 
one of the options for third-line treatment as indication was changed and approved to “unresectable, 
advanced/recurrent colorectal cancer” in March 2015. 
As mentioned in Section 4.2, anti-EGFR antibody agents and chemotherapy has shown that it also 
has anti-tumor effect in patients that have become resistant to chemotherapy. As for panitumumab 
and TAS-102 also, further anti-tumor effect can be expected from combination use. For combination 


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therapy to be assessed in this clinical research, panitumumab and TAS-102 were used as alone 
treatment and combined. Therefore, panitumumab will be given at a dose of 6 mg/kg every 2 weeks, 
TAS-102 will be given 35 mg/m2/dose for 5 consecutive days orally followed by 2 days of washout 
and after repeating this twice, 14 days of washout will be implemented and if safety and tolerability 
is confirmed, the dosage and administration will be the RD for the combination therapy. 
6.2.2.2 Rationale for planned number of subjects 
In the phase I part for the assessment of tolerability and RD of panitumumab and TAS-102 
combination therapy, 6 to 12 subjects were included according to the “Guidelines for clinical 
evaluation methods of anti-cancer drugs” (PFSB/ELD notification No. 1101001, 01/Nov/2005). 
Also, in this study as efficacy will be assessed on PFS rate as primary endpoint, according to the 
above guideline and precedent overseas clinical trial results, number of subjects were set as to 
confirm the expected PFS rate to overwhelm the PFS rate threshold. 
In the panitumumab monotherapy vs. BSC as third-line treatment control trial in patients with 
unresectable, advanced/recurrent colorectal cancer (20020408 study4)), the PFS median were 8.0 
weeks for the panitumumab group and 7.3 weeks for the BSC group. In retrospectively conducted 
KRAS wild-type population and KRAS/NRAS wild-type population, PFS median were 12.3 weeks 
and 14.1 weeks respectively in the panitumumab group. On the other hand, in the panitumumab 
monotherapy vs. cetuximab monotherapy control study (ASPECCT study) in patients with KRAS 
wild-type unresectable, advanced/recurrent colorectal cancer that became resistant to 
fluoropyrimidine agents, OXA, and IRI17), the secondary endpoint PFS were 4.1 months for 
panitumumab and 4.4 months for cetuximab and showed no difference (hazard ratio [HR], 1.00; 
two-sided 95% confidence interval [CI], 0.88–1.14).  Further, PFS rate at 6 months was 33% 
(two-sided 95% CI, 29% to 37%) for the panitumumab group. 


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Figure 6.b ASPECCT study Progression-free survival 
On the other hand, for TAS-102, in the domestic phase II study in previously treated subjects with 
metastatic, unresectable, colorectal cancer refractory or intolerant to fluoropyrimidine agents, OXA, 
and IRI, and has treatment history of 2 regimens of standard chemotherapy, the secondary endpoint 
PFS median assessed by the Investigator were 1.0 months in the placebo group but significantly 
prolonged to 2.7 months in the TAS-102 group (HR = 0.35, two-sided 95% CI 0.25–0.50, p<0.0001) 
As increased anti-tumor effect can be expected by using TAS-102 in combination with panitumumab 
treatment which is the standard treatment for patients with unresectable, advanced/recurrent 
colorectal cancer, the PFS rate at 6 months in this study was assumed to be 48% and this was set as 
the expected value for the panitumumab treatment in combination with TAS-102 therapy in patients 
with RAS wild-type unresectable, advanced/recurrent colorectal cancer. Also, for the threshold 
where further development for panitumumab treatment in combination with TAS-102 may be 
considered not necessary, it was assumed to be 29% from the CI lower limit of the PFS rate at 6 
months in the ASPECCT study. 17) 
For the main analysis, based on the observed PFS rate at 6 months from start of treatment, binomial 
test will be conducted on the null hypothesis “the true PFS rate at 6 months from start of treatment 
will be not more than the PFS threshold rate where value is determined invalid”. With the PFS 
threshold rate at 29%, PFS expected rate at 48% at 6 months from start of treatment, and one-sided 
significant level at 5%, power at 80%, the necessary number of subjects will be 47. Taking into 
consideration of ineligible or discontinued subjects at approximately 10%, the target number of 
subjects was set to 52 (including subjects that received RD in the phase I part). 
PFS rate at 6 month in panitumumab arm is: 33% (95% CI: 29% - 37%) 


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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 sponsor should immediately discontinue the study when at least one of the following criteria is 
applicable. 
 
When new information or other evaluation on the safety or efficacy of protocol treatment 
becomes available which shows a change in the known risk/benefit profile of the concerned 
compound, and risks/benefits are no longer tolerable for subject participation in the study. 
 
When suspension or discontinuation of the clinical study is notified by the DMC. 
 
Occurrence of serious violation of Ethical Guideline for Clinical Research or ICH-GCP which 
may endangers safety of subjects. 
 
6.3.2 Criteria for discontinuation of clinical study at a study site 
A study site may be notified to discontinue clinical study if the site (including the investigator) is 
found in significant violation of Ethical Guideline for Clinical Research, 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 sponsor, the study site director or the investigator decides to suspend or 
discontinue the entire clinical study or clinical study at a study site, a study-specific procedure will 
be provided by the sponsor. The procedure will be followed by applicable study sites during the 
course of clinical study suspension or discontinuation. 
6.4 
Procedures for protocol amendment 
When protocol amendment is required, the sponsor and the research steering committee chairman 
will assess and determine the propriety of the amendment. 
The protocol will be amended when the following purposes are applicable, and when an amendment 
is made, the content will be notified to all study site investigators. Then, investigators should 
confirm the content of the amendment of the protocol and submit a letter of agreement to the sponsor 
to prove agreement for protocol amendment. 


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[When amendment of protocol is required] 
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 subject 
4. 
Dose alteration (including addition of treatment group) 
5. 
Critical change or addition to inclusion/exclusion criteria 
6. 
Change in planned number of subjects 
7. 
Change of plan or description of content due to occurrence of serious adverse event, etc. 
8. 
Following discussion between the sponsor and the research steering committee chairman, 
that it is determined to be applicable to critical change 
Upon receiving the above notification, investigators of the study sites will be reviewed by the ethics 
review board again and must obtain approval from the study site director according to the 
regulations at each site when necessary. 


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7.0 
SELECTION OF STUDY SUBJECTS 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 based on the following criteria. 
1. 
In the opinion of the investigator* or the subinvestigator, the patient is capable of understanding 
and complying with protocol requirements. 
*: A personnel taking part in conducting the study and presides over the study related activities 
within the belonging study site. 
2. 
Patients who signs and dates a written ICF prior to the initiation of any study procedures 
3. 
Patients aged ≥ 20 to < 75 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 who have measurable lesion (refer to Appendix A) according to Response Evaluation 
Criteria in Solid Tumors (hereinafter referred to as RECIST) ver 1.1 
6. 
Patients with colorectal cancer refractory or intolerant* to chemotherapy including 
fluropyrimidines, oxaliplatin (OXA), irinotecan (IRI) and angiogenesis inhibitors (bevacizumab, 
aflibercept, ramycirumab, etc.) 
*: Refractory or intolerant if applicable to any of the following 
1) If recurrence is observed during supportive chemotherapy before or after surgery or from 
imaging diagnosis within 6 months of completion. 
2) If imaging or clinical progression is observed during or within 3 months from the last 
administration of chemotherapy for advanced cancer 
3) When it is determined that resumption is not possible due to intolerable adverse event 
toxicities (serious allergic reaction, accumulative neuropathy, etc.) 
7. 
Patients classified as KRAS/NRAS wild-type** by KRAS/NRAS testing*. 
*: KRAS/NRAS test will be performed using 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 


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8. 
Patients who may receive oral administration 
9. 
Patients who satisfy the following criteria for the major organ function in tests performed 
within two weeks (14 days) prior to enrollment. 
(1) Neutrophil count 1.5 × 103/L 
(2) Platelet count 10.0 × 104/L 
(3) Hemoglobin 8.0 g/dL 
(4) Total blood bilirubin 1.5 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 
10. Eastern Cooperative Oncology Group (hereinafter referred to as ECOG) performance status 
(P.S.) has been determined as 0-1. 
11. 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 treatment history of anti-EGFR antibody drugs (cetuximab, panitumumab), 
regorafenib and TAS-102 
2. 
Patients who have received radiotherapy and chemotherapy for primary disease as previous 
treatment and ≥ 2 weeks (14 days) have not passed since the last treatment at scheduled start 
day of treatment. However, excluding therapy received for pain relief of bone metastasis site 
3. 
Patients with known brain metastasis or strongly suspected of brain metastasis 
4. 
Patients with synchronous cancers or metachronous cancers with a disease-free period of 5 
years (excluding colorectal cancer) excluding mucosal cancers cured or be possibly cured by 
regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, 
bladder cancer, etc.) 
5. 
Patients with body cavity fluid that requires treatment (pleural effusion, ascites, pericardial 
effusion, etc.) 
6. 
Patients who do not want to use contraception to prevent pregnancy, and women who are 
pregnant or breast-feeding, or test positive for pregnancy 
7. 
Patients who have received other study drugs and ≥ 4 weeks (28 days) have not passed since at 
scheduled start day of treatment. 
8. 
Patients with disease requiring systemic steroids for treatment (excluding topical steroids) 
9. 
Patients with history or obvious and extensive computerized tomography (hereinafter referred 
to as CT) findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, 


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etc.) 
10. Patients with serious concurrent medical condition (intestinal paralysis, gastrointestinal 
obstruction, intestinal obstruction, uncontrollable diarrhoea, diabetes mellitus being treated with 
continuous use of insulin or that is difficult to control, renal failure, hepatic failure, psychiatric 
disorder, cerebrovascular disorder, gastrointestinal ulceration requiring blood transfusion) 
11. Patients with serious drug hypersensitivity (excluding allergic reaction to OXA) 
12. Patients with local or systemic active infection requiring treatment, or fever indicating infection 
13. Patients with heart failure or serious heart disease of class II by New York Heart Association 
(NYHA). 
14. Patients with active hepatitis B 
15. Patients with known HIV infection 
16. Patients who have adverse event from previous treatment that has not recovered to at least 
Grade 1 (Grade 2 for peripheral sensory neuropathy) by Common Terminology Criteria for 
Adverse Events (hereinafter referred to as CTCAE, Japanese edition JCOG version v4.03) 
(excluding hemoglobin content) 
17. Patients with known BRAF mutation. 
18. 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 protocol treatment 
7.3.1 Procedures for registration and initiation of protocol treatment 
The investigator or subinvestigator will register subjects according to the following procedure. 
1. The investigator, subinvestigator or study collaborator should pre-register the subject who has 
been given written information on informed consent by entering the identification code and date 
of informed consent discussion into the Web case registration system. * 
 
*: The study collaborator may enter data into the Web case registration system by instruction of 
the investigator or the subinvestigator. 
2. After pre-registration, the investigator, subinvestigator or study collaborator should enter the 
necessary items into the Web case registration system (formal registration) for a subject who has 
given consent. After formal registration, eligibility of a prospective subject is judged by the Web 
case registration system and the registration will be completed. 
3. The investigator, subinvestigator and study collaborator will check the registration result on the 
Web case registration system. The registration result will be sent via e-mail from the Web case 
registration system to the investigator, subinvestigator and study collaborator. 
PPD


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4. The investigator or the subinvestigator should start the protocol treatment within 2 weeks (14 
days) of registration (including the same day of week as the day of enrollment). However, if 
protocol treatment cannot be initiated within 4 weeks of registration or predicted that the 
initiation of protocol will be after 4 weeks from registration, this must be reported to the study 
office before protocol treatment initiation. See Section 1.3 for study office contacts. 
 
7.3.2 Contacts for enrollment procedure 
Case enrollment center: 
 
 E-mail:
 
[E-mail receipt confirmation] 
 Tel: 
 
[Reception hours] 
PPD
PPD
PPD
PPD
PPD


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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. The drugs used for this study 
should be ethical drugs used by the study site. See the latest package insert for details and handling 
of each drug. 
8.1 
Definition of protocol treatment 
With protocol treatment in principle, combination therapy with panitumumab and TAS-102 
stipulated in the “8.2 treatment regimen” will be conducted, and 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 (such as in case of PD). 
Protocol treatment in principle will be initiated within 14 days of entry. 
 
8.2 
Treatment regimen 
The treatment regimen shown below should be administered (28 days [Day1-28] as one course) until 
any of the criteria specified in “8.7 Criteria for discontinuation of protocol treatment for each subject” 
is met. For administration of each drug, see “8.3 Recommended dose of protocol treatment”, “8.4 
Criteria for administration” and “8.5 Criteria for protocol treatment change”. 
Table 8a Treatment regimen of combination therapy with panitumumab + TAS-102 
Drug 
Dose 
Method of 
administration 
Date of 
administration 
Panitumumab 
6 mg/kg 
IV drip infusion 60 
min* 
Day 1, 15 
TAS-102 
35 mg/m2 
Oral 
administration 
(twice daily**) 
Day 1-5 
Day 8-12 
*: When the dose at one time exceeds 1,000 mg, intravenously administer it over 90 min or longer 
after dilution with JP physiological saline to make approximately 150 mL. 
**: Within 1 hour of breakfast and dinner as reference. When TAS-102 is given at fasting state, 
elevation of Cmax of trifluridine (FTD) is observed, therefore fasting should be avoided. 
***: Oral drug intake will start from Day 1 after dinner or the next morning and to oral drug intake 
on Day 6 after breakfast or after dinner will be the 5 day intake (however, in the phase I part, 
after dinner on Day 1 will be the start). 
****: Oral drug intake will start from Day 8 after dinner or the next morning and to oral drug intake 
on Day 13 after breakfast or after dinner will be the 5 day intake (however, in the phase I part, 
after dinner in Day 8 will be the start). 


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Table 8.c TAS-102 dosage when dose is adjusted 
TAS-102 dosage 
(twice daily) 
Body 
surface 
area 
(m2) 
One dose 
(mg) 
Dose per day 
(mg) 
One dosage 
15 mg tablet 
20 mg tablet 
Drug reduction (35 mg/m2 to 30 mg/m2) 
30 mg/m2 
(60 mg/m2/day) 
< 1.09 
30 
60 
2 
0 
1.09 – 1.24 
35 
70 
1 
1 
1.25 – 1.39 
40 
80 
0 
2 
1.40 – 1.54 
45 
90 
3 
0 
1.55 – 1.69 
50 
100 
2 
1 
1.70 – 1.94 
55 
110 
1 
2 
1.95 – 2.09 
60 
120 
0 
3 
2.10 – 2.28 
65 
130 
3 
1 
2.29 
70 
140 
2 
2 
Drug reduction (30 mg/m2 to 25 mg/m2) 
25 mg/m2 
(50 mg/m2/day) 
< 1.10 
25 
50 
2 (after dinner) 
1 (after 
breakfast) 
1.10 – 1.29 
30 
60 
2 
0 
1.30 – 1.49 
35 
70 
1 
1 
1.50 – 1.69 
40 
80 
0 
2 
1.70 – 1.89 
45 
90 
3 
0 
1.90 – 2.09 
50 
100 
2 
1 
2.10 – 2.29 
55 
110 
1 
2 
2.30 
60 
120 
0 
3 
Drug reduction (25 mg/m2 to 20 mg/m2) 
20 mg/m2 
(40 mg/m2/day) 
< 1.14 
20 
40 
0 
1 
1.14 – 1.34 
25 
50 
2 (after dinner) 
1 (after 
breakfast) 
1.35 – 1.59 
30 
60 
2 
0 
1.60 – 1.94 
35 
70 
1 
1 
1.95 – 2.09 
40 
80 
0 
2 
2.10 – 2.34 
45 
90 
3 
0 
2.35 
50 
100 
2 
1 
*: If TAS-102 is to be given 50 mg/day, 20 mg will be given after breakfast, 30 mg after dinner. 
 
8.4 
Criteria for administration 
In principle, the day (Day 29) that is 4 weeks after the starting day of treatment (Day 1) in the 
previous course will be Day 1 of the subsequent course (however, if the actual starting day is the 
next morning, the day before the starting day will be Day 1). Postponement or acceleration due to 


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holidays is allowed. See ”Table 9.c Allowance range for protocol treatment and laboratory 
tests”. 
It should be confirmed that all of the criteria for initiation of protocol treatment (Table 8.d, Table 
8.e) are satisfied on the starting day of treatment of each course. However, the latest data obtained 
from 2 days before treatment to the starting day of treatment may be used as test value. 
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, and if only one drug 
satisfies the criteria for start of treatment then monotherapy with that drug may be allowed. However, 
at the starting point of the second course of the phase I part, both drugs are required to meet the 
treatment initiation criteria. If start of treatment with TAS-102 is postponed, the starting day 
thereafter (if the actual staring day is  next morning, the day before) will be Day 1 of the course and 
that will be the schedule starting point, and if treatment with TAS-102 is determined to be 
discontinued and monotherapy with panitumumab is to be continued, the starting day of 
monotherapy with panitumumab will be defined as the start of course (Day 1), and the course will be 
defined as to give panitumumab on Day 1 and Day 15 between Day 1 and Day 28. However, while 
monotherapy with panitumumab is ongoing and treatment does not start beyond 42 days from 
scheduled start of treatment (starting day of treatment of previous course as Day 1, if treatment does 
not start by Day 57), protocol treatment will be discontinued. Postponement of start of treatment due 
to holidays is allowed. 
 
Also, if start of treatment with panitumumab is postponed or discontinued, the starting day of 
treatment with TAS-102 (if the actual staring day is next morning, the day before) will be Day 1 of 
the course and that will be starting point for the schedule thereafter. However, while monotherapy 
with TAS-102 is ongoing and treatment does not start beyond 28 days from scheduled start of 


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treatment (starting day of treatment of previous course as Day 1, if treatment does not start by Day 
57), protocol treatment will be discontinued. Postponement of start of treatment due to holidays is 
allowed. 
 


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Table 8.d. Criteria for initiation of treatment with panitumumab 
Item 
Criteria for initiation 
Skin symptom (e.g., rash acneiform, dry skin, 
paronychia) 
≤ Grade 2 
Hypomagnesaemia * 
≤ Grade 2 
Treatment may be postponed when suspension is needed at the discretion of the investigator or 
the subinvestigator due to adverse events not listed above. 
*: When accompanied by abnormal ECG findings requiring treatment such as significant QTc 
prolongation, discontinuation or suspension of panitumumab should be considered irrespective of 
the severity of hypomagnesaemia. 
Table 8.e Criteria for initiation of treatment with TAS-102 
Item 
Criteria for initiation 
Hemoglobin concentration 
≥8.0 g/dL 
Neutrophil count 
≥ 1.5 × 103 μL 
Platelet count 
≥ 7.5 × 104/μL 
Total bilirubin 
≤ 1.5 mg/dL 
AST 
≤ 100 IU/L 
(≤ 200 IU/L with liver metastasis) 
ALT 
Serum creatinine 
≤ 1.5 mg/dL 
Periphial sensory neuropathy 
≤ Grade 2 
Other non-hematological toxicity 
(excluding 
alopecia, 
dygeusia, 
pigmentation, underlying disease related 
symptoms) ≤ Grade 1 
Treatment may be postponed when suspension is needed at the discretion of the investigator or the 
subinvestigator due to adverse events not listed above. 
8.5 
Criteria for protocol treatment change 
8.5.1 Criteria for suspension/dose reduction of panitumumab 
The criteria for suspension/dose reduction and doses of panitumumab are shown in Table 8.f and 
Table 8.g, respectively. 


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Table 8.f Criteria for suspension/dose reduction of panitumumab 
Item 
Grade 
Dose adjustment for the next dose of panitumumab 
Skin disorder 
≥ 3 
Dose reduction by 1 level after suspension 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
less within 6 weeks (42 days). 
Hypomagnesaemia * 
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 due to adverse events not listed above. 
*: When accompanied by abnormal ECG findings requiring treatment such as significant QTc 
prolongation, discontinuation or suspension of panitumumab should be considered irrespective of the 
severity of hypomagnesaemia. 
**: Allergic reaction, anaphylactoid reaction, and chills, fever, and dyspnea occurring within 24 hours 
after the initial dose 
***: 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.g Doses 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) 
The administration of panitumumab may be postponed (skipped) and only TAS-102 therapy 
performed when the subject meets the panitumumab suspension criteria (in this case, the day of 
starting the next course (Day 1) will be the day of starting TAS-102 therapy). When the actual day of 
initiating administration starts on the morning of the next day, the day before starting administration 
will be Day 1. For the next dose of panitumumab, treatment will be resumed after it is confirmed that 
the subject does not meet the criteria for suspension of panitumumab, but if panitumumab cannot be 
administered for more than 28 days after the scheduled day of treatment initiation, panitumumab 
treatment will be discontinued. 
 
8.5.2 Criteria for suspension/dose reduction of TAS-102 
The criteria for suspension/dose reduction and doses of TAS-102 are shown in Tables 8.h-j. 


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Table 8.h Criteria for suspension of TAS-102 
Item 
Suspension criteria 
Hemoglobin concentration 
< 7.0 g/dL 
Neutrophil count 
< 1.0 × 103/Λ 
Platelet count 
< 5.0 × 104/Λ 
Total bilirubin 
> 2.0 mg/dL 
AST 
> 100 U/L 
(> 200 U/L with liver metastasis) 
ALT 
Serum creatinine 
> 1.5 mg/dL 
Periphial sensory neuropathy 
Grade 3 or higher 
Other non-hematologic toxicity 
Grade 3 or higher 
Dose suspension is allowed as necessary at the discretion of the investigator or the subinvestigator 
due to adverse events not listed above. 
 
If adverse events meeting the criteria for dose reduction of TAS-102 shown in Table 8.i occur during 
the previous course (including the suspension period), dose will be reduced in course units, with a 
daily dose unit of reduction of 10 mg/m2/day, when TAS-102 is resumed. However, the minimum 
dose will be 40 mg/ m2/day (Table 8.j). 
Table 8.i Criteria for dose reduction of TAS-102 
Item 
Criteria for dose reduction 
Neutrophil count 
< 0.5 × 103/Λ 
Platelet count 
< 5.0 × 104/Λ 
Dose reduction is allowed as necessary at the discretion of the investigator or the subinvestigator due 
to adverse events not listed above. 
 
Table 8.j Doses of TAS-102 
Dose reduction 
level 
TAS-102 
Initial dose 
35 mg/m2 (70 mg/m2/day) 
-1 
30 mg/m2 (60 mg/m2/day) 
-2 
25 mg/m2 (50 mg/m2/day) 
-3 
20 mg/m2 (40 mg/m2/day) 
-4 
Discontinuation (no resumption) 
When the subject meets the criteria for suspension of TAS-102, administration of TAS-102 will be 
suspended, and only panitumumab therapy will be administered. For the next dose of TAS-102, 


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TAS-102 treatment will be resumed after it is confirmed that the subject meets the criteria for 
initiation of TAS-102 treatment (however, when the subject satisfies the criteria for initiation of 
treatment from Day 13 to Day 28 of the suspension period, treatment will be resumed on Day 29). 
However, if TAS-102 cannot be administered for more than 28 days from the scheduled day of 
initiation of treatment, treatment with TAS-102 will be discontinued. (At this time, the day of 
initiating panitumumab monotherapy after it is determined that treatment with TAS-102 will be 
discontinued will be defined as the day for starting the course (Day 1), and the course will be defined 
as the administration of panitumumab between Day 1 and Day 28 on Days 1 and 15.) 
 
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 each subject 
The number of doses is not specified. 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. For 
subjects discontinuing before enrollment, see 9.3 Records of subjects who discontinued before 
enrollment. 
1. Lack of efficacy (exacerbation) 
When PD is evident in the clinical or imaging evaluation 
2. Adverse event 
Discontinuation of treatment due to 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 “4. Death during protocol treatment” and not in 
this item. 
Protocol treatment is postponed due to adverse event for 58 days or more after the day of 
starting the last course. However, postponement due to holidays is allowed. 
3. Voluntary discontinuation 
A subject wishes to discontinue study participation. The reason for discontinuation should be 
recorded in CRF when it is clarified. 


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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 
Death before discontinuation of protocol treatment is decided. Date of death, reason of death 
(protocol treatment related, primary disease, others) should be described in the CRF. 
5. Significant deviation from the protocol 
When study continuation may cause intolerable risk to the health of a subject because the 
subject was found not to satisfy the inclusion criteria specified in the protocol after enrollment 
or the protocol has not been observed. 
6. Lost to follow-up 
When subject fails to make visits and cannot be contacted. The attempts that were made to 
contact the subject should be recorded in the source documents. 
7. Discontinuation of the entire study 
For example, when the sponsor decides to discontinue the clinical study upon the 
recommendation of the DMC. See 6.3.1 Criteria for discontinuation of entire clinical study for 
details. 
8. Pregnancy 
When a female subject is found to be pregnant. 
Note: Study participation should be immediately discontinued when pregnancy is known. See 
“9.2.13 Pregnancy” for procedures. 
9. Others 
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 Subject 
The investigator or the subinvestigator may discontinue a subject’s study participation at any time 
during the study when the subject meets the study termination criteria described in Section 8.7. In 
addition, a subject may discontinue his or her participation without giving a reason at any time 
during the study. Should a subject’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/evaluation scheduled at the time of discontinuation. 
 


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8.9 
DLT 
In this study, DLT will be assessed based on the toxicity in 6 subjects at maximum enrolled in phase 
I part. The sponsor will confirm the opinion of the DMC in a suitable manner when evaluating DLT. 
8.9.1 DLT Evaluation Period 
The DLT evaluation period will be the period from Day 1 of Course 1 of protocol treatment to Day 1 
of Course 2. However, it is mandatory that the treatment initiation criteria for both panitumumab and 
TAS-102 be satisfied in order to start Course 2 of protocol treatment. Furthermore, the DLT 
evaluation period will be the period until the test day at discontinuation of protocol treatment for 
subjects who could not start Course 2 of protocol treatment until Day 57 due to adverse events and 
discontinued the protocol treatment. 
 
8.9.2 Subjects Included in the DLT Evaluation 
Subjects enrolled in the phase I part of the study will be included in the DLT evaluation. Subjects 
will be excluded from the DLT evaluation if at least the designated dose of protocol treatment is not 
administered by the end of Course 1 (except when the protocol treatment is discontinued due to 
DLT), if there are major protocol deviations such as the use of contraindicated drugs, or if the 
subject is determined to be unsuitable for the DLT evaluation. The designated dose is 75% (15 
doses) of the total number of doses (20 doses) of panitumumab (2 doses of 6 mg/kg) and TAS-102 (2 
doses daily of 35 mg/m2) on Days 1-5 and Days 8-12. 
 
8.9.3 DLT Criteria 
DLT is defined as any adverse event for which a causal relationship with protocol treatment cannot 
be denied falling in the following categories. Adverse events will be graded according to the 
“Common Terminology Criteria for Adverse Events (CTCAE), ver. 4.03.” Further, DLT will be 
assessed from Day 1 of course 1 of protocol treatment, and if DLT does not occur by Day 1 of 
course 2, it will be handled as no occurrence of DLT in the subject. Adverse events that can clearly 
be denied of causal relationship with the protocol treatment will not be considered DLT. If serious 
adverse event or unexpected adverse event occurs which causal relationship with the protocol 
treatment cannot be denied other than the following, it may be determined as to whether or not to 
handle it as DLT in consultation with the Investigator, the Research Steering Committee and the 
sponsor. 
1. 
Persistent Grade 4 neutropenia for more than 7 days under maximum supportive therapy 


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2. 
Febrile neutropenia 
3. 
Blood platelete decreased of Grade 3 requiring platelet transfusion or blood platelete decreased 
of Grade 4 
4. 
If start of second course is delayed for more than 14 days due to adverse event related to 
protocol treatment 
5. 
Grade 3 or higher non-hematologic toxicity that is clinically problematic however the following 
will not be applicable as DLT. 
- Grade 3 gastrointestinal symptoms that can be controlled with supportive care (appropriate 
use of antiemetics, antidiarrheals, etc.) 
- Grade 3 or higher electrolyte abnormalities that are not deemed clinically problematic 
 
8.10 
Replacement/Addition of Subjects 
Should there be, during the DLT evaluation period in the phase I part of the study, a major deviation 
from the protocol affecting the DLT evaluation for a reason other than an adverse event classified as 
a DLT or if DLT cannot be evaluated appropriately, that subject can be excluded from the DLT 
evaluation and a new subject can be enrolled and added to that cohort. 
 
8.11 
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 
subjects 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 (BRM) therapy 
- 
Antibody therapy 
- 
Gene therapy 
 
Other antibody therapy (except for denosumab) 
 
Flucytosine (antifungal) 


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 
Radiotherapy for primary disease 
Except for treatment for pain relief of bone metastasis site is allowed. 
 
Hyperthermia therapy for primary disease 
 
Study drug and unapproved drug 
 
8.12 
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 The type of G-CSF products administered should depend on the insurance 
coverage. 
 
Nausea/vomiting 
Premedication including prophylactic administration of antiemetics is allowed. Premedication 
with 5-HT3 (serotonin) receptor antagonists, NK1 (neurokinin 1) receptor antagonists, steroids, 
and antihistamines may be carried out using the method employed at each study site. 
 
Diarrhoea 
Fluids and electrolyte balance will be followed adequately, and suitably supplemented, as 
necessary. If careful observation suggests that it is necessary, administration of an antidiarrheal 
such as loperamide hydrochloride may be considered. 
 
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 by slowing the infusion speed may be considered. 
 
Pulmonary fibrosis (interstitial pneumonia) 
If it 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 which have been continued from 
before the start of this study are allowed. 
In addition, it is recommended that the supportive care shown below be performed at the discretion 
of the investigator 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) 


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- 
External salicylic acid petrolatum (10%) 
- 
External steroid therapy (example) 
 
Face: hydrocortisone butyrate (0.1%) 
 
Trunk: difluprednate (0.05%) 
- 
Moisturizer (example): heparin analog lotion 
- 
Sunscreen (example): not containing 4-aminobenzoic acid, SPF (Sun Protection Factor) 30, 
PA (Protection grade of UVA)++. Apply before going out to block ultraviolet rays (UVA 
and UVB). 
Dermatopathy prevention with humectants, suntan lotion, antibiotic or external steroids may be 
carried out using the method employed at each study site, based on non-Japanese29) and 
Japanese reports30), etc. 
 
Electrolyte abnormality (e.g., hypomagnesaemia, hypocalcaemia) 
- 
ECG: ECG may be performed to determine whether there are abnormal ECG findings 
requiring treatment such as significant QTc prolongation. When any abnormal ECG 
findings requiring treatment are observed, suspension of panitumumab should be 
considered irrespective of the serum magnesium concentration. 
- 
Magnesium supplementation (example): intravenous infusion of magnesium sulfate 
(10 mmol) over 60 min 
 
8.13 
Recommended follow-up therapy 
Approved drugs (e.g., regorafenib) should be used as appropriately 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 
(phase I part of the study)” in the phase I part of the study and “Table 9.b Study calendar 
(phase II part of the study)” in the phase II part of the study. The same investigator or the 
subinvestigator should perform tests/observations/evaluation of subjects in principle. For the 
allowance range of protocol treatment and various laboratory tests, see “Table 9.c Allowance range 
for protocol treatment and laboratory tests” 
 
 


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Table 9.a Study calendar (phase I part of the study) 
Item 
At 
enrollme
nt 
Protocol treatment period 
Follow-up 
period# 
Course 1 
Second and later 
courses 
Discontinuat
ion 
of protocol 
treatment † 
Reference day: 
Number of days 
counted from the first 
day of each course 
-14, -1 
1 
8 
15 
22 
1 
15 
Informed 
consent 
obtained*1 
● 
 
 
 
 
 
 
 
 
Patient Background 
● 
 
 
 
 
 
 
 
 
RAS status*2 
● 
 
 
 
 
 
 
 
 
Clinical findings*3 
● 
● 
● 
● 
● 
● 
● 
● 
 
Height*2 
● 
 
 
 
 
 
 
 
 
Body weight*4 
●*7 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
ECOG P.S. *3 
●*7 
● 
○ 
○ 
○ 
● 
○ 
● 
 
Compliance*3 
 
● 
○ 
○ 
 
● 
○ 
 
 
Hematology*5 
●*7 
● 
● 
● 
● 
● 
● 
● 
 
Serum chemistry*5 
●*7 
● 
● 
● 
● 
● 
● 
● 
 
Immunology 
(HBs antigen)*6 
● 
 
 
 
 
 
 
 
 
Tumor marker 
 
●*8 
 
 
 
<- ●*9-> 
● 
 
Imaging tests 
(thoracoabdominal-pel
vic CT/MRI) 
●*10 
 
 
 
 
<- ●*9-> 
○*11 
○ 
Follow-up treatment 
 
 
 
 
 
 
 
 
● 
Survival survey 
 
 
 
 
 
 
 
 
● 
Adverse events 
- 
<-     ●     -> 
○ 
●: Mandatory, ○: Perform as necessary 
†: Perform within 28days of discontinuation or earlier date than start of follow-up treatment, as well as possible. 
#: Perform every 6 months as a guide with protocol discontinuation date as starting point. 
*1: Consent must be obtained before enrollment. Further, consent should be obtained after RAS status has been 
identified. 
*2: Values obtained after the diagnosis of colorectal cancer may be used. 
*3: When the visit day is the treatment day, this will be done before administration. 
*4: Measurement is not mandatory during protocol treatment period. Even if measured, it is unnecessary to record 
in the CRF. 
*5: Testing will be performed from 2 days before to the day of the visit during each course. 
*6: Test results from up to one year before obtaining consent may be used. It is unnecessary to record this in the 
CRF. However, follow JSH Guidelines for the Management of Hepatitis B virus infection for the measurement 
of HBs antibody, HBc antibody and HBV-DNA. 
*7: If done within 14 days before enrollment, results from before obtaining informed consent may be used. 


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*8: If it has been performed within 28days before treatment day, the test for Course 1 may be omitted. 
*9: Measure once every 8 weeks (56 days) with Day 1 of Course 1 as starting point. However, reduce the frequency 
to once every 12 weeks (84 days) when one year has passed since initiation of protocol treatment. 
*10: 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 is performed within 4 weeks (28 days) prior to enrollment. 
*11: This is only done when the subject is discontinued for a reason other than imaging results (PD). 
Table 9.b Study calendar (phase II part of the study) 
Item 
At 
enrollme
nt 
Protocol treatment period 
Follow-up 
period# 
Course 1 
Second and later 
courses 
Discontinuation 
of protocol 
treatment † 
Number of days 
counted from the first 
day of each course 
-14, -1 
1 
15 
22 
1 
15 
Informed 
consent 
obtained*1 
● 
 
 
 
 
 
 
 
Patient Background 
● 
 
 
 
 
 
 
 
RAS status*2 
● 
 
 
 
 
 
 
 
Clinical findings*3 
● 
● 
● 
● 
● 
● 
● 
 
Height*2 
● 
 
 
 
 
 
 
 
Body weight*4 
●*7 
○ 
○ 
○ 
○ 
○ 
 
 
ECOG P.S. *3 
●*7 
● 
○ 
○ 
● 
○ 
● 
 
Compliance*3 
 
● 
○ 
 
● 
○ 
 
 
Hematology*5 
●*7 
● 
● 
● 
● 
● 
● 
 
Serum chemistry*5 
●*7 
● 
● 
● 
● 
● 
● 
 
Immunology 
(HBs antigen)*6 
● 
 
 
 
 
 
 
 
Tumor marker 
 
●*8 
 
 
<-●*9-> 
● 
 
Imaging tests 
(thoracoabdominal-pel
vic CT/MRI) 
●*10 
 
 
 
<-●*9-> 
○*11 
○ 
Follow-up treatment 
 
 
 
 
 
 
 
● 
Survival survey 
 
 
 
 
 
 
 
● 
Adverse events 
- 
<-      ●      -> 
○ 
●: Mandatory, ○: Perform as necessary 
†: Perform within 28days of discontinuation or earlier date than start of follow-up treatment, as well as possible. 
#: Perform every 6 months as a guide with protocol discontinuation date as starting point. 
*1: Consent must be obtained before enrollment. Further, consent should be obtained after RAS status has been 
identified. 
*2: Values obtained after the diagnosis of colorectal cancer may be used. 
*3: When the visit day is the treatment day, this will be done before administration. 


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*4: Measurement is not mandatory during protocol treatment period. Even if measured, it is unnecessary to record 
in the CRF. 
*5: Testing will be performed from 2 days before to the day of the visit during each course. 
*6: Test results from up to one year before obtaining consent may be used. It is unnecessary to record this in the 
CRF. However, follow JSH Guidelines for the Management of Hepatitis B virus infection for the measurement 
of HBs antibody, HBc antibody and HBV-DNA. 
*7: If done within 14 days before enrollment, results from before obtaining informed consent may be used. 
*8: If it has been performed within 28 days before treatment day, the test for Course 1 may be omitted. 
*9: Measure once every 8 weeks (56 days) with Day 1 of Course 1 as starting point. However, reduce the frequency 
to once every 12 weeks (84 days) when one year has passed since initiation of protocol treatment. 
*10: 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 is performed within 4 weeks (28 days) prior to enrollment. 
*11: This is only done when discontinuation is for a reason other than imaging results (PD). 
Table 9.c Allowance range for protocol treatment and laboratory tests 
Performed items 
Protocol specification 
Allowance range 
Clinical Laboratory test values 
(During protocol treatment) 
Course 1: Day 1, 8, 15, 22 
(phase I part of the study) or 
Day 1, 15, 22 (phase II part of 
the study) 
Course 2: Day 1, 15 
From Day -2 before scheduled 
day 
(However, Mg is tested once 
per course.) 
Protocol treatment 
Day 1, 15, 29 (Day 29 is equal 
to Day 1 of next course) 
Scheduled day ±3 days 
Tumor markers and imaging 
tests (during protocol treatment) 
Protocol treatment ≤ 1 year: 8 
weeks (56 days) 
Scheduled day ±1 week (7 
days) 
Protocol treatment > 1 year: 12 
weeks (84 days) 
Scheduled day ±2 week (14 
days) 
9.2 
Collection/test/observation items and procedures during the clinical 
study 
The investigator or the subinvestigator will perform the following as scheduled in “9.1 Study 
calendar” or “Table 9.b Study calendar”. 
9.2.1 Informed consent procedure 
Consent should be obtained from subject before initiation of study procedures. 
A unique subject ID code to anonymize the subject will be assigned to each subject at the time of 
obtaining consent. The subject ID code will be used throughout the study period and not changed. 
The method for obtaining consent is described in Section “15.3 Written information and subject’s 
consent.” 
 


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9.2.2 Enrollment and protocol treatment 
For procedures and storage of enrollment and initiation of protocol treatment, see: “7.3 Procedures 
for Enrollment and Protocol Treatment.” 
 
9.2.3 Subject demographics 
For demographic data of the subject, 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 
 
Solitary/Multiple 
 
Primary tumor site (cecum, ascending colon, transverse colon, descending colon, sigmoid 
colon, rectosigmoid, rectum) 
(2) Information on metastasis 
• 
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 “1 organ”. For example, even if it is observed in cervical lymph 
node and thoracic lymph node, it will be counted as 1 organ. 
• 
Organs with metastasis (liver, lung, peritoneum, lymph node*, bone, adrenal gland, skin, 
and others**) 
*: Does not include regional lymph node, other lymph nodes in several sites will be 
counted as “1 organ”. For example, even if it is observed in cervical lymph node and 
thoracic lymph node, it will be counted as 1 organ. 
**: Name of organ to be recorded in CRF 
(3) History of treatment 
• 
History of surgery in primary tumor site/palliative metastasis site and history of colostomy 
/bypass surgery 
- 
Subjects with history, the date of surgery 
However, endoscopic surgery, which is not considered a history of surgery, should 
not be entered into the CRF. 
• 
History of radiotherapy (radical irradiation) 
- 
Subjects with history, the date of final dose 
However, irradiation for pain relief (palliative irradiation) in the bone metastasis site, 
which is not considered as radiotherapy, should not be entered into the CRF. 
• 
Treatment history for subjects with unresectable lesions 
- 
Description of first-, second-, and third-line treatment (FOLFOX, FOLFOX + 
anti-angiogenic agent (e.g., bevacizumab); CapeOX, CapeOX + anti-angiogenic agent 
(e.g., bevacizumab); FOLFIRI, FOLFIRI + anti-angiogenic agent (e.g., 
bevacizumab); IRIS, IRIS + anti-angiogenic agent (e.g., bevacizumab); IRI, IRI + 
anti-angiogenic agent (e.g., bevacizumab); FOLFOXIRI, FOLFOXIRI + 
anti-angiogenic agent (e.g., bevacizumab); SOX, SOX + anti-angiogenic agent (e.g., 


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bevacizumab); SOX, SOX + anti-angiogenic agent (e.g., bevacizumab); other), date 
of initiation of first-line treatment 
• 
History of preoperative and/or postoperative adjuvant chemotherapy 
- 
Subjects with history, history of preoperative and/or postoperative adjuvant 
chemotherapy with OXA, date of final treatment 
 
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. 
 
9.2.5 Clinical findings 
Medical examination will be performed prior to protocol treatment. In particular, the following 
symptoms at the medical examination will be confirmed. 
Allergic reaction, rash acneiform, cutaneous dryness, paronychia, infusion reaction (infusion related 
reaction), anorexia, diarrhoea, nausea, vomiting, oral mucositis, hypomagnesemia, blood neutrophil 
count decreased, febrile neutropenia, reduced blood platelet count, peripheral sensory neuropathy, 
thromboembolism, gastrointestinal perforation, interstitial pneumonia, fatigue. 
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 “10.0 Adverse event” for definition of adverse event. 
 
9.2.6 Body weight, height 
Body weight at enrollment should be measured within 2 weeks (14 days) before enrollment 
(including the same day of week as the day of enrollment) and recorded in the CRF. Height obtained 
after the diagnosis of colorectal cancer may be used. 
 


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9.2.7 Eastern Cooperative Oncology Group Performance Status (ECOG) 
Performance Status 
ECOG Performance Status (P.S.) will be assessed according to Table 9.d. P.S. at enrollment will be 
determined within 2 weeks (14 days) prior to enrollment (including same day of the week as the day 
of enrollment). P.S. before initiation of each course will be determined before administration on 
treatment day. P.S. at discontinuation will be determined as much as possible within 4 weeks (28 
days) after discontinuation or before the initiation of follow-up treatment whichever date is earlier. 
Table 9.d Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) 
P.S. 
Definition 
0 
Fully active, 
able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair 
 
9.2.8 Compliance 
The investigator or the subinvestigator should record the compliance with protocol treatment in the 
CRF as follows: 
• 
Doses and treatment days for panitumumab 
• 
Doses, treatment initiation day, and number of doses of TAS-102 
 
9.2.9 Clinical laboratory tests 
In principle, 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). 
Testing will be performed from 2 days before to the day of the visit during the protocol treatment 
period. 
Tests at discontinuation will be conducted as much as possible within 4weeks (28 days) after 
discontinuation or before the initiation of follow-up treatment whichever date is earlier. 
Test items and notes are listed in Table 9.e to Table 9.g. 


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immunosuppressive therapy for autoimmune diseases such as rheumatological diseases in view of the risk of 
reactivation of HBV. The frequency of reactivation of HBV and the occurrence and progression to fulminant 
status of hepatitis with standard chemotherapy and immunosuppressive therapy is not known, and there is 
insufficient evidence related to guidelines. In addition, treatment with nucleotide analogues does not 
completely guarantee prevention of progression to a fulminant status. 
Note 1) Screening will be conducted for HBV carriers and subjects with previous infections prior to 
immunosuppressive therapy or chemotherapy. First, HBs antigen will be measured to identify HBV carriers. In 
HBs antigen-negative subjects, HBc antibody and HBs antibody will be measured to identify subjects with 
previous infections. Highly sensitive techniques should be used to measure HBs antigen, HBc antibody, and 
HBs antibody. In subjects positive for HBs antibody only (HBs antigen-negative and HBc antibody-negative), 
HBV reactivation will be reported, and action should be taken according to guidelines, except when the subject 
is known to have been vaccinated. 
Note 2) When a subject is HBs antigen-positive, consult with a hepatologist. A hepatologist should be consulted when 
administering nucleotide analogues to any subjects. 
Note 3) Antibody titers may decrease when initially starting chemotherapy in subjects who are being retreated but 
have not been measured for HBc antibody and HBs antibody and subjects who have already been started on 
immunosuppressive therapy, and detailed examinations should be performed, e.g., measuring HBV DNA 
levels. 
Note 4) Screening for HBV DNA will be performed by real time PCR in subjects with previous infections. 
Note 5) 
a. Caution is required with subjects receiving chemotherapy with rituximab, a steroid, and fludarabine and 
hematopoietic stem cell transplantation because they are at high risk of HBV reactivation from previously 
infected people. HBV DNA should be monitored once a month during and for a period of at least 12 months 
after completion of therapy. Subjects receiving hematopoietic stem cell transplantation require long-term 
monitoring after transplantation. 
b. There is also a risk of HBV reactivation with combination therapy using standard chemotherapy and 
molecularly targeted drugs having an immunological effect, although the frequency of reactivation is low. As 
a general guideline, HBV DNA levels should be monitored every 1 to 3 months, but the frequency and time of 
monitoring should take the nature of the treatment into consideration. Action should be taken prudently in the 
case of hematological malignancies. 
c. There is also a risk of HBV reactivation with immunosuppressive therapy using corticosteroids, 
immunosuppressives, and molecularly targeted drugs having an immunosuppressive or immunomodulating 
effect. With immunosuppressive therapy, HBV DNA levels should be monitored monthly for at least 6 
months after staring or changing the therapy. After the first 6 months, the frequency and time of monitoring 
should take the nature of the treatment into consideration. 
Note 6) Administration of nucleotide analogues should be started as early as possible before starting 
immunosuppressive therapy or chemotherapy. However, deaths from fulminant hepatitis during prophylactic 
nucleotide analogue therapy have been reported in HBs antigen-positive patients with a high viral load, and the 
viral load should therefore be reduced before starting immunosuppressive therapy or chemotherapy. 
Note 7) Administration of nucleotide analogues should be started immediately when HBV DNA has reached 2.1 log 
copies/mL or higher during or after completion of immunosuppressive therapy or chemotherapy. During 
immunosuppressive therapy or chemotherapy, a hepatologist should be consulted about the action to be taken 
without immediately discontinuing the immunosuppressive agent or anti-neoplastic agent with an 
immunosuppressive action. 
Note 8) The recommended nucleotide analogue is entecavir. 
Note 9) Termination of nucleotide analogue treatment may be considered when the following conditions are satisfied. 
In subjects who are HBs antigen-positive at screening: when the criteria for terminating nucleotide analogue 
treatment in chronic hepatitis B are satisfied. In subjects who are HBc antibody-positive or HBs 
antibody-positive at screening: (1) Nucleotide analogue treatment should continue for at least 12 months after 
completing immunosuppressive therapy or chemotherapy. (2) Normalization of ALT (GPT) should be 
achieved during this period of continued treatment. (unless ALT is abnormal for a reason other than HBV). 
(3) Sustained negative HBV DNA should be maintained during this period of continued treatment. 
Note 10) Subjects should be followed vigilantly, including HBV DNA monitoring, for at least 12 months after 
terminating nucleotide analogue treatment. The follow-up should be based on the Precautions for Use in the 
package insert of the nucleotide analogue used. Nucleotide analogue treatment should be resumed 
immediately when HBV DNA reaches 2.1 log copies/mL or higher in subjects being followed. 


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Table 9.f Clinical laboratory tests performed during the protocol treatment period 
Hematology 
Serum chemistry 
Tumor markers 
Neutrophil count * 
Platelet count * 
Hemoglobin content 
* 
Total bilirubin * 
ALT* 
AST* 
Creatinine * 
Mg *** 
Albumin * 
Na* 
K* 
Ca* 
CEA**, † 
*: 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. 
**: If it had been conducted within 28 days before treatment day, it may be omitted. 
***: May be measured once during each course. 
†: Measure every 8 weeks (56 days) with Day 1 of Course 1 as starting point. However, when 1 year has passed since 
initiation of protocol treatment, once every 12 weeks (84 days). 
Table 9.g Laboratory tests performed at the time of discontinuation 
Hematology 
Serum chemistry 
Tumor markers 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
Albumin 
Na 
K 
Ca 
CEA* 
*: If ≥ 28days has not passed since the last measurement, the test can be omitted. 
 
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 is 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 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 CRF. 


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After initiation of protocol treatment, imaging test will be performed every 8 weeks (56 days) with 
protocol treatment initiation date (Day 1) of Course 1 as the starting point. However, when 1 year 
has passed since initiation of protocol treatment, imaging may be performed once every 12 weeks 
(84 days), counting from the point in time at which 1 year has passed. (For details, see “Table 9.a 
Study calendar (phase I part of the study)” or “Table 9.b Study calendar (phase II part of the study).” 
Thoracoabdominal-pelvic CT (in principle, contrast CT; a slice width of 5 mm or less is 
recommended, 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, brain MRI / CT and a neck CT will 
be performed. 
In principal, the same modality should be used for imaging test during protocol treatment throughout 
the study period. 
The investigator or the subinvestigator should evaluate the test results according to the RECIST v1.1 
(see Appendix A) and enter the determined results into the CRF. 
Furthermore, for subjects withdrawn from the study for any reason other than imaging test results 
such as clinical PD, imaging test specified at the time of discontinuation should be performed within 
4 weeks (28 days) including the day of decision (including the same day of week as the day of 
decision). 
If the subject is not determined to have PD on imaging up to the time of withdrawal, the following 
information should be collected until the subject dies or the sponsor terminates the study, even after 
follow-up treatment has been started. 
 
Day of decision on clinical PD (only when the subject is not determined to have clinical PD by 
the time of discontinuation) 
 
It will not be necessary to collect information if the subject is determined to have 
radiological PD before the subject is determined to have clinical PD. 
 
Day of decision on radiological PD 
 
The day of decision on radiological PD will be collected, regardless of the state of clinical 
PD. The final imaging test date will be collected in subjects not determined to have 
radiological PD during the follow-up period as well. 
 
Date of last confirmed progression-free survival 
 
The date of last confirmed progression-free survival will be collected in subjects not 
determined to have either clinical PD or radiological PD during the follow-up period as 
well. 
However, when follow-up is not possible due to withdrawal of consent, loss to follow-up, etc., the 
date of the last visit will be entered in the CRF as the date of last confirmed progression-free 
survival. 


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9.2.11 Follow-up treatment 
The following information will be collected when follow-up treatment is performed after 
discontinuation of protocol treatment. If several types of follow-up treatment are performed, 
information will only be collected on the follow-up treatment immediately following discontinuation 
of protocol treatment. 
- 
Name of drugs used (regorafenib, other) 
- 
Initiation date 
9.2.12 Survival survey 
After discontinuation of protocol treatment, every subject will be followed-up to confirm survival of 
subjects 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 subject dies or 
the sponsor terminates the study. 
• 
Survival survey date 
• 
Date of death or last confirmed date of survival 
- 
If deceased, the reason of death (death from primary disease/others) 
 
9.2.13 Pregnancy 
When it becomes apparent that a female subject is pregnant, with consent from female subject, the 
investigator or the subinvestigator should notify the primary care physician (obstetrician and 
gynecologist, etc.) that the female subject was participating in a clinical study at the time she became 
pregnant and provide details of protocol treatment. 
For every female subject reported to have become pregnant, the investigator or subinvestigator 
should follow-up to delivery including result of premature delivery with consent from the female 
subject and report to the sponsor using the specified follow-up form. Evaluation after delivery will 
also be conducted. 
 
9.3 
Records of subjects who discontinued before enrollment 
Every subject who has signed the ICF and dropped-out before enrollment should be registered in the 
Web registration center and a CRF should be prepared. 
The following items are to be entered in the CRF. 
• 
Date of consent obtained 


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• 
Date of birth (the age at enrollment) 
• 
Sex 
• 
Eligibility 
• 
Reason for discontinuation 
For subjects who drop-out from the study before enrollment, the main reason for dropping-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 subject ID code of a subject withdrawn from the study before enrollment should not be reused. 
 
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
Adverse events are any unfavorable medical events encountered in a subject treated with a drug. 
They are not limited to the events with clear causal relationship with treatment with the concerned 
drug. 
In other words, adverse events are any unfavorable or unintended sign (including clinically 
problematic abnormalities of laboratory test data), symptoms or diseases that develop after 
administration of a drug irrespective of a causal relationship with the relevant drug. 
 
10.1.2 Items to be considered concerning adverse events 
Generally unfavorable findings are shown below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent event of 
the existing symptom is not considered an adverse event) 
• 
Requiring action or medical practice 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation of protocol treatment (panitumumab + TAS-102 combination 
therapy) or of combination therapy or change in dose 
• 
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, 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 judges the change to 
have exceeded the normal physiological variation range of the subject). Retest and/or continued 
monitoring of abnormality are not considered medical practice. Also, repeated or additional conduct 


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of non-invasive 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 CRF that the adverse event 
is an aggravation of the concurrent disease (e.g., “aggravation of hypertension”, etc.). 
When a subject has an existing symptom that is transient (e.g., asthma, epilepsy) and incidence of 
the symptom is increased, or the symptom becomes serious or severe, it should be recorded as an 
adverse event. When a subject has a chronic disease (e.g., cataract, rheumatoid arthritis) and the 
symptom is aggravated more than anticipated, it should be recorded as an adverse event. The 
investigator 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 which resulted 
from previously planned surgery is reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a subject 
(cosmetic surgery, etc.) is not considered an adverse event. However it should be recorded in the 
source documents. Complications due to a non-urgent surgery should be reported as an adverse 
event. 


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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 or on imaging 
progression of pre-existing cancer (including new metastasis) is confirmed, 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 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), serious adverse event is an event that: 
1. 
Results in death during protocol treatment* and all deaths irrespective of a causal relationship 
with protocol treatment. 
*: Period from initiation of protocol treatment up to 4 weeks (28 days) after discontinuation of 
protocol treatment or initiation of follow-up 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 follow-up 
treatment 
3. 
Is life-threatening. The term “life-threatening” refers to an event in which the subject was at 
risk of death during onset of the adverse event; it does not refer to an event which 
hypothetically might have caused death if it were severer. 
4. 
Requiring hospitalization or prolongation of hospitalization 
However, hospitalization or prolongation of hospitalization for the following reasons will not 
be handled as a serious adverse event. 
(1) Preplanned inpatient hospitalization or prolongation of existing hospitalization 


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(2) Inpatient hospitalization or prolongation of existing hospitalization unrelated to an adverse 
event 
5. 
Results in persistent or significant disability/incapacity. 
6. 
Leads to a congenital anomaly/birth defect. 
7. 
Other medically significant condition: medically important event which causes a risk to a 
subject even if it is not immediately life-threatening, nor does it result in death or 
hospitalization, or requires an action or treatment to prevent the results shown in 1 to 6 above. 
 
10.1.4 Special interest adverse event for sponsor 
Adverse events listed in Table 10.a “Takeda Medically Significant AE List” will be handled as 
“special interest adverse event” for sponsor irrespective of severity determined by the investigator or 
the subinvestigator. Further, any adverse events listed in Table 10.a that has been determined as 
serious by the investigator or the subinvestigator will be handled as serious adverse event. 
Table 10.a Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion and 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of infection 
by a medicinal product 
Confirmed or suspected endotoxin shock 
 
10.1.5 Severity of adverse events 
The severity of adverse event is classified into 5 grades (Grade 1-5) as follows based on the 
Common Terminology Criteria for Adverse Events (hereafter referred to as CTCAE, Japanese 
edition JCOG version 4.03), of the National Cancer Institute, USA. Furthermore, the grade for 
adverse events not listed in CTCAE will be classified according to the following criteria. 


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Table 10.b CTCAE (Japanese edition JCOG version 4.03) Grade 
Grade 1 
Mild; asymptomatic or slightly symptomatic; only clinical or test findings; or 
requiring no treatment 
Grade 2 
Moderate; requiring the least treatment or local or non-invasive treatment; or 
interfering with age-appropriate activities of daily living except for self-care 
activities* 
Grade 3 
Severe or medically critical, but not immediately life-threatening; requiring 
hospitalization or prolongation of existing hospitalization; disabling/incapacitating; 
or interfering with self-care activities of daily living** 
Grade 4 
Life-threatening; or requiring emergent treatment 
Grade 5 
Death due to an adverse event 
AE: Adverse Event, “;” stands for “or” 
*: Activities of daily living except for self-care activities include meal preparation, shopping for daily necessities and 
clothings, phone call, and financial management. 
**: Self-care activities of daily living include bathing, dressing, eating, toilet, and oral drug intake, and indicate that a 
person is not confined to bed. 
 
10.1.6 Causality of adverse events 
Causal relationship between protocol treatment (panitumumab + TAS-102 combination therapy) and 
adverse events, and causal relationship between panitumumab and adverse events (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 or panitumumab although other 
factors such as underlying disease, complications, concomitant drugs/treatment are 
also presumed. 
Not 
related 
An adverse event with no chronological correlationship with protocol treatment 
(chemotherapy, 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 Date of onset of adverse events 
The date of onset of adverse events will be determined according to the following criteria. 
Adverse event, etc. 
Date of onset 
Signs, symptoms, and 
diseases (diagnoses) 
The subject, investigator, or subinvestigator will record the date on 
which the sign or symptom of an adverse event is first noticed. 
Asymptomatic diseases 
The date on which diagnosis is confirmed by testing will be 
recorded. 
Even if testing reveals old findings or if the time of occurrence can 
generally be estimated, the date on which diagnosis is confirmed 
will be recorded. 
Aggravation of concurrent 
medical conditions 
The subject, investigator, or subinvestigator will record the date on 
which a disease or aggravation of a disease is first noticed. 
Test results that became 
abnormal after initiation of 
protocol treatment 
The test date on which abnormal test results determined to be 
clinically problematic were observed will be recorded. 
Test results that are abnormal 
at initiation of protocol 
treatment and aggravated in 
later testing 
The date on which the time profile of a laboratory value shows a 
clear increase or decrease, based on medical judgment, will be 
recorded. 
 
10.1.8 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”. 


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10.1.9 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 has not returned to normal or baseline 
 
when the subject 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 aggravated compared with the date of onset 
 
irreversible congenital anomaly 
 
when a subject died where the concerned adverse event is not a direct cause 
of death and the concerned adverse event remained not recovered 
Recovered 
with sequelae 
 
disability which disturbs daily life 
Death 
 
direct relationship between death and the concerned adverse event 
 
“Direct relationship” means that the concerned adverse event was the cause 
of death, or the concerned adverse event was clearly responsible for death. 
 
Outcome of an adverse event which was not determined (judged, presumed) a 
direct cause of death observed in the same subject 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. 
 
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 follow-up treatment, whichever 
date is earlier. In addition, adverse event causal relationship cannot be ruled out of protocol 
treatment collected later 4 weeks (28 days) after discontinuation of protocol treatment or initiation of 
follow-up treatment. 


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10.2.1.2 Reporting of adverse events 
At each visit of subject, 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 a question such as “how has your condition been since the last 
visit?” to a subject. 
The investigator or the subinvestigator should follow up all subjects who developed adverse events 
irrespective of a causal relationship with protocol treatment until disappearance of symptoms or 
abnormal laboratory values, 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, date of onset, 
severity, seriousness, causal relationship with protocol treatment (unrelated or related), further if 
event 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 as well as date of resolution 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. 
When the investigator or the subinvestigator judges that a serious adverse event has occurred based 
on the reporting by a subject, etc., or results of various tests, imaging findings or definitive diagnosis, 
etc., it should be reported immediately to the director of the study site. 
Also, the investigator or the subinvestigator should report to the sponsor (see attached sheet for 
contact information) within 72 hours of recognition of onset of event. Further, the investigator 
should submit a formal report within 10 calendar days to the sponsor. 
Furthermore, the content below which is to be reported to the sponsor within 72 hours is mandatory, 
and other items should be reported as much as possible. 
• 
Brief description of adverse event and the reason for why it was determined as serious 
• 
Study title 


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• 
Subject ID code 
• 
Name of study site 
• 
Name of investigator or the subinvestigator 
• 
Name of protocol treatment being conducted 
• 
Determined causal relationship 
 
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 the 
director of study site and the sponsor. When requested by the sponsor or the study site committee 
such as the ethics review committee, related data of the study site (e.g., ECG, laboratory test values, 
summary of discharge report, result of autopsy, etc.) should be provided. 
 
10.2.4 Reporting of additional information concerning adverse events 
If the sponsor requests 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 in the EDC system or submit a report within the period specified by 
the sponsor. 
 
10.2.5 Dissemination of unknown serious adverse event to joint research 
institutions 
If the director of the study site receives a report of an unexpected serious adverse event, for which a 
direct causal relationship with protocol treatment cannot be denied, from the investigator or 
subinvestigator, the director should ask the opinion of a study site committee such as the ethics 
review committee and add the items below to the report submitted by the investigator, and 
disseminate it to the monitoring committee and research institutions that are jointly conducting 
clinical study through the sponsor. 


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• 
Date of review, summery of review, result, necessary action, etc., related to the study site 
committee such as ethics review committee. 
 
10.2.6 Reporting of serious adverse events, etc., to ethics review committee, etc., 
and regulatory authorities 
If the director of the study site receives report of serious adverse event from the investigator, the 
director should ask opinion of the ethics review committee, etc., and disseminate the study sites that 
are conducting clinical study through the sponsor or the CRO (research secretariat office) consigned 
by the sponsor. 
If the director of the study site receives report of unexpected serious adverse event, the director 
should add the items below to the report submitted by the investigator, and prepare unexpected 
serious adverse event report and report to the Minister of Health, Labour and Welfare, and 
disseminate the study sites that are conducting clinical study (report to the Minister of Health, 
Labour and Welfare, and dissemination to study sites through sponsor is also possible). 
• 
Action taken for serious adverse event 
(discontinuation of new enrollment, revision of ICF, re-consent from other subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to ethics review 
committee, etc. 
• 
Dissemination to joint research institutions. 
The sponsor should report according to regulations, unexpected serious adverse drug reactions and 
other serious adverse events that are subject to emergency reporting to regulatory authorities, the 
investigator and director of study site. 
From the time point of first acknowledging the event or receiving additional information, the 
sponsor or the CRO (research secretariat office) consigned by the sponsor should comply with 
regulatory required time frame for reporting, and make emergency report concerning unexpected 
serious adverse drug reactions and expected serious adverse drug reactions to regulatory authorities. 
Also, the sponsor 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 clinical study. The study site should submit copies of emergency 
report documents to the ethics review committee, etc. 
 
 


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11.0 
COMMIITTEES 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 sponsor, research steering committee chairman, 
research steering committee members and statistics representative, and the sponsor or its designee 
will act as the secretariat. 
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 
Data monitoring committee 
The Data Monitoring Committee (hereinafter referred to as DMC) will be established according to 
the ICH E6 (1.25), and the sponsor or its designee will serve as the secretariat of the DMC. 
The purpose of the DMC is to evaluate safety report data (including DLT occurring during the DLT 
evaluation period of the phase I part of the study) independent of the research steering committee 
concerning the appropriateness of continuing the study, or changing, discontinuing, suspending, or 
other measures regarding the study, and to submit the results to the sponsor. The sponsor will 
determine whether to continue, discontinue, or change the study based on the results. 
The sponsor will prepare the DMC procedures (DMC charter) specifying the details such as the 
objective, roles, and responsibilities of the DMC, and management procedure. DMC members are 
listed in Section 1.2. 
 
 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Detailed procedure of data management is described in data management plan. Adverse events and 
concurrent conditions should be coded using MedDRA. 
12.1 
Case report form 
The investigator or the subinvestigator should prepare the case report form (CRF) for all subjects 
who have given consent. 
The sponsor or its designee should provide study sites with access authorization to the electronic 
data capture (hereinafter referred to as EDC). The sponsor should provide the investigator, 
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 the sponsor. The CRF will be prepared 
in Japanese. Data will be directly entered in preparing the CRF. 
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, date of 
change or correction, and its reason. 
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 bear 
full responsibility for the accuracy and reliability of all the 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 and 
“panitumumab” 
When the investigator or the subinvestigator makes a change or correction in the data entered into 
the CRF after fixation of clinical data base, a record (Data Clarification Form) of change or 
correction in the CRF provided by the sponsor should be used. The investigator should confirm that 
the record of change or correction in the CRF is accurate and complete, and sign or write name/ affix 
a seal, and date it. 
The sponsor or its designee should confirm CRF has been prepared appropriately. The sponsor or its 
designee should have access to the medical records of study subjects and in-house records to ensure 
the accuracy of the CRF as necessary. The completed CRF is the property of the sponsor, and the 
investigator or the subinvestigator should not disclose the information to a third party without a 
written permission from the sponsor. 


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12.2 
Time limit for data input into the EDC 
The sponsor or its designee should request the investigator or the subinvestigator to promptly enter 
EDC during the period from enrollment of subject to the end of follow-up. 
It is recommended that after consent has been obtained from subject, 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 much as possible. 
1. 
At enrollment: within 2 weeks (14 days) after enrollment (within 1 week (7 days) of course 1 of 
the phase I part of the study (the DLT evaluation period)) 
2. 
During protocol treatment: within 2 weeks (14 days) after the final day of each course (the 
starting day of the next course) (within 1 week (7 days) of course 1 of the phase I part of the 
study (the DLT evaluation period)) 
3. 
At discontinuation of protocol treatment: within 4 weeks (28 days) after the day of 
discontinuing protocol treatment (within 2 weeks (14 days) of course 1 of the phase I part of the 
study (the DLT evaluation period)) 
4. 
Imaging test results: within two weeks (14 days) after evaluation of efficacy 
5. 
Follow-up period: within two weeks (14 days) after request for follow-up 
6. 
Inquiry about data input items: within two weeks (14 days) from inquiry 
 
12.3 
Storage of records 
The investigator or the director of study site should store the following materials including those 
specified in Section 14.1 and study specific documents to be used by the sponsor or its designee for 
investigation and audit. The materials include a list of subject screening, medical records, signed and 
dated original consent form, and a record of change and correction of the CRF (copy)/electronic 
copy of electronic CRF containing audit trail. Also, the investigator and the director of study site 
should store the essential documents until the date that passes five years after discontinuation or 
completion of the study. However, when the sponsor requires a longer storage period, the director of 
the study site will discuss the period and methods of storage with the sponsor. 
Further, the investigator and the director of the study site will store the essential documents until the 
sponsor notifies that storage is no longer necessary. 


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13.0 
STATISTICAL ANALYSIS METHODS 
The statistics representative or his/her designee (a personnel belonging to an institution independent 
from sponsor, analysis personnel) will conduct analysis. Sponsor will not be involved in analysis. 
13.1 
Statistical and analytical plans 
The statistics representative or analysis personnel should start preparing the statistical analysis plan 
(SAP) (first version) and establish the SAP (first version) before conducting the final analysis. The 
SAP (first version) should be finalized before data fixation. 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, subject evaluability, and appropriateness of the 
planned analysis methods. 
 
13.2 
Statistical analysis of the phase I part of the study 
13.2.1 Analysis set 
Two analysis sets will be created for the phase I part of the study: “set of enrolled subjects who 
received at least one dose of protocol treatment and satisfied all of the enrollment criteria” and the 
“DLT evaluation set.” The “DLT evaluation set” will be based on the definition subjects included in 
the DLT evaluation in Section 8.9.2. 
 
13.2.2 Analysis of demographic and other baseline characteristics 
The following analyses will be performed in “set of enrolled subjects who received at least one dose 
of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
Demographic factors will be tabulated for each subject. Frequency will be tabulated for discrete data, 
and summary statistics will be calculated for continuous data. 
 
13.2.3 Safety analysis 
13.2.3.1 Primary endpoint and analysis method 
[Primary endpoint] 
Incidence of DLT with panitumumab + TAS-102 combination therapy 


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[Analysis method] 
The incidence of DLT will evaluated in the DLT evaluation set according to Section 6.1 Study 
Design (Figure 6.a Outline of study design). In addition, a table listing each DLT event that occurs 
will be prepared. 
 
13.3 
Statistical analysis of the phase II part of the study 
13.3.1 Analysis sets 
In the phase II part of the study, statistical analysis will be performed in a “full analysis set” and 
“safety analysis set”. The “full analysis set” is the main efficacy analysis set, and is defined as 
“subjects enrolled in phase I and 2 who received at least one dose of protocol treatment (RD) and 
satisfied all of the enrollment criteria”. RD is recommended dose which is confirmed in the Phase I 
part. The "safety analysis set" is defined as “subjects enrolled in phase I and II who received at least 
one dose of panitumumab and/or TAS-102”. Additionally, all subjects who are enrolled in this study  
is defined as "all enrolled subjects". 
The statistics representative and analysis personnel should finalize statistic alalysis plan before data 
fixation based on the confirmation of the definition of analysis sets and appropriateness of analytical 
handling rules of the subject data in the analysis sets and addition of handling rule for the sssues 
which are not determined at planning. 
 
13.3.2 Analysis of demographic and other baseline characteristics 
Perform the following analysis in the “all renrolled subjects set” and “full analysis set”. 
In the analysis of the main subject demographic factors, frequency will be tabulated for discrete data, 
and summary statistics will be calculated for continuous data. 
 
13.3.3 Efficacy analysis 
13.3.3.1 Primary endpoint and analysis method 
[Primary endpoint] 
PFS rate 6 months after enrollment 
The PFS rate 6 months after enrollment, the primary endpoint, is the gross proportion of surviving 
subjects without documented progression up to 6 months after enrollment, counting from the day of 


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enrollment. Subjects with no imaging data on progression at 6 months after enrollment and subjects 
lost to follow-up will be included in the denominator, but will not be handled as progression-free. 
The criteria for determining progression are described in “13.3.3.2 Secondary Endpoints and 
Analytical Methods for Them”. 
[Main analysis] 
The following analysis will be performed in the “full analysis set”. 
PFS rate at 6 months is calculated by counting of subjects each subjects with progression, not 
progression, or unconfirmed at 6 months. "At 6 months" in the main analysis is defined as 24 weeks 
(8 weeks x 3) with time window of 2 weeks before and after. Based on the observed PFS rate at 6 
months from the day of enrollment, binomial test will be conducted on the null hypothesis “value 
will be determined invalid at PFS rate ≤ 29%”. Significant level will be 2.5% (one-sided) in main 
analysis. For interval estimation, accurate 90% confidence interval (two-sided) based on binomial 
distribution will be used. 
13.3.3.2 Secondary endpoints and analysis method 
[Secondary endpoints] 
• 
Progression-free survival (PFS) 
PFS is the period from the day of enrollment until the day of documented progression or the 
day of death due to all causes whichever comes earlier. 
Progression will include both PD based on diagnostic imaging assessed according to RECIST 
ver 1.1 (see Appendix A) and primary disease progression that cannot be confirmed by 
diagnostic imaging (clinical progression). When progression is documented by diagnostic 
imaging, the day that the diagnostic imaging is performed will be the progression date. For 
clinical progression, the day of the clinical determination will be the progression date. In a case 
where, for example, tumor diameter has become extremely small, if the status is determined to 
be “not definite progression” clinically, although the assessment is PD according to the 
response criteria, the assessment of PD according to the response criteria will take precedence 
and the status will be considered progression. (In this case, the clinical determination on 
continuing protocol treatment will take precedence.) Even if the assessment is not PD according 
to the response criteria, if there is definite clinically documented progression, the clinical 
determination will take precedence and the status will be considered progression. For surviving 
subjects without documented progression, the period will be cut off on the final day when a 
progression-free status is confirmed (final day of confirming progression-free survival). 
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 by 


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telephone only will not be allowed.) Events and the cut-off will also be handled the same way 
in subjects who have discontinued protocol treatment for reasons such as toxicity and refusal of 
treatment, even if another (follow-up) therapy is added. Thus, the time of treatment 
discontinuation or the day of follow-up treatment initiation will not be the cut-off. 
[Analysis method] 
Show the Kaplan-Meier survival curve until the onset of event in the “full analysis set” and 
calculate the point estimation value of survival rate and its 95% confidence intervals 
(two-sided) at the quantile of PFS and specified time points. The Log-Log conversion of 
Brookmeyer and Crowley23) will be used to calculate the 95% confidence intervals of the 
quartiles for PFS. 
• 
Overall survival (OS) 
OS is the period from the day of enrollment until death by all causes. For surviving subjects, the 
period is terminated on the final day of confirming survival or data cut-off date, whichever 
occurs earlier. 
[Analysis method] 
The analysis will be performed in the same manner as for PFS in the “full analysis set”. 
 
Response rate (RR) 
RR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver 1.1 (see Appendix A) is either CR or PR. Overall response will be graded by 
favorability in the order of CR, PR, SD, PD, and NE. Best overall resonse is the best response 
recorded in the throughout of all courses. 
[Analysis method] 
RR of target lesion and its 95% confidence interval (two-sided) will be calculated in the “full 
analysis set”. 
 
Duration of response (DOR) 
DOR is the period from the day when either CR or PR is first confirmed until the day of 
documented progression or the day of death due to all causes, whichever occurs earlier. For 
surviving subjects without documented progression, the period will be cut off on the final day 
when specified diagnostic imaging reveals no PD (final day of confirming progression-free 
survival). For surviving subjects without documented progression 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 progression-free 
survival). 


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[Analysis method] 
Show the Kaplan-Meier survival curve until the onset of event for the subjects who showed 
response among the “full analysis set” and calculate the point estimation value of survival rate 
and its 95% confidence interval (two-sided) at the quantile of survival period and specified time 
points. 
 
Disease control rate (DCR) 
DCR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver 1.1 (see Appendix A) is CR, PR, or SD. Overall response will be graded by 
favorability in the order of CR, PR, SD, PD, and NE 
[Analysis method] 
DCR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set”.  
 
Time to treatment failure (TTF) 
TTF is the period from the day of enrollment until the day of the decision to discontinue 
protocol treatment, the day of documented progression during protocol treatment, or the day of 
death due to all causes whichever comes earlier.. Subjects not included above criteria will be 
sonsored at the starting date of dose in the final course 
[Analysis method] 
The analysis of TTF will be performed in the same manner as for PFS in the “full analysis set”. 
13.3.3.3 Data conversion method and handling of missing data 
Details are separately determined in the SAP. 
13.3.3.4 Level of significance, confidence coefficient 
 
Significance level: Main analysis only, 5% (one-sided); other analyses, 5% (two-sided) 
 
Confidence coefficient: Main analysis only, 90% (two-sided); other analyses, 95% (two-sided) 
 
13.3.4 Safety analysis 
The following analysis will be performed in the “full analysis set” and “safety analysis set”. 
13.3.4.1 Treatment-Emergent Adverse Events 
Treatment-Emergent Adverse Events (TEAE) are adverse events which develop after initiation of 
protocol treatment. 
Perform the following analysis for TEAE. Code TEAE using MedDRA and summarize by Preferred 
Term (PT) and System Organ Class (SOC). 


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 
Frequency tabulation of all TEAE 
 
Frequency tabulation of TEAE for which the causal relationship with protocol treatment was 
“related” 
 
Frequency tabulation of TEAE for which the causal relationship with panitumumab was 
“related” 
 
Frequency tabulation of all TEAE by severity 
 
Frequency tabulation of TEAE by severity for which the causal relationship with protocol 
treatment was “related” 
 
Frequency tabulation of TEAE by severity for which the causal relationship with panitumumab 
was “related” 
 
Frequency tabulation of TEAE for action taken for protocol treatment was “discontinuation” 
 
Frequency tabulation of TEAE by severity for action taken for protocol treatment was 
“discontinuation” 
 
Frequency tabulation of serious TEAE 
 
Frequency tabulation of serious TEAE for which the causal relationship with protocol treatment 
was “related” 
 
Frequency tabulation of serious TEAE for which the causal relationship with panitumumab 
treatment was “related” 
 
Frequency tabulation of non-serious TEAE with >5%. 
 
Frequency tabulation of non-serious TEAE with >5% for which the causal relationship with 
protocol treatment was “related”. 
 
Frequency tabulation of non-serious TEAE with >5% for which the causal relationship with 
panitumumab was “related”. 
 
Frequency tabulation of TEAE with ≥Grade 3. 
 
Frequency tabulation of TEAE with ≥Grade 3 for which the causal relationship with protocol 
treatment was “related”. 
 
Frequency tabulation of TEAE with ≥Grade 3 for which the causal relationship with 
panitumumab was “related”. 
 
The incidence rate of TEAE with ≥Grade 3 
 
The incidence rate of TEAE with ≥Grade 3 for which the causal relationship with protocol 
treatment was “related”. 
 
The incidence rate of TEAE with ≥Grade 3 for which the causal relationship with panitumumab 
was “related”. 
Main skin toxicitywill be analyszed samely as described above (7.2.5.1～7.2.5.20) 
The worst Grade in each subjects will be caluculated. The incidence rate of TEAE with ≥Grade 3 
and the 95% confidence intervals using Agresti-Coull methods will be calculate. Similarly, incidence 
rate and the 95% confidence interval of TEAE will be calculated in the number of TEAE incidence 
with ≥Grade 3 as the numerator, and the TEAE collecting periods as the denominator. 
The 95% confidence intervals is culculated by the fomula following; 


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The 95% confidence intervals of incidence rate = incidence rate± 1.96ඨ
incidence rate
during the TEAE collocting period 
 
13.4 
Criteria for interim analysis and premature discontinuation 
No interim analyses are scheduled. 
 
13.5 
Determination of the planned number of subjects 
See “6.2.2.2 Rationale for planned number of subjects“. 
 
 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of study sites 
The sponsor or its designee will perform periodic monitoring of study sites during the study to 
confirm that the study is carried out in accordance with all specifications in the protocol. Central 
monitoring and site visit monitoring, when necessary, will be performed in this study. 
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, based on the data collected by EDC. Central 
monitoring will be conducted twice a year in principle, and periodic monitoring report will be 
prepared. Periodic monitoring report will be evaluated by research steering committee and feedback 
will be given to study sites when necessary. 
Detailed procedures for central monitoring will be determined in the separately prepared procedures. 
 
14.1.2 Site visit monitoring 
Site visit monitoring is conducted to confirm that the study is carried out safely and in compliance 
with the protocol and the data are accurately collected by checking the data entered into the EDC 
against source documents. Source documents are the original documents, data and records. The 
investigator and the director of study site will ensure that the sponsor or its designee and the ethics 
review committee, etc., have access to the source documents. 
The sponsor or its designee will access the records including the list of subject screening, medical 
records, signed and dated original consent forms to confirm that the study is appropriately conducted 
in compliance with the protocol. Also, confirm the consistency between CRF and the related source 
documents. The investigator and the subinvestigator and other personnel involved in the study will 
spare sufficient time to facilitate monitoring procedures during visits to the study site. 
Prior to site visit monitoring, study sites will be randomly selected to perform Source Documents 
Verification (SDV) for the enrolled subjects. 
The frequency and procedures of study site visit monitoring should follow separately prepared 
procedure manual. 


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14.1.3 Deviations from Ethical Guideline for Clinical Research, ICH-GCP, and 
Protocol 
The investigator or the subinvestigator should record all deviations from Ethical Guideline for 
Clinical Research, ICH-GCP, and protocol. 
The investigator or the subinvestigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a prior 
written agreement with the sponsor or a prior approval from ethics review committee, etc. In the 
event of a deviation or change, the investigator should notify the sponsor and the director of the site 
of the deviation or change as well as its reason in a written form, and retain a copy of the written 
form. When necessary, the investigator may consult and agree with the sponsor on a protocol 
amendment. If the protocol is to be amended, the amendment proposal should be submitted to the 
director of the site as soon as possible and an approval should be obtained from site committee such 
as ethics review committee. 
 
14.2 
Quality assurance 
The sponsor or its designee and site committee such as ethics review committee will perform audit at 
the study site when necessary. In such a case, the auditor designated by the sponsor should contact 
the study site in advance to determine the date of audit. The auditor may request a visit to other sites 
that will be used during the study. The investigator and the director of 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., subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
Ethical Guideline for Clinical Research and the ICH-GCP. Each investigator will conduct the study 
according to regulatory requirements and in accordance with Appendix B “Responsibilities of the 
Investigator”. 
 
15.1 
Approval by the study site committee such as the ethics review 
committee 
The study site committee such as the ethics review committee is constituted according to regulations. 
The sponsor or its designee should obtain the document listing the name and title of each committee 
member. 
The sponsor or its designee should provide related documents to the study site committee such as the 
ethics review committee for review and approval of the protocol. In addition to the protocol, a copy 
of informed consent form, written materials related to subject recruitment, advertisement, and other 
documents required by regulation, when necessary, should be submitted to the central committee or 
the study site committee such as the ethics review committee to obtain approval. The sponsor should 
notify the study site, the investigator and the subinvestigator after confirming the appropriateness of 
the regulatory documents of the study site. Protocol procedures such as obtaining consent should not 
be started until the study site, the investigator and the subinvestigator receive the notification. 
The study site should comply with all the requirements specified by the study site committee such as 
the ethics review committee. The requirements include notifications to committees such as the ethics 
review committee, for instance, revision of the protocol, revision of the informed consent form, 
revision of materials related to subject recruitment, report on safety in accordance with the 
regulatory requirement, report on study implementation state at intervals determined by the study 
site committee such as the ethics review committee, and study completion report. The sponsor or its 
designee should obtain written approval from the study site committee such as the ethics review 
committee related to the above mentioned items and all related materials. 
 
15.2 
Conflict of interests 
This study will be conducted with support from sponsor. Prior to conduct of the study, the 
investigator should appropriately manage according to the study site regulation, that this study has 
no conflict of interests (hereinafter referred to as COI). 24)~28) 


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The study site should comply with all the requirements specified by the ethics review committee, etc. 
The requirements include the COI self-declaration, protocol, and informed consent form. 
15.3 
Written information and subject’s consent 
The informed consent form contains specific requirements of the Declaration of Helsinki, Ethical 
Guideline for Clinical Research and the ICH-GCP and all applicable laws and regulations. The 
informed consent form specifies the use of personal information and medical information of subjects 
in this study (both in and outside Japan: supply to a third party), and disclosure. Written explanation 
explains in detail the general idea and purpose of the study, and its possible risks and benefits. The 
informed consent form also clarifies the conditions for study participation and states the fact that 
subjects can discontinue study participation at any time without giving reasons and without loss of 
benefits in treatment. In principal, the items below are described. 
1) Clinical study and informed consent form 
2) Disease and 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 
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 subject) 
and study duration 
8) The estimated number of patients participating in the study 
9) The reason for being selected as subject 
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 


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18) Status related to funding of study, etc., study site related conflict of interest and personal 
benefits upon study, etc., study staff related conflict of interest upon study 
19) Intellectual property rights 
20) Possibility that the data is 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 they consist 
26) Issues to be followed 
27) Notification of new information and study discontinuation 
28) Explanation that on the premises of patients privacy being preserved, monitoring personnel, 
audit personnel and ethic review committee will have access to sample/information of 
subjects in the study within the scope of necessity. 
29) Explanation that informed consent cannot be obtained from anyone but the patient him or 
herself. 
The investigator is responsible for preparation, content, and the site committee such as ethics review 
committee approval of the informed consent form. The informed consent form should be approved 
by the site committee such as ethics review committee before use. 
The informed consent form should be written in a language easily understood by subjects. The 
investigator or the subinvestigator is responsible for providing detailed explanation of the informed 
consent form to subjects. Information should be provided orally and in writing as much as possible 
by the method deemed appropriate by the site committee such as ethics review committee. 
The investigator or the subinvestigator should ensure that the subjects have (1) an opportunity to 
inquire about the study and (2) sufficient time to determine study participation. When a subject 
decides to participate in the study, the subject should sign or write name/affix seal, and date the 
consent form prior to study participation. The investigator and the subinvestigator should request the 
subject to sign or write name/affix seal using a legal name and not a popular name with black or blue 
ballpoint pen. The investigator or the subinvestigator should also sign or write name/affix seal, and 
date the consent form prior to subject 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 which was signed or 
contains name/ affixed seal. The investigator or the subinvestigator should document in the subject’s 
medical record the date when the subject signed or wrote name/ affixed seal on the consent form. A 


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copy of the consent form with signature or name typed with seal affixed should be provided to the 
subject. 
The investigator or the subinvestigator should take the same procedures taken for obtaining the 
initial consent for newly obtaining consent from the concerned subject when the informed consent 
form is revised. The date of obtaining new consent should be recorded in the subject’s medical 
record, and a copy of the revised consent form should be provided to the subject. 
 
15.4 
Subject confidentiality 
The sponsor and its designee should comply with the principles of protection of the subject’s right 
against invasion of privacy. The subject ID code in this study is used to connect the clinical study 
database and related study documents of the sponsor with the source data of subjects. The limited 
information of subjects such as sex, age, and date of birth may be used within the scope of all 
applicable laws and regulations for identification of subjects and confirmation of accuracy of subject 
ID code. 
In compliance with Ethical Guideline for Clinical Research and the ICH-GCP, the sponsor should 
request the investigator for the access to the original laboratory test data, ECG, record of 
hospitalization/discharge during study period, and the original medical records such as autopsy 
report (source data or materials) by a monitor or the person designated by the sponsor, auditor 
designated by the sponsor, and the ethical committee, etc. The investigator or the subinvestigator 
should obtain approval from subject concerning access to the original medical records by a monitor 
when obtaining consent from a subject (see Section 15.3). 
When providing a copy of source documents to the sponsor, the investigator or the subinvestigator 
should delete the information leading to identification of an individual (name and address of subject, 
other personal information not recorded in CRF of subject). 
 
15.5 
Contacts for inquiries from subjects and concerned people 
The investigator should establish a contact service to respond to inquiries concerning this study from 
subjects or concerned people. Details of the contacts for inquiries will be described in the ICF. 
 


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15.6 
Advantages and disadvantages to subjects 
15.6.1 Advantage to subjects 
This study is performed as part of normal medical practice, and no advantage is expected by 
participating in this study. 
 
15.6.2 Disadvantage to subjects 
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 the sponsor. The intellectual property 
rights regarding the pharmaceutical products manufactured and/or distributed by Takeda 
Pharmaceutical Company Limited also belong to Takeda Pharmaceutical Company Limited. Data 
generated from this study may be made available for secondary use (e.g., meta-analysis) without any 
link to personally identifying information only with approval from the research steering committee 
chairman 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 the sponsor. 
 
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 director of the study site written summary of results of the 
study and provide the sponsor with all the results and data obtained from the study. Only the sponsor 
may disclose the study information to other investigators or subinvestigators during the study period 
except for a case required by laws and regulations. The sponsor will be responsible for publication of 


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the protocol and study-related results (including the public web site) except for other cases permitted 
in the study contract. 
During study period and after the end of study, the sponsor or its designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. 
The sponsor may publish the data and information obtained from the study (including the data and 
information provided by the investigator) based on the agreement with the research steering 
committee chairman. 
The investigator or the subinvestigator should obtain the prior written approval from the sponsor 
when publishing the information obtained in this study at an academic conference, etc. 
The sponsor should report to the director of the study site that final publication of the study result 
has been made. 
 
15.8.2 Clinical study registration 
Takeda Pharmaceutical Company Limited will ensure timely publication of the information of a 
clinical study and registration of all clinical researches in patients under way all over the world, prior 
to study initiation, with ClinicalTrials.gov, JAPIC, and UMIN to comply with the applicable 
laws/regulations and guidelines. The city and country where a study is performed, and the subject 
recruitment status should be registered as well as the contact information of Takeda Pharmaceutical 
Company Limited to enable general access. 
 
15.8.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited will post the results of a clinical study on 
ClinicalTrials.gov, JAPIC, and UMIN as specified by the applicable laws and/or regulations 
irrespective of results. 
 
15.8.4 Method of storage and destruction of material/information concerning 
clinical study 
The director of the study site should appropriately retain the material/information related to this 
study for at least to the date passing 5 years from the date of reporting of the ending of the study 
from the investigator or to the date passing 3 years from the date of reporting of final publication of 
the study result, whichever date is later. 


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15.9 
Insurance and compensation for injury 
The subjects participating in this study will be compensated for any injury resulting from 
participation in the study according to local regulations applicable to the study site. It should be 
noted that any treatment provided will be covered by health insurance, and no monetary 
compensation will be provided. 


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16.0 
REFEREnCES 
1) The Editorial Board of Cancer Statistics in Japan. Cancer Statistics in Japan 2014. 
Foundation for Promotion of Cancer Research: 2014. 
2) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines for the 
treatment of colorectal cancer 2014. Kanehara & CO., LTD. 
3) Pharmaceutical interview form. Panitumumab (genetical recombination) injection, latest 
version. 
4) Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label 
phase III trial of panitumumab plus best supportive care compared with best supportive 
care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin 
Oncol. 2007;25(13):1658-64. 
5) Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, 
phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin 
(FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously 
untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 
2010;28(31):4697-705. 
6) Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized 
phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) 
compared with FOLFIRI alone as second-line treatment in patients with metastatic 
colorectal cancer. J Clin Oncol. 2010;28(31):4706-13. 
7) Muro K, Yoshino T, Doi T, Shirao K, Takiuchi H, Hamamoto Y, et al. A phase 2 clinical 
trial of panitumumab monotherapy in Japanese patients with metastatic colorectal cancer. 
Jpn J Clin Oncol. 2009;39(5):321-6. 
8)  Boku N, Sugihara K, Kitagawa Y, Hatake K, Gemma A, Yamazaki N, et al. 
Panitumumab in Japanese Patients with Unresectable Colorectal Cancer: A Post-marketing 
Surveillance Study of 3085 Patients. Jpn J Clin Oncol. 2014;44(3):214-223. 
9)  Pharmaceutical interview form. Lonsurf combination tablets, latest version. 
10) Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated 
metastatic colorectal cancer: a doubleblind, randomised, placebo-controlled phase 2 trial. 
Lancet Oncol 2012; 13: 993, 1001  
11) Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et 
al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 
2015; 14;372(20):1909-19. 
12) Kuboki Y, Nishina T, Shinozaki E, Yamazaki K, Shitara K, Wataru Okamoto W, et al. 
An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for 
metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE). J Clin 
Oncol 2015; 33 suppl; abstr 3544 
13) Patterson SD, Marc P, Salvatore S, Eric VC, Yves H, Jean-Luc VL, et al. Comprehensive 
analysis of KRAS and NRAS mutations as predictive biomarkers for single agent 
panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer 
(mCRC) study (20020408). J Clin Oncol 31, 2013 (suppl; abstr 3617) 


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14) Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. 
Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J 
Med. 2013;369(11):1023-34. 
15) Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. 
Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in 
metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 
2014 Aug 12. pii: mdu378. Review. 
16) Japanese Society of Medical Oncology. Guidance for measuring RAS (KRAS/NRAS) 
mutations in colorectal cancer patients, ver.2, April 2014. 
17) Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. Panitumumab versus 
cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic 
colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority 
phase 3 study. Lancet Oncol, 15 2014;15:569–579 
18) Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab 
monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal 
cancer. N Engl J Med 2004; 351: 337-45. 
19) Andre T, Blons H, Mabro M, Chibaudel B, Bachet JB, Tournigand C, et al. Panitumumab 
combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer 
refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational 
molecular study. Ann Oncol 2013; 24: 412-9. 
20) Tsukihara H, Nakagawa F, Sakamoto K, Ishida K, Tanaka N, Okabe H, et al. Efficacy of 
combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together 
with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. 
Oncol Rep. 2015;33(5):2135-42. 
21) Bijnsdorp IV, Kruyt FA, Fukushima M, Smid K, Gokoel S Peters GJ. Molecular 
mechanism underlying the synergistic interaction between trifluorothymidine and the 
epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. 
Cancer Sci 2010;101: 440 -7 
22) Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. 
K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer. N Eng J 
Med 2008; 359 (17);1757-65 
23) Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics 1982; 38:  29-41. 
24) Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, 
Sports, Science and Technology dated November 1, 2002) 
25) Guidelines for determining the conflict of interest polity for clinical researches (Review 
group for ethical aspects of clinical researches and conflict of interest, March 2006) 
26) Guidelines on the Management of Conflict of Interest (Conflict of Interest: COI) in 
Health and Labour Sciences Research (March 31, 2008) 
27) Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
28) Common guidelines for conflict of interest (COI) in clinical research (Japanese Society 
of Internal Medicine, Japan Society of Hepatology, Japanese Circulation Society, Japan 
Endocrine Society, Japan Diabetes Society, Japanese Respiratory Society, Japanese 


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Society of Hematology, Japanese Society of Allergology, Japanese Association for 
Infectious Diseases, Aug 2011) 
29) Lacouture ME, Mitchell EP, Piperdi B et al. Skin toxicity evaluation protocol with 
panitumumab (STEPP), a Phase II, open-label, randomized trial evaluating the impact of a 
pre-Emptive Skin treatment regimen on skin J. Clin. Oncol. 28, 1351–1357 (2010). 
30) Kobayashi Y, Komatsu Y, Yuki S, Fukushima H, Sasaki T, Iwanaga I, et al. Randomized 
controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic 
colorectal cancer: HGCSG1001 study; J-STEPP. Future Oncol. 2015 Feb;11(4):617-27. 
 


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Appendix A 
Evaluation according to RECIST ver 1.1 
Evaluation will be conducted according to RECIST ver 1.1 as follows. 
1. 
Definition of measurable lesion 
Lesion that fulfills any of the conditions below will be considered as a measurable lesion. 
(1) Lesions other than malignant lymph node (non-nodal lesion) that meet either of the below 
1) 
CT scan slice thickness no greater than 5 mm or MRI largest diameter at least10 mm 
2) 
CT scan slice thickness greater than 5 mm or MRI largest diameter is 2 folds or more 
the slice thickness 
(2) Malignant lymph node CT scan slice thickness 5 mm or less and short diameter at least 15 
mm 
(Malignant lymph node with short diameter at least 10 mm and less than 15 mm will be a 
non-target lesion, lymph node with short diameter of less than 10 mm will not be 
considered as a lesion) 
Any other lesion besides the above will be considered as non-measurable lesions. 
Note that lesions below will be considered as non-measurable lesions irrespective of test 
method or size of lesion: 
 
Bone lesions 
 
Cystic lesions 
 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy 
 
Leptomeningeal disease lesion 
 
Ascites, pleural effusion, pericardial effusion 
 
Lymphangitic involvement of skin or lung 
 
Abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques 
2. 
Baseline documentation of target lesions 
From measurable lesions observed before initiation of protocol treatment, select 5 
lesions highest in diameter (long diameter for non-nodal lesion and short diameter 
for malignant lymph node), 2 lesions at most for 1 organ and determine them as 
target lesions. Upon selection, organs with measurable lesions should be included evenly, and 
select in consideration of those that lend themselves to reproducible repeated measurements 
(lesions with large diameter but difficult to measure should be avoided). 
For chosen target lesion, in order from head to tail, record site, lesion diameters (long diameter 
for non-nodal target lesions, short axis for nodal target lesion) and a sum of diameters 
(hereinafter referred to as SoD) of all target lesions should be recorded. 
3. 
Baseline documentation of non-target lesions 
Lesions not selected for target lesion should be recorded as present or absent non-target lesion 
irrespective of whether measurement is possible or not. Multiple non-target lesions in the same 


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organ can be recorded as 1 lesion (e.g. multiple enlarged pelvic lymph nodes, multiple liver 
metastases) 
4. 
Tumor response criteria 
Evaluate target lesion and non-target lesion using the same method as at enrollment according 
to “9.2.10 Imaging test (thoracoabdominal-pelvic CT/MRI)“, and record diameter of target 
lesion, presence or absence of non-target lesion or onset of new lesion. 
5. 
Response criteria of target lesion 
 
CR (Complete Response): 
Disappearance of all non-nodal target lesions and all lymph node target lesions short axis 
<10mm If nodal target lesion is selected at baseline, response criteria may be CR even 
though SoD is not 0 mm. 
 
PR (Partial Response): 
At least a 30% decrease in the SoD of target lesions, taking as reference the baseline SoD. 
 
PD (Progressive Disease): 
Taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study), at least a 20% increase in the SoD of target lesions, and the sum must 
also demonstrate an absolute increase of at least 5 mm. 
 
SD (Stable Disease): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest SoD while on study. 
 
Not all Evaluated: 
When test cannot be conducted for some reason, or cannot be determined as CR, PR, PD 
or SD. 
SoD before treatment – SoD at evaluation 
Reduction ratio of SoD =   ――――――――――――――――――  × 100% 
SoD before treatment 
 
SoD at evaluation – Smallest SoD 
Increase ratio of SoD  =  ――――――――――――――――――  × 100% 
Smallest SoD 
 
* 
Diameter of target lesion is recorded with actual measurements (e.g., even if under 5 
mm) as much as possible, but when target lesion is determined as “too small to 
measure”, irrespective of CT slice thickness, if it is determined that tumor lesion no 
longer exists and the diameter will be recorded as 0 mm, whereas if it is determined 
to exist the diameter will be 5 mm. 


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* 
If reduction ratio meets the PR criteria and increase ratio meets the PD criteria at the 
same time, criteria will be determined as PD. 
* 
If one lesion is divided during treatment, each diameter should be added to the SoD. 
* 
If multiple lesions agglutinate and the border cannot be distinguished, the diameter of 
the agglutinated lesion should be added to the SoD. 
* 
Whenever lesions are in contact, if the borders of the lesions are distinguishable, the 
diameter of each lesion should be added to the SoD. 
6. 
Response criteria of non-target lesion 
 
CR (Complete Response): 
Disappearance of all non-nodal non-target lesions and all lymph nodes short axis <10mm 
 
Non-CR/non-PD: 
Persistence of one or more non-target lesion(s) including lymph nodes short axis ≥ 10 mm 
and/or maintenance of tumor marker either of which the level is above the common normal 
limits. 
 
PD (Progressive Disease): 
“Unequivocal progression” of existing non-target lesions (including recurrence). 
When the patient has measurable lesion: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. When response criteria for target lesion is SD or PR, an increase of non-target 
lesion that will overwhelm the tumor burden decrease will be determined as “unequivocal 
progression”, and if not it will be Non-CR/non-PD. 
When the patient has only non-measurable lesion: a 20% increase diameter in a 
non-measurable lesion, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ will be determined as “unequivocal progression”. 
 
Not all Evaluated: 
When test cannot be conducted for some reason, or cannot be determined as CR, 
Non-CR/non-PD, or PD. 
7. 
Appearance of new lesions 
When a lesion that was not present at baseline has been observed after initiation of treatment, 
this will be determined as appearance of “new lesion”. However, “new lesion” should not 
attributable to differences in scanning technique, change in imaging modality or findings 
thought to represent something other than tumor. For example, necrosis of a liver lesion may be 


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reported as a “new” cystic lesion, which it is not. A newly identified lesion in a location by test 
that was not mandatory at baseline (evaluation before enrollment) is considered a new lesion 
If a lesion disappears and reappears later, measurement will be continued. However, the 
response at the time of reappearance of the lesion will be different depending on other lesions. 
If lesion has reappeared after CR, it will be determined as PD at the time of reappearance. On 
the other hand, if it was PR or SD, when the once disappeared lesion reappears, in order to 
calculate the response, the diameter of the lesion will be added to the rest of the lesions. Thus, 
when there are a number of lesions still existing, if one lesion apparently “disappears” and 
reappears later, from that alone, it will not be determined as PD but if the SoD of all the lesions 
meet the PD criteria, it will be determined as PD. The reason for this is that there is an 
understanding that most of the lesions do not truly “disappear” and yet it cannot be extracted 
due to the limit to resolution of imaging modality. 
If there is a possibility of new lesion but cannot be confirmed, it should not be determined as a 
new lesion but re-examination by imaging test should be conducted after clinically appropriate 
interval. If new lesion is confirmed by imaging test re-examination, the date of the imaging test 
that confirmed the new lesion will be the time point for appearance of new legion. 
8. 
Overall Response 
Overall Response will be determined with combination of target lesion response, non-target 
lesion response, appearance of new lesion according to Tables A.1 and A.2 below. 
Table A.1 Overall response at each time point: When patient has target lesion (with or without 
non-target lesion) 
Target lesion 
Non-target lesion 
New lesion 
Overall 
response 
CR 
CR 
Absent 
CR 
CR 
Non-CR/non-PD 
Absent 
PR 
CR 
Not determined 
Absent 
PR 
PR 
Non-PD or defect in evaluation Absent 
PR 
SD 
Non-PD or defect in evaluation Absent 
SD 
Defect in 
evaluation 
Non-PD 
Absent 
NE 
PD 
Any 
Present or 
absent 
PD 
Any 
PD 
Present or 
absent 
PD 
Any 
Any 
Yes 
PD 


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9. 
Best Overall Response 
Response will be more favorable in the following order: CR>PR>SD>PD>NE. The most 
favorable overall response through the entire course will be the best overall response. 
When response could not be determined by imaging due to an obvious aggression of disease or 
death before the first response determination, it will be determined as PD. When response could 
not be determined by imaging due to discontinuation from toxicity or rejection by subject 
before the first response determination, it will be determined as NE. 


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Appendix B 
 
Responsibilities of the investigator 
1. 
To appropriately conduct the study in accordance with the protocol, Ethical Guideline for 
Clinical Research and the ICH-GCP considering the human rights, safety, and wellbeing of 
human subjects. 
2. 
When assigning a part of important duties related to this study to subinvestigators or study 
collaborators, prepare a list of subinvestigators or study collaborators, which will be submitted 
to the director of study site as necessary. 
3. 
To prepare the informed consent form and revise it as necessary. 
4. 
To check the contents of the study contract. 
5. 
To provide sufficient information on the protocol, drug and duties of each personnel to 
subinvestigators and study collaborators, and give guidance and supervision. 
6. 
To select subjects who satisfy the protocol, give explanation using written information, and 
obtain consent in writing. 
7. 
To be responsible for all medical judgments related to the study. 
8. 
Corresponding to request from the director of the study site, report the latest progress status at 
least once a year to the director of the study site. 
9. 
To request COI committee of each study site to review and approve that there is no COI issues 
in conducting this study. 
10. To ensure together with the director of study site that sufficient medical care is provided to 
subjects for all study-related clinically problematic adverse events throughout the period of 
subject’s study participation and thereafter. 
11. When a subject is treated at another medical institution or department, inform a physician of the 
medical institution or department in writing of the subject’s study participation and study 
completion/discontinuation after obtaining the subject’s consent, and prepare the record. 
12. When emergency report of serious adverse events, etc. is required, immediately report it in 
writing to the director of the study site and the sponsor. 
13. To prepare accurate and complete CRF and submit it to the sponsor with an electronic 
signature. 
14. To inspect and check the contents of CRF prepared by subinvestigators, or transcribed by study 
collaborators from the source data, and submit it to the sponsor with an electronic signature. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 
16. To report the study completion in writing to the director of study site. 


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CONFIDENTIAL 
 
 
 
PROTOCOL 
 
 
A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 for patients with RAS (KRAS, NRAS) wild-type, unresectable, 
advanced/recurrent colorectal cancer 
 
APOLLON study 
A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 for patients with RAS wild-type metastatic colorectal cancer refractory to 
standard chemotherapy 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Panitumumab-1501 
Version 
First Edition 
Product name 
Panitumumab 
Creation date 
October 27, 2015 
 
 


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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 applicable institutional review committee 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 Principals 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science 
and Technology and the Ministry of Health, Labour and Welfare, December 22, 2014). 
• 
International Conference on Harmonisation E6 Good Clinical Practice (hereinafter referred to 
as “GCP”) (including ICH-GCP). 
• All applicable laws and regulations, including, without limitation, data privacy laws, conflict 
of interest guidelines. 
 
1.2 
Clinical Study Administrative Structure 
This study will be conducted under the following administrative structure. 
Clinical research steering committee 
Research steering committee chairman: 
Research steering committee members: 
Data Monitoring Committee (hereinafter referred to as DMC) 
DMC chairman: 
DMC members: 
PPD
PPD
PPD


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Statistics Representative: 
 
Also, terms used in this protocol will be defined as follows: 
Study site: 
A corporation an administrative organization or a sole proprietor conducting the study, except for 
sites performing only a part of the study related activities on consignment such as sample/ 
information storage and statistic processing. 
Joint research institution: 
An institution jointly conducting the study based on the protocol, and will include institutions that 
will additionally obtain sample/ information from study subjects and providing them to other 
study sites. 
Study staff: 
Investigators and other staff personnel conducting the study (including activities performed in 
institutions that collect and provide samples/ information), except for personnel who only 
provides existing samples/information besides study site or partially engage in the study related 
activity on consignment. 
Investigator: 
A personnel taking part in conducting the study and presides over the study related activities 
within the belonging study site. 
Study site director: 
Director of a corporation, an administrative organization or a sole proprietor conducting the study 
Study subjects: 
A person who is applicable to either of the following: 
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 
PPD
PPD


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1.3 
Contacts for protocol inquiries 
Study office:
 
E-mail: 
 
Tel: 
 
[Reception hours] 
 
1.4 
Contacts for enrollment procedure 
Case enrollment center: 
 
 E-mail:
 
[E-mail receipt confirmation] 
 Tel: 
 
[Reception hours] 
 
1.5 
Sponsor 
Takeda Pharmaceutical Company Limited, 
Strategic Medical Research Planning, Global Medical Affairs Department, Japan Oncology Business 
Unit 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS 
1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY MANAGEMENT 
INFORMATION ..................................................................................................................... 3 
1.1 
Clinical Study Principals .................................................................................................. 3 
1.2 
Clinical Study Administrative Structure ........................................................................... 3 
1.3 
Contacts for protocol inquiries ......................................................................................... 5 
1.4 
Contacts for enrollment procedure ................................................................................... 5 
1.5 
Sponsor ............................................................................................................................. 5 
2.0 
STUDY SUMMARY ............................................................................................................ 13 
3.0 
LIST OF ABBREVIATIONS ............................................................................................... 22 
4.0 
INTRODUCTION ................................................................................................................. 24 
4.1 
Background .................................................................................................................... 24 
4.1.1 
Etiology of colon cancer .......................................................................................... 24 
4.1.2 
Standard treatment for colon cancer ........................................................................ 24 
4.1.3 
Efficacy and safety of panitumumab in patients with unresectable, 
advanced/recurrent colorectal cancer....................................................................... 26 
4.1.4 
Efficacy and safety of TAS-102 for unresectable, advanced/recurrent colorectal 
cancer ....................................................................................................................... 30 
4.1.5 
RAS (KRAS/NRAS) mutation and panitumumab in unresectable, advanced/recurrent 
colorectal cancer ...................................................................................................... 32 
4.2 
Rationale for the proposed study .................................................................................... 33 
5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY ............................................................ 38 
5.1 
Objective ........................................................................................................................ 38 
5.2 
Definition of endpoints ................................................................................................... 38 
5.2.1 
Definition of endpoints for phase I part ................................................................... 38 
5.2.2 
Definition of endpoints for phase II part ................................................................. 38 
5.3 
Rationale for the endpoints ............................................................................................. 39 
5.3.1 
Primary endpoint ..................................................................................................... 39 
5.3.2 
Secondary endpoints ................................................................................................ 39 
6.0 
CLINICAL STUDY DESIGN .............................................................................................. 40 
6.1 
Clinical study design ...................................................................................................... 40 
6.2 
Rationale for study design .............................................................................................. 41 


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6.2.1 
Study population ...................................................................................................... 41 
6.2.2 
Treatment regimens and planned number of subjects.............................................. 42 
6.3 
Discontinuation of entire clinical study or discontinuation of clinical study at a study 
site .................................................................................................................................. 45 
6.3.1 
Criteria for discontinuation of entire clinical study ................................................. 45 
6.3.2 
Criteria for discontinuation of clinical study at a study site .................................... 45 
6.3.3 
Procedures of clinical study suspension and discontinuation of entire clinical study 
or study at a study site ............................................................................................. 45 
6.4 
Procedures for protocol amendment ............................................................................... 45 
7.0 
SELECTION OF STUDY SUBJECTS AND ENROLLMENT ........................................... 47 
7.1 
Inclusion criteria at enrollment ....................................................................................... 47 
7.2 
Exclusion criteria at enrollment ...................................................................................... 48 
7.3 
Procedures for registration and protocol treatment ........................................................ 49 
7.3.1 
Procedures for registration and initiation of protocol treatment .............................. 49 
7.3.2 
Contacts for enrollment procedure .......................................................................... 50 
8.0 
PROTOCOL TREATMENT ................................................................................................. 51 
8.1 
Definition of protocol treatment ..................................................................................... 51 
8.2 
Treatment regimen.......................................................................................................... 51 
8.3 
Recommended dose of protocol treatment ..................................................................... 52 
8.4 
Criteria for administration .............................................................................................. 53 
8.5 
Criteria for protocol treatment change ............................................................................ 56 
8.5.1 
Criteria for suspension/dose reduction of panitumumab ......................................... 56 
8.5.2 
Criteria for suspension/dose reduction of TAS-102 ................................................ 57 
8.6 
Criteria for dose increase of protocol treatment ............................................................. 59 
8.7 
Criteria for discontinuation of protocol treatment for each subject ................................ 59 
8.8 
Procedures for Discontinuation or Withdrawal of a Subject .......................................... 60 
8.9 
DLT ................................................................................................................................ 61 
8.9.1 
DLT Evaluation Period ............................................................................................ 61 
8.9.2 
Subjects Included in the DLT Evaluation ................................................................ 61 
8.9.3 
DLT Criteria ............................................................................................................ 61 
8.10 
Replacement/Addition of Subjects ................................................................................. 62 


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8.11 
Contraindicated drugs/therapies ..................................................................................... 62 
8.12 
Recommended supportive care and combination medications ....................................... 63 
8.13 
Recommended follow-up therapy .................................................................................. 64 
9.0 
PROTOCOL, EVALUATION ITEMS AND PROCEDURES FOR OBSERVATIONS .... 65 
9.1 
Study calendar ................................................................................................................ 65 
9.2 
Collection/test/observation items and procedures during the clinical study ................... 68 
9.2.1 
Informed consent procedure .................................................................................... 68 
9.2.2 
Enrollment and protocol treatment .......................................................................... 69 
9.2.3 
Subject demographics .............................................................................................. 69 
9.2.4 
Concurrent medical condition.................................................................................. 70 
9.2.5 
Clinical findings ...................................................................................................... 70 
9.2.6 
Body weight, height ................................................................................................. 70 
9.2.7 
Eastern Cooperative Oncology Group Performance Status (ECOG) Performance 
Status ....................................................................................................................... 71 
9.2.8 
Compliance .............................................................................................................. 71 
9.2.9 
Clinical laboratory tests ........................................................................................... 71 
9.2.10 Imaging test (thoracoabdominal-pelvic CT/MRI) ................................................... 74 
9.2.11 Follow-up treatment ................................................................................................ 76 
9.2.12 Survival survey ........................................................................................................ 76 
9.2.13 Pregnancy ................................................................................................................ 76 
9.3 
Records of subjects who discontinued before enrollment .............................................. 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 
10.1.3 Serious adverse events ............................................................................................. 80 
10.1.4 Special interest adverse event for sponsor ............................................................... 81 
10.1.5 Severity of adverse events ....................................................................................... 81 
10.1.6 Causality of adverse events ..................................................................................... 82 
10.1.7 Date of onset of adverse events ............................................................................... 83 
10.1.8 Action taken for protocol treatment ......................................................................... 83 


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10.1.9 Outcome .................................................................................................................. 84 
10.2 
Procedures ...................................................................................................................... 84 
10.2.1 Collection and reporting of adverse events.............................................................. 84 
10.2.2 Collection and reporting of serious adverse events ................................................. 85 
10.2.3 Follow-up of serious adverse events ........................................................................ 86 
10.2.4 Reporting of additional information concerning adverse events ............................. 86 
10.2.5 Dissemination of unknown serious adverse event to joint research institutions ...... 86 
10.2.6 Reporting of serious adverse events, etc., to ethics review committee, etc., and 
regulatory authorities ............................................................................................... 87 
11.0 
COMMIITTEES ESTABLISHED FOR THIS STUDY ....................................................... 88 
11.1 
Research steering committee .......................................................................................... 88 
11.2 
Data monitoring committee ............................................................................................ 88 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS................................................ 89 
12.1 
Case report form ............................................................................................................. 89 
12.2 
Time limit for data input into the EDC ........................................................................... 90 
12.3 
Storage of records ........................................................................................................... 90 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................................. 91 
13.1 
Statistical and analytical plans ........................................................................................ 91 
13.2 
Statistical analysis of the phase I part of the study ......................................................... 91 
13.2.1 Analysis set .............................................................................................................. 91 
13.2.2 Analysis of demographic and other baseline characteristics ................................... 91 
13.2.3 Safety analysis ......................................................................................................... 91 
13.3 
Statistical analysis of the phase II part of the study ........................................................ 92 
13.3.1 Analysis sets ............................................................................................................ 92 
13.3.2 Analysis of demographic and other baseline characteristics ................................... 92 
13.3.3 Efficacy analysis ...................................................................................................... 92 
13.3.4 Safety analysis ......................................................................................................... 95 
13.4 
Criteria for interim analysis and premature discontinuation .......................................... 96 
13.5 
Determination of the planned number of subjects .......................................................... 96 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 97 
14.1 
Monitoring of study sites ................................................................................................ 97 


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14.1.1 Central monitoring ................................................................................................... 97 
14.1.2 Site visit monitoring ................................................................................................ 97 
14.1.3 Deviations from Ethical Guideline for Clinical Research, ICH-GCP, and Protocol 98 
14.2 
Quality assurance............................................................................................................ 98 
15.0 
ETHICAL CONDUCT OF CLINICAL STUDY.................................................................. 99 
15.1 
Approval by the study site committee such as the ethics review committee .................. 99 
15.2 
Conflict of interests ........................................................................................................ 99 
15.3 
Written information and subject’s consent ................................................................... 100 
15.4 
Subject confidentiality .................................................................................................. 102 
15.5 
Contacts for inquiries from subjects and concerned people ......................................... 102 
15.6 
Advantages and disadvantages to subjects ................................................................... 103 
15.6.1 Advantage to subjects ............................................................................................ 103 
15.6.2 Disadvantage to subjects ....................................................................................... 103 
15.7 
Attribution of study results and access rights ............................................................... 103 
15.7.1 Attribution of study results .................................................................................... 103 
15.7.2 Data access rights .................................................................................................. 103 
15.8 
Reporting of results, Publication, disclosure, and clinical study registration policy .... 103 
15.8.1 Reporting of results, publication and disclosure .................................................... 103 
15.8.2 Clinical study registration ...................................................................................... 104 
15.8.3 Clinical trial results disclosure............................................................................... 104 
15.8.4 Method of storage and destruction of material/information concerning clinical study104 
15.9 
Insurance and compensation for injury ........................................................................ 105 
16.0 
REFERENCES .................................................................................................................... 106 
LIST OF IN-TEXT TABLES 
Table 4.a Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study ......... 27 
Table 4.b Common adverse events (≥ 20%) noted in a Japanese phase II clinical study of 
Panitumumab monotherapy.............................................................................................. 28 
Table 4.c Common adverse events in specified drug use surveillance in Japan ................................. 29 
Table 4.d Common adverse events (occurrence 10%) noted in Japanese clinical study .................... 31 
Table 4.e Common adverse events (occurrence 10%) noted in the phase III global clinical study .... 32 
Table 4.f Comparison of rate of adverse events .................................................................................. 36 


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Table 4.g Comparison of rate of adverse events ................................................................................. 36 
Table 8a Treatment regimen of combination therapy with panitumumab + TAS-102 ....................... 51 
Table 8.b TAS-102 dosage ................................................................................................................. 52 
Table 8.c TAS-102 dosage when dose is adjusted .............................................................................. 53 
Table 8.d. Criteria for initiation of treatment with panitumumab ....................................................... 56 
Table 8.e Criteria for initiation of treatment with TAS-102 ............................................................... 56 
Table 8.f Criteria for suspension/dose reduction of panitumumab ..................................................... 57 
Table 8.g Doses of panitumumab ....................................................................................................... 57 
Table 8.h Criteria for suspension of TAS-102 .................................................................................... 58 
Table 8.i Criteria for dose reduction of TAS-102 ............................................................................... 58 
Table 8.j Doses of TAS-102 ............................................................................................................... 58 
Table 9.a Study calendar (phase I part of the study) ........................................................................... 66 
Table 9.b Study calendar (phase II part of the study) ......................................................................... 67 
Table 9.c Allowance range for protocol treatment and laboratory tests ............................................. 68 
Table 9.d Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) .......................... 71 
Table 9.e Laboratory tests performed at the time of enrollment ......................................................... 72 
Table 9.f Clinical laboratory tests performed during the protocol treatment period ........................... 74 
Table 9.g Laboratory tests performed at the time of discontinuation ................................................. 74 
Table 10.a Takeda Medically Significant AE List .............................................................................. 81 
Table 10.b CTCAE (Japanese edition JCOG version 4.03) Grade ..................................................... 82 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a Anti-tumor effect from combination use of FTD and panitumumab in KRAS wild-type 
colorectal cancer cell strain (SW48 and LIM1215, both are KRAS/BRAF wild type) ..... 34 
Figure 6.a Outline of study design ...................................................................................................... 40 
Figure 6.b ASPECCT study Progression-free survival ....................................................................... 44 
Figure 8.a Combination therapy with panitumumab and TAS-102 .................................................... 52 
Figure 9.a JSH Guidelines for the Management of Hepatitis B virus infection .................................. 72 
 
LIST OF APPENDICES 
Appendix A 
Evaluation according to RECIST ver 1.1 .............................................................. 109 


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Appendix B 
Responsibilities of the investigator ........................................................................ 114 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Test product: 
Panitumumab 
Study title: 
A phase I/II study for the safety and efficacy of Panitumumab in combination with TAS-102 for patients 
with RAS (KRAS, NRAS) wild-type unresectable, advanced/recurrent colorectal cancer 
APOLLON study (A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 for patients with RAS wild-type metastatic colorectal cancer refractory to standard 
chemotherapy) 
Protocol number: Panitumumab-1501 
Clinical study design: 
This phase I/II study is a multi-center, open-label single-arm study that consists of a phase I part (dose 
de-escalation) which will assess the tolerability, safety and Recommended Dose (hereinafter referred to as 
RD) of Panitumumab in combination with TAS-102 as primary objective, and a phase II part which will 
assess the efficacy and safety of Panitumumab in combination with TAS-102 as primary objective in 
patients with RAS wild-type unresectable, advanced/recurrent colorectal cancer. In the phase I part, the 
subjects will be included sequentially into Cohort 1 and 2, 3 subjects each with the same dosage and 
administration. In the phase II part, 46 subjects will be included additionally for RD confirmed in the 
phase I part. 
 


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In the phase I part, each cohort will be conducted with 3 subjects, the sponsor will assess tolerability of 
the dosage and administration based on the incidence of Dose Limiting Toxicity (hereinafter referred to as 
DLT) during the assessment period and determine whether or not to move on to the next cohort (opinion 
from the Data Monitoring Committee [hereinafter referred to as DMC] will be confirmed appropriately 
upon determination). Therefore, in Cohort 1, if occurrence of DLT is ≤ 2 subjects out of 3, the dosage and 
administration will be determined tolerable and will move on to Cohort 2. However, if DLT is observed 
in 2 subjects during DLT assessment period in Cohort 1, subjects will be included one at a time in Cohort 
2 in consideration for safety to assess DLT. Similarly 3 subjects will be included in Cohort 2 and DLT 
will be assessed in a total of 6 subjects of Cohort 1 and 2 at most. If DLT is observed in 3 subjects 
included in Cohort 1, or DLT is observed in 3 subjects from a total of 6 subjects of Cohort 1 and 2, the 
sponsor will promptly request to postpone new enrollment of subjects to each site and after consultation 
with the Research Steering Committee and DMC on the continuation of the study, will determine whether 
or not to continue the study. 
If study is to be continued, taking in account of the adverse event that occurred, either panitumumab or 
TAS-102 or both drugs will be reduced one step and re-conducting the phase I part similarly will be 
considered. If DLT is observed in 3 subjects after reducing 1 step of panitumumab or TAS-102 or both 
drugs, the study will be discontinued. 
If DLT is observed in ≤ 2 subjects from a total of 6 subjects of Cohort 1 and 2, the sponsor will 
comprehensively assess with the Research Steering Committee based on the safety data of the phase I 
part, and after confirming the opinion of DMC, will determine the transit to phase II part. 
In the phase II part, in addition to the 6 subjects who received RD dose in the phase I part, a target of 46 
subjects are to be accumulated (a total of 52 subjects). 
Objective: 
Phase I part 
Assess RD (Recommended Dose) of panitumumab in combination with TAS-102 in patients with RAS 
wild-type unresectable, advanced/recurrent colorectal cancer 
Phase II part 
Assess efficacy and safety of panitumumab in combination with TAS-102 in patients with RAS wild-type 
unresectable, advanced/recurrent colorectal cancer 
Study population: patients with RAS wild-type unresectable, advanced/recurrent colorectal cancer 
refractory or intolerant to fluropyrimidines, oxaliplatin, irinotecan and angiogenesis inhibitors 
(bevacizumab, aflibercept, ramycirumab, etc.) 
Planned number of subjects: 
A maximum of 58 subjects 




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Dose limiting toxicity (DLT) definition 
In this study, DLT will be assessed based on the adverse events observed in 6 subjects at maximum 
enrolled in phase I part. DLT will be defined as follows [definition and grade will be based on Common 
Terminology Criteria for Adverse Events (CTCAE) ver4.03]. Further, DLT will be assessed from Day 1 
of course 1 of protocol treatment, and if DLT does not occur by Day 1 of course 2, it will be handled as 
no occurrence of DLT in the subject.  Adverse events that can clearly be denied of causal relationship 
with the protocol treatment will not be assessed as DLT.  If serious adverse event or unexpected adverse 
event occurs which causal relationship with the protocol treatment cannot be denied other than the 
following, it may be determined as to whether or not to handle it as DLT in consultation with the 
Investigator, the Research Steering Committee and the sponsor. 
1. 
Persistent Grade 4 neutropenia for more than 7 days under maximum supportive therapy 
2. 
Febrile neutropenia 
3. 
Blood platelete decreased of Grade 3 requiring platelet transfusion or blood platelete decreased of 
Grade 4 
4. 
If start of second course is delayed for more than 14 days due to adverse event related to protocol 
treatment 
5. 
Grade 3 or higher non-hematologic toxicity that is clinically problematic however the following will 
not be applicable as DLT. 
-Grade 3 gastrointestinal symptoms that can be controlled with supportive care (appropriate use of 
antiemetics, antidiarrheals, etc.) 
-Grade 3 or higher electrolyte abnormalities that are not deemed clinically problematic 
Duration of treatment (as a guide): 
6 months 
Period of evaluation: 
12 months 
Inclusion criteria at enrollment: 
1. 
In the opinion of the investigator* or the subinvestigator, the patient is capable of understanding and 
complying with protocol requirements. 
*: A personnel taking part in conducting the study and presides over the study related activities 
within the belonging study site. 
2. 
A patient who can sign and date a written, informed consent form prior to the study enrollment. 
3. 
Patients aged ≥ 20 to < 75 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 who have measurable lesion (refer to Appendix A) according to Response Evaluation 


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Criteria in Solid Tumors (hereinafter referred to as RECIST) ver 1.1 
6. 
Patients with metastatic colorectal cancer refractory or intolerant* to chemotherapy including 
fluropyrimidines, oxaliplatin, irinotecan and angiogenesis inhibitors (bevacizumab, aflibercept, 
ramycirumab, etc.) 
*: Refractory or intolerant if applicable to any of the following 
1) If recurrence is observed during supportive chemotherapy before or after surgery or from imaging 
diagnosis within 6 months of completion. 
2) If imaging or clinical progression is observed during or within 3 months from the last 
administration of chemotherapy for advanced cancer  
3) When it is determined that resumption is not possible due to intolerable adverse event (serious 
allergic reaction, accumulative neuropathy, etc.) 
7. 
Patients classified as KRAS/NRAS wild-type** by KRAS/NRAS testing*. 
*: KRAS/NRAS test will be performed using 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 may receive oral administration 
9. 
Patients who satisfy the following criteria for the major organ function in tests performed within two 
weeks (14 days) prior to enrollment. 
(1) Neutrophil count 1.5 × 103/L 
(2) Platelet count 10.0 × 104/L 
(3) Hemoglobin 8.0 g/dL 
(4) Total blood bilirubin 1.5 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 
10. Eastern Cooperative Oncology Group (hereinafter referred to as ECOG) performance status (P.S.) 
has been determined as 0-1. 
11. Life expectancy of 3 months (90 days) after enrollment. 


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Exclusion criteria at enrollment: 
1. 
Patients who have treatment history of anti-EGFR antibody drugs (cetuximab, panitumumab), 
regorafenib and TAS-102 
2. 
Patients who have received radiotherapy and chemotherapy for primary disease as previous 
treatment and ≥ 2 weeks (14 days) have not passed since the last treatment at scheduled start day of 
treatment. However, excluding therapy received for pain relief of bone metastasis site 
3. 
Patients with known brain metastasis or strongly suspected of brain metastasis 
4. 
Patients with synchronous cancers or metachronous cancers with a disease-free period of 5 years 
(excluding colorectal cancer) However, excluding mucosal cancers cured or be possibly cured by 
regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder 
cancer, etc.) 
5. 
Patients with body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, 
etc.) 
6. 
Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant 
or breast-feeding, or test positive for pregnancy 
7. 
Patients who have received other study drugs and ≥ 4 weeks (28 days) have not passed since at 
scheduled start day of treatment. 
8. 
Patients with disease requiring systemic steroids for treatment (excluding topical steroids) 
9. 
Patients with history or obvious and extensive computerized tomography (CT) findings of interstitial 
pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) 
10. Patients with serious concurrent medical condition (intestinal paralysis, gastrointestinal obstruction, 
intestinal obstruction, uncontrollable diarrhoea, diabetes mellitus being treated with continuous use 
of insulin or that is difficult to control, renal failure, hepatic failure, psychiatric disorder, 
cerebrovascular disorder, gastrointestinal ulceration requiring blood transfusion) 
11. Patients with serious drug hypersensitivity (excluding allergic reaction to oxaliplatin) 
12. Patients with local or systemic active infection requiring treatment, or fever indicating infection 
13. Patients with heart failure or serious heart disease of class II by New York Heart Association 
(NYHA). 
14. Patients with active hepatitis B 
15. Patients with known HIV infection 
16. Patients who have adverse event from previous treatment that has not recovered to at least Grade 1 
(Grade 2 for peripheral sensory neuropathy) by CTCAE, Japanese edition JCOG version v4.03) 
(excluding hemoglobin content) 
17. Patients with known BRAF mutation. 
18. 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) 
Primary endpoint for phase I part:  
Primary endpoint: 


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Incidence of DLT in panitumumab treatment in combination with TAS-102 
Endpoints for phase II part: 
(Regarding efficacy and other endpoints, subjects who have received RD in the phase I part will also be 
included) 
Primary endpoint: 
Efficacy 
Progression-free survival rate at 6 months (PFS rate) 
Secondary endpoints: 
Safety 
Percentage of subjects with adverse events 
Efficacy 
Overall survival (OS) 
Progression-free survival (PFS) 
Response rate (RR) 
Duration of response (DOR) 
Disease control rate (DCR) 
Time to treatment failure (TTF) 
Additional endpoints: 
Follow-up therapy and its rate 
Statistical method: 
In the phase I part, incidence of DLT will be assessed in DLT assessment study population. 
The primary objective for phase II part is to explore the additional effect on PFS rate in panitumumab 
monotherapy when TAS-102 is used in combination with PFS rate at 6 months as primary endpoint. 
PFS rate at 6 months is the crude rate of subjects who survived or were not determined as progressive at 6 
months from the day of enrollment. Based on the observed PSF rate at 6 months from the day of 
enrollment, binomial test will be conducted on the null hypothesis “value will be determined invalid at 
PSF rate ≤ 29%”. Significant level will be 2.5% (one-sided) in main analysis. For interval estimation, 
accurate 90% confidence interval (two-sided) based on binomial distribution will be used. 
PFS is the period from the day of enrollment until the day of documented progression or the day of death 
due to all causes whichever comes earlier. Kaplan-Meier method will be used to illustrate progression 
free curve and quantile point and its 95% confidence interval (two-sided) of PFS will be calculated. 
Rationale for planned number of subjects: 
In the phase I part for the assessment of tolerability, 6 to 12 subjects were included according to the 


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“Guidelines for clinical evaluation methods of anti-cancer drugs” (PFSB/ELD notification No. 1101001, 
01/Nov/2005). 
Also, in the phase II part as efficacy will be assessed on PSF rate at 6 months as primary endpoint, 
according to the above guideline and precedent overseas clinical trial results, number of subjects were set 
as to confirm the expected PFS rate to overwhelm the PFS rate threshold. 
In the panitumumab monotherapy vs. best supportive care (BSC) as third-line treatment control trial in 
patients with unresectable, advanced/recurrent colorectal cancer (trial 20020408), the PFS median, the 
primary endpoint, were 8.0 weeks for the panitumumab group and 7.3 weeks for the BSC group. In 
retrospectively conducted KRAS wild-type population and KRAS/NRAS wild-type population, PFS 
median were 12.3 weeks and 14.1 weeks respectively in the panitumumab group. On the other hand, in 
the panitumumab monotherapy vs. cetuximab monotherapy control study (ASPECCT study) in patients 
with KRAS wild-type unresectable, advanced/recurrent colorectal cancer that became resistant to 
fluoropyrimidine agents, OXA, and IRI, the secondary endpoint PFS were 4.1 months for panitumumab 
and 4.4 months for cetuximab and showed no difference (hazard ratio [HR], 1.00; two-sided 95% 
confidence interval [CI], 0.88–1.14). Further, PFS rate at 6 months was 33% (two-sided 95% CI, 29% to 
37%) for the panitumumab group. 
 
On the other hand, for TAS-102, in the domestic phase II study in previously treated subjects with 
unresectable, advanced/recurrent colorectal cancer refractory or intolerant to fluoropyrimidine agents, 
OXA, and IRI and has treatment history of 2 regimens of standard chemotherapy, the secondary endpoint 
PFS median assessed by the Investigator were 1.0 months in the placebo group but significantly 
prolonged to 2.7 months in the TAS-102 group (HR = 0.35, two-sided 95% CI 0.25 to 0.50, p<0.0001). 
As increased anti-tumor effect can be expected by using TAS-102 in combination with panitumumab 
treatment which is the standard treatment for patients with unresectable, advanced/recurrent colorectal 
cancer, the PFS rate at 6 months in this study was assumed to be 48% and this was set as the expected 
PFS rate at 6 month in panitumumab arm is: 33% (95% CI: 29% - 37%) 


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value for the panitumumab treatment in combination with TAS-102 therapy in patients with RAS 
wild-type unresectable, advanced/recurrent colorectal cancer. Also, for the threshold where further testing 
for panitumumab treatment in combination with TAS-102 may be considered not necessary, it was 
assumed to be 29% from the CI lower limit of the PFS rate at 6 months in the ASPECCT study. 
For the main analysis, based on the observed PSF rate at 6 months from start of treatment, binomial test 
will be conducted on the null hypothesis “the true PSF rate at 6 months from start of treatment will be not 
more than the PFS threshold rate where value is determined invalid”. With the PFS threshold rate at 29%, 
PFS expected rate at 48% at 6 months from start of treatment, and one-sided significant level at 5.0%, 
power at 80%, the necessary number of subjects will be 47. Taking into consideration of ineligible or 
discontinued subjects at approximately 10%, the target number of subjects was set to 52 (including 
subjects that received RD in the phase I part). 
Study period: 
Total study period: November 2015 to December 2017 (26 months) 
Enrollment period: November 2015 to December 2016 (14 months) 
Follow-up period: 12 months after completion of enrollment 
 


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3.0 
LIST OF ABBREVIATIONS 
List of 
Abbreviations 
Unabbreviated expression 
5-FU 
fluorouracil 
ALT 
ALanine aminoTransferase 
AST 
ASpartate aminoTransferase 
BSC 
Best Supportive Care 
COI 
Conflict of Interest 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for 
Adverse Events 
DCR 
Disease Control Rate 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
FTD 
Trifluridine 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
HBs 
Hepatitis B surface 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on 
Harmonization 
IRI 
IRInotecan 
JCOG 
Japan Clinical Oncology Group 
KRAS 
Kirsten rat Sarcoma-2 virus 
l-LV 
Levofolinate calcium 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
MTD 
Maximum Tolerated Dose 
NRAS 
Neuroblastoma Rat Sarcoma 
NYHA 
New York Heart Association 
OS 
Overall Survival 
OXA 
OXAliplatin 


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List of 
Abbreviations 
Unabbreviated expression 
Unequivocal 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PR 
Partial Response 
P.S. 
Serformance Status 
RAS 
RAt Sarcoma 
RD 
Recommended Dose 
RECIST 
Response Evaluation Criteria In Solid 
Tumors 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOP 
Standard Operating Procedures 
TPI 
Tipiracil hydrochloride 
TEAE 
Treatment-Emergent Adverse Event 
TTF 
Time to Treatment Failure 
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 2014,” 1) and “Site-specific Cancer Prevalence” in 2010 in Japan, 
colon cancer was the third most prevalent cancer in men (14.5%) and the second in women (15.1%). 
According to “Site-specific Cancer Deaths (2013),” in men, lung cancer was the leading cause of 
cancer death (accounting for 24.0% of cancer deaths), followed by gastric cancer (14.7%) and 
hepatic cancer (9.1%); colorectal cancer (colon cancer and rectal cancer combined) accounted for 
11.9% of cancer deaths which exceeded the death rate of hepatic cancer, representing that colorectal 
cancer is the third leading cause of cancer death. In women, lung cancer (14.0%) was also the 
leading cause of cancer death, followed by gastric cancer (11.3%) and colon cancer (10.0%); deaths 
from colorectal cancer (colon cancer and rectal cancer combined) accounted for 14.9% of cancer 
deaths, representing that colorectal cancer is the first leading cause of cancer death. 
 
4.1.2 Standard treatment for colon cancer 
The “Guidelines for Treatment of Colorectal Cancer (2014)”2) classify the standard treatment of 
colorectal cancer according to staging as follows: endoscopic resection for Stage 0, in which the 
lesion is limited in the mucosa; Surgical resection for Stage I to III with postoperative adjuvant 
chemotherapy for Stage II which is at high risk or 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 treatment 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 or bevacizumab or CapeOX (XELOX) therapy + bevacizumab*1 
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 (XELOX) therapy: combination chemotherapy with capecitabine and OXA 
2. 
FOLFIRI therapy + bevacizumab*1 
FOLFIRI therapy: combination chemotherapy with 5-FU, l-LV and irinotecan (hereinafter 
referred to as IRI) 
3. 
FOLFOX therapy + cetuximab*1, 2 or panitumumab*1, 2 
4. 
FOLFIRI therapy + cetuximab*1, 2 or panitumumab*1, 2 


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5. 
FOLFOXIRI therapy FOLFOXIRI therapy: combination chemotherapy with OXA, IRI, 5-FU 
and l-LV 
6. 
FL*3 or Capecitabine+ bevacizumab*1 or UFT + l-LV 
UFT: combination preparation of tegafur and uracil 
*1:  Combination with molecular-targeted drugs such as bevacizumab or anti-epidermal 
growth factor receptor (hereinafter referred to as EGFR) antibody is recommended, but if 
it is not an indication mono-chemotherapy will be conducted. 
*2:  Indication only for KRAS wild-type 
*3:  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 of patients who have received an OXA-based regimen as a first-line treatment, while 
OXA-based regimens are recommended for patients who have received an IRI-based regimen. This 
principle also applies to molecular-targeted drugs concomitantly used for second-line treatment. For 
KRAS wild-type colorectal cancer, bevacizumab is recommended as a second-line treatment of 
patients who have received an anti-EGFR antibody as a first-line treatment, while switching to an 
anti-EGFR antibody or continued use of bevacizumab is an option as a second-line treatment of 
patients who have received bevacizumab as a first-line treatment. Regimens that can be used for 
second-line treatment are as follows. 
1. 
If subject becomes resistant to regimen including OXA 
1) FOLFIRI ± bevacizumab or IRI alone or IRI + S-1 (IRIS) 
2) FOLFIRI (or IRI alone) + cetuximab or panitumumab (KRAS wild-type) 
2. 
If subject becomes resistant to regimen including IRI 
1) FOLFOX or CapeOX (XELOX) ± bevacizumab 
3. 
If patient becomes resistant to regimen including fluropyrimidines, OXA, IRI 
1) IRI + cetuximab or panitumumab (KRAS wild-type) 
2) Cetuximab or panitumumab monotherapy (KRAS wild-type) 
For third-line treatment and onwards, IRI + cetuximab or panitumumab combination therapy (KRAS 
wild-type) and cetuximab or panitumumab monotherapy (KRAS wild-type), and regorafenib 
monotherapy, TAS-102 monotherapy or symptomatic therapies are currently recommended. 


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4.1.3 Efficacy and safety of panitumumab in patients with unresectable, 
advanced/recurrent colorectal cancer 
4.1.3.1 Panitumumab 
EGFR is a member of the ErbB family of transmembrane receptor tyrosine kinases constantly 
expressed in epithelial-derived tissues, has been shown to be overexpressed in various types of solid 
tumors. Colorectal cancer is characterized by high EGFR expression, and the EGFR signaling 
pathway has been shown to play in the pathogenesis and progression of tumors. Binding of 
epidermal growth factor (hereinafter referred to as EGF), the major ligand of EGFR, to EGFR is 
considered to induce auto-phosphorylation of EGFR and activation of various signaling pathways, 
resulting in induction of cellular proliferation, inhibition of apoptosis, and increased production of 
inflammatory cytokines and angiogenesis factors. Panitumumab is a human IgG2 monoclonal 
antibody that binds to EGFR with specificity and high affinity, and inhibits the proliferation of tumor 
cells by competitively inhibiting the binding of the ligand to EGFR3). 
4.1.3.2 Clinical study results for panitumumab in the U.S. and Europe 
As a clinical trial of panitumumab monotherapy for colorectal cancer, a phase III study was 
conducted to compare best supportive care (hereinafter referred to as BSC) vs. BSC + panitumumab 
therapy in patients with unresectable, recurrent/advanced, EGFR-positive colorectal cancer that 
became resistant to fluoropyrimidine agents, OXA, and IRI (BSC group, 232 patients; BSC + 
panitumumab group, 231 patients)4). The median of the primary endpoint of progression free 
survival (hereinafter referred to as PFS) with BSC alone at 7.3 weeks, whereas with BSC + 
panitumumab therapy at 8weeks, significantly longer than that of BSC, showed 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 primarily due to the fact 
that 173 subjects (75%) in the BSC group received follow-up therapy with panitumumab. Also, a 
phase III randomized control study comparing cetuximab monotherapy and panitumumab 
monotherapy in patients with KRAS wild-type unresectable, recurrent/advanced colorectal cancer 
(anti-EGFR antibody untreated) after they became resistant to fluoropyrimidine agents, OXA, and 
IRI has been reported (ASPECCT study).17) In this study, the median of OS which is the primary 
endpoint was 10.4 months for the panitumumab group (499 subjects) compared to 10.0 months for 
cetuximab group (500 subjects) and this indicated that panitumumab is non-inferior to cetuximab 
(HR = 0.97, two-sided 95% CI 0.84 to 1.11) PFS which is the secondary endpoint were 4.1 months 
for panitumumab group and 4.4 months for cetuximab group and showed no difference (HR = 1.00, 
two-sided 95% CI 0.88 to 1.14). 


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With regard to clinical study of combination of chemotherapy and panitumumab, a phase III clinical 
study (PRIME Study) has been reported, in which FOLFOX4 monotherapy vs. FOLFOX4 therapy + 
panitumumab (given at a dose of 6 mg/kg every 2 weeks) as a first-line treatment was compared in a 
total of 1,183 patients (593 in monotherapy group, 590 in panitumumab group)5). The primary 
endpoint of median PFS in KRAS wild-type patients was 9.6 months and significantly longer in the 
FOLFOX4 + panitumumab group as compared with 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, diarrhoea, and hypomagnesaemia 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 2 
patients (Table 4.a). 
Table 4.a Grade 3/4 adverse events reported in KRAS wild-type patients in the PRIME study 
Adverse event 
FOLFOX4 + panitumumab 
(n = 322) 
FOLFOX4 alone 
(n = 327) 
n 
% 
n 
% 
Any adverse drug 
reaction 
270 
84 
227 
69 
Leukopenia 
136 
42 
134 
41 
Skin disorder 
116 
36 
7 
2 
Diarrhoea 
59 
18 
29 
9 
Nerve disorder 
52 
16 
51 
16 
Hypokalaemia 
32 
10 
15 
5 
Malaise 
30 
9 
10 
3 
Stomatitis 
28 
9 
2 
< 1 
Hypomagnesaemia 
20 
8 
1 
< 1 
Paronychia 
11 
3 
0 
0 
Pulmonary embolism 
9 
3 
5 
2 
Febrile neutropenia 
8 
2 
7 
2 
infusion reaction 
2 
< 1 
- 
- 
 
With regard to second-line treatment, a phase III clinical study (Study 20050181) has been 
conducted, in which FOLFIRI monotherapy vs. FOLFIRI therapy + panitumumab (given at a dose 
of 6 mg/kg every 2 weeks) was compared6). The primary endpoints were PFS and OS in KRAS 
wild-type patients. In KRAS wild-type patients, 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, the OS median were 12.5 months in the 
FOLFIRI alone group and 14.5 months in the FOLFIRI + panitumumab group (HR = 0.85, 
two-sided 95% CI 0.70 to 1.04, p=0.12) and showed no significant difference. The response rate 


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(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 diarrhoea and hypomagnesaemia 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 Study5) and Study 200501816) described above, in which the presence/absence of 
KRAS 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. 
4.1.3.3 Clinical study results for panitumumab in Japan 
In a Japanese phase I clinical study of panitumumab, panitumumab was administered at the same 
dosing regimens with which the drug was confirmed to be safe and effective in overseas studies; i.e., 
a dose of 2.5 mg/kg once weekly, 6 mg/kg once every 2 weeks, and 9 mg/kg once every 3 weeks. 
Each of these dosing regimens was evaluated in 6 patients, and tolerance was ratified in overseas 
clinical trial. 
In a Japanese phase II clinical study of panitumumab monotherapy, 7) 52 patients with previously 
treated, unresectable colorectal cancer were enrolled. In this study, the 6 mg/kg biweekly regimen of 
panitumumab, which was the recommended dosing regimen in the overseas phase III clinical study, 
was well tolerated, and the incidence of adverse events was similar to that observed in the U.S. and 
Europe (Table 4.b). In addition, 7 patients (13.5%) had partial response (hereinafter referred to as 
PR), and this Japanese study yielded an RR of 13.5% (two-sided 95% CI: 5.6 to 25.8),a time to 
treatment failure of 11.4 weeks (two-sided 95% CI: 8.4 to 15.0), a 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 U.S and Europe. 
On the basis of the above results, panitumumab was approved in April 2010 for the treatment of 
unresectable, advanced/recurrent colorectal cancer in Japan as well. 
Table 4.b Common adverse events (≥ 20%) noted in a Japanese phase II clinical study of 
Panitumumab monotherapy 
Adverse event 
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 


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Adverse event 
Panitumumab Monotherapy (n = 52) 
Any Grade 
Grade 3 or higher 
n 
% 
n 
% 
Acne 
42 
81 
1 
2 
Dry skin 
32 
62 
0 
 
Skin rash 
24 
46 
1 
2 
Pruritus 
17 
33 
0 
 
Paronychia 
17 
33 
1 
2 
Hypomagnesaemia 
17 
33 
0 
0 
Malaise 
13 
25 
0 
0 
Stomatitis 
12 
23 
0 
0 
Anorexia 
11 
21 
1 
2 
 
4.1.3.4 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, 8) the median of treatment period (first day of treatment to the final day of treatment) for 
the 3,085 patients who were subject to safety evaluation was 113 days (range: 1 to 559 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), 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. 
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) 
Any Grade 
Grade 3 or 
higher 
Any Grade 
Grade 3 or 
higher 
Intensively investigated 
item 
n 
% 
n 
% 
n 
% 
n 
% 
Skin & subcutaneous tissue 
disorders (SOC) 
918 
73.2 
118 
9.4 
1446 
79.0 
274 
15.0 
Paronychia 
272 
21.7 
33 
2.6 
459 
25.1 
99 
5.4 
Interstitial lung disease* 
16 
1.3 
- 
- 
23 
1.3 
- 
- 
Infusion reaction 
17 
1.4 
1 
0.1 
30 
1.6 
5 
0.3 
Hypomagnesaemia 
257 
20.5 
61 
4.9 
263 
14.4 
62 
3.4 
Hypocalcaemia 
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 


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4.1.4 Efficacy and safety of TAS-102 for unresectable, advanced/recurrent 
colorectal cancer 
4.1.4.1 TAS-102 
TAS-102 is a new nucleoside anticancer agent formulated with trifluridine (FTD) and tipiracil (TPI) 
prepared at a molar ratio of 1 : 0.5. FTD is an anticancer active ingredient of TAS-102 and TPI is an 
inhibitor specific to thymidine phosphorylase (TPase) which is a FTD decomposing enzyme.9) FTD 
will show anti-tumor effect when administered orally and taken in by DNA, while on the other hand, 
FTD will be metabolized promptly through first-pass effect of oral administration. Therefore, in 
order to have FTD taken in by DNA efficiently, it is necessary to inhibit TPase that engages in 
metabolizing FTD and it is necessary to administer FTD in combination with TPI. In the non-clinical 
study, in a nude mouse subcutaneously implanted with human tumor-derived cell line, as the FTD 
amount taken in DNA and tumor proliferation inhibitory effect had correlated it was presumed that 
tumor proliferation inhibitory effect of TAS-102 is based on FTD and tumor proliferation inhibitory 
effect shows effectiveness when FTD is taken in by DNA. Also, when FTD alone is orally given to 
monkies, FTD could hardly be observed in blood, whereas in combination with TPI that inhibits 
TPase which is a FTD decomposing enzyme, FTD blood concentration was maintained. 
4.1.4.2 Clinical study results for TAS-102 
In Japan, after the phase I study in patients with solid tumors (J001 study) had been conducted, a 
phase II control study (J003 study) with OS as primary endpoint and PFS, DCR, etc. as secondary 
endpoints and the objective of assessing the superiority of TAS-102 group over placebo group in 
patients (number of safety assessed subjects: TAS-102 group 113, placebo group 57, efficacy 
assessed: TAS-102 group 112, placebo group 57) that have received previous treatment of 2 
regimens including fluoropyrimidine agents, OXA, and IRI and with refractory or intolerant, 
unresectable, advanced/recurrent colorectal cancer was conducted. 10) TAS-102 was given 35 
mg/m2/dose orally twice daily for 5 consecutive days, followed by 2 days of washout and after this 
was repeated twice, 14 days washout was implemented. As a result, OS prolongation was observed 
in the TAS-102 group compared to the placebo group. In the TAS-102 group, the OS median was 
9.0 months, and by independent diagnostic imaging organization PFS median was 2.0 months, DCR 
was 43.8% (49/112 subjects).Common adverse events (occurrence 10%) noted in Japanese clinical 
study in 119* subjects are shown in Table 4.d. 
*: 6 subjects who were given the same dosage and regimen as the J003 study in the Japanese phase I 
study (J001 study) were added to the 113 subjects of the Japanese phase II study (J003 study) 


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Table 4.d Common adverse events (occurrence 10%) noted in Japanese clinical study 
Adverse event 
Any Grades 
(n = 119) 
Grade 3 or 
higher 
(n = 119) 
n 
% 
n 
% 
Hematocrit decreased 
34 
28.6 
1 
0.8 
Haemoglobin decreased 
76 
63.9 
22 
18.5 
Lymphocyte count 
decreased 
40 
33.6 
13 
10.9 
Neutrophil count decreased 
87 
73.1 
61 
51.3 
Platelet count decreased 
49 
41.2 
5 
4.2 
Red blood cell count 
decreased 
38 
31.9 
1 
0.8 
White blood cell count 
decreased 
91 
76.5 
36 
30.3 
Diarrhoea 
40 
33.6 
6 
5.0 
Nausea 
75 
63.0 
3 
2.5 
Stomatitis 
18 
15.1 
- 
- 
Vomiting 
34 
28.6 
3 
2.5 
Fatigue 
63 
52.9 
7 
5.9 
Blood albumin decreased 
13 
10.9 
- 
- 
Blood bilirubin increased 
23 
19.3 
1 
0.8 
Weight decreased 
14 
11.8 
- 
- 
Protein urine present 
14 
11.8 
- 
- 
Decreased appetite 
66 
55.5 
3 
2.5 
On the other hand, a phase III global study (RECOURSE study) with OS as primary endpoint and 
PFS, DCR, etc. as secondary endpoints and the objective of assessing the superiority of TAS-102 
over placebo in patients (number of safety assessed subjects: TAS-102 group 533, placebo group 
265, efficacy assessed: TAS-102 group 534, placebo group 266) that have received previous 
chemotherapy of 2 regimens and with refractory or intolerant to fluoropyrimidine agents, IRI,OXA, 
bevacizumab and anti-EGF-R antibody agents (KRAS wild-type), unresectable, advanced/recurrent 
colorectal cancer, was conducted.11) As a result, OS significantly prolonged in the TAS-102 group 
compared to placebo group. In the TAS-102 group, the OS median was 7.1 months, and by 
independent diagnostic imaging organization PFS median was 2.0 months, DCR was 44% (221/502 
subjects). 
Common adverse events (occurrence 10%) noted in the phase III global clinical study in 533 
subjects are shown in Table 4.e. 


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Table 4.e Common adverse events (occurrence 10%) noted in the phase III global clinical study 
Adverse event 
Any Grades 
(n = 533) 
Grade 3 or 
higher 
(n = 533) 
n 
% 
n 
% 
Aneamia 
168 
31.5 
65 
12.2 
Neutropenias 
153 
28.7 
107 
20.1 
Neutrophil count decreased 
145 
27.2 
83 
15.6 
White blood cell count 
decreased 
140 
26.3 
52 
9.8 
Platelet count decreased 
77 
14.4 
13 
2.4 
Diarrhoea 
126 
23.6 
12 
2.3 
Nausea 
210 
394 
5 
0.9 
Asthenia 
58 
10.9 
9 
1.7 
Fatigue 
132 
24.8 
11 
2.1 
Decreased appetite 
141 
26.5 
9 
1.7 
Regarding combination of TAS-102 and antibody drugs, a phase I/II study in combination with 
bevacizumab was conducted in Japan. 12) Patients with colorectal cancer refractory/intolerant to 
anticancer agent therapies including 5-FU, OXA, IRI, and anti VEGF inhibitors (bevacizumab, etc.), 
anti EGFR antibody agents (in cases of RAS wild-type) and has no treatment history of regorafenib 
and TAS-102, and DLT was not observed in the phase I part (6 subjects), RD was determined at 35 
mg/m2 of TAS-102 given twice daily and 5 mg/day of bevacizumab. For efficacy, 21 subjects (total 
from phase I part and phase II part) were analyzed and PFS at week 16 was 42.9%. Also, from the 
assessment by the attending physician PFS median was 24.1 weeks, DCR was 72%. Neutropenia as 
drug related adverse event (Grade 3: 56%, Grade 4: 12%), leukopenia (Grade 3: 40%), febrile 
neutropenia (Grade 3: 16%) were many but no study related deaths. In 17 subjects (68%) start of 
treatment was delayed, in 6 subjects (24%) dose reduction of TAS-102 was necessary, many of the 
causes were neutrophenia. Therefore, tolerance and efficacy has been observed in combination 
therapy with TAS-102 and bevacizumab for unresectable, advanced/recurrent colorectal cancer after 
becoming refractory to standard treatment. 
4.1.5 RAS (KRAS/NRAS) mutation and panitumumab in unresectable, 
advanced/recurrent colorectal cancer 
In a phase III randomized control study (Study 200404084)) of panitumumab monotherapy that 
investigated its efficacy as a third-line treatment in patients with unresectable, advanced/recurrent 
colorectal cancer after receiving standard treatment, the enrolled subjects were analyzed for the 
relationship of 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) in the 


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tumor using 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), the PFS median was 14.1 weeks and significantly prolonged by 7.1 weeks in the 
panitumumab combination group as compared with 7.0 weeks in the BSC group (HR = 0.36, two 
sided 95% CI 0.25 to 0.52, p<0.001). On the other hand, in patients with RAS mutation (KRAS or 
NRAS mutation), the median PFS was 7.3 weeks in the BSC group as compared with 7.4 weeks in 
the panitumumab combination group and did not show significant difference. (HR = 0.97, two sided 
95% CI 0.73 to 1.29). 13) 
Among the patients enrolled in the PRIME study, were analyzed for the relationship of the presence 
or absence of mutations in the genes of KRAS exons 2, 3, 4, NRAS exons 2, 3, 4, and BRAF exon 15 
(codon 600) with PFS and OS. 5) In patients with RAS wild-type, the OS median was 25.8 months 
and significantly prolonged by 5.6 month in the FOLFOX4 + panitumumab group as compared with 
20.2 months in the FOLFOX4 alone group (HR = 0.77, two sided 95% CI 0.64 to 0.94, p = 0.009). 
On the other hand, in patients with RAS mutation, the OS median was 15.5 months and significantly 
shorter in the FOLFOX4 + panitumumab group as compared with 18.7 months in the FOLFOX4 
alone group (HR = 1.21, two sided 95% CI 1.01 to 1.45, p = 0.04). 14) 
Also, in addition to the above studies, patients with KRAS (exons 3 and 4) and NRAS (exons 2, 3 and 
4) mutations other than KRAS exon 2 showing ineffectiveness to anti-EGFR antibody drugs in 
several post hoc analysis has been reported, 15)and for patients determined as having wild-types and 
currently measuring KRAS exon 2 only, it has been recognized that presence/absence of other RAS 
(KRAS/NRAS, hereinafter referred to as RAS) mutations should be added, and “Guidance for 
measuring RAS (KRAS/NRAS) mutations in colorectal cancer patients” 16) has been published from 
Japanese Society of Medical Oncology. 
 
4.2 
Rationale for the proposed study 
For the treatment of KRAS wild-type, unresectable, advanced/recurrent colorectal cancer it is 
recommended to use molecular target drugs of either anti-VEGF antibody agents or anti-EGFR 
antibody agents in combination with FOLFOX or FOLFIRI treatment. OXA combination treatment 
+ anti-VEGF antibody agent for first-line treatment, and if IRI + anti-VEGF antibody agent is used 
in second-line treatment, anti-EGFR antibody agents alone based on the results from 20020408 
study4) or ASPECCT study17), or IRI + anti-EGFR antibody agents based on results from BOND 
study18) or GERCOR study19), etc. for third-line treatment is used often. 
Combination therapy with anti-EGFR antibody agents and chemotherapy has shown that it also has 
antitumor effect in patients that have become resistant to chemotherapy. In the BOND study in 


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which cetuximab alone group and cetuximab + IRI combination group were compared in patients 
with colorectal cancer that have become resistant to IRI, in spite of the fact that the patient group had 
already been IRI resistant, it has been reported that cetuximab + IRI combination group had superior 
antitumor effect and PFS (for RR, cetuximab + IRI combination group was 22.9% [two-sided 95% 
CI 17.5 to 29.1%], IRI group was 10.8% [two-sided 95% CI 5.7 to 18.1%], P=0.007; for PFS, 
cetuximab + IRI combination group was 4.1 months, IRI group was 1.5 months, P<0.001 by the 
log-rank test). 18) Also in the phase II GERCOR study19) where panitumumab and IRI combination 
therapy was used in patients with colorectal cancer refractory to standard treatment, in spite of the 
fact that it included patients that had already become IRI resistant, anti-tumor effect was observed 
with combination use of panitumumab and IRI, and indicated that panitumumab and IRI 
combination therapy was a superior treatment than that of panitumumab monotherapy (PFS median 
in KRAS wild-type was 6.3 months, 95% CI 3.7 to 8.7). 
As indicated in Section 4.1.4.2, regarding combination use of TAS-102 and antibody agents, 
tolerance and efficacy has been observed with TAS-102 and bevacizumab combination therapy in 
patients with unresectable, advanced/recurrent colorectal cancer after being refractory to standard 
treatment. For combination use of panitumumab and TAS-102, currently there is no clinical data that 
would confirm its efficacy, while in non-clinical studies in vitro tests show anti-tumor effect 
increases by combination use of FTD which is the active component of TAS-102 and panitumumab 
compared to using them alone in KRAS wild-type colorectal cancer cell strain (Figure 4.a, in-house 
data). 
 
Figure 4.a Anti-tumor effect from combination use of FTD and panitumumab in KRAS wild-type 
colorectal cancer cell strain (SW48 and LIM1215, both are KRAS/BRAF wild type) 
In a colorectal cancer cell strain trans planted mouse model, it was indicated that a higher anti-tumor 
effect may be obtained with combination use of panitumumab and TAS-102 compared to preparing 
them alone, and also weight decrease, etc. or increase of other toxicities have not been observed. 20) 
Although the mechanism of action is not known for this combination use effect, from the in vitro test 
lo g  F T D  c o n c .[M ]
%  o f C o n tro l
-9
-8
-7
-6
-5
-4
0
5 0
1 0 0
1 5 0
SW48
LIM1215
パニツムマブ
7.81 ng/mL
コントロール
パニツムマブ
31.3 ng/mL
パニツムマブ
125 ng/mL
パニツムマブ
500 ng/mL
パニツムマブ
コントロール
パニツムマブ
パニツムマブ
パニツムマブ
0.78 ng/mL
3.13 ng/mL
12.5 ng/mL
50.0 ng/mL
-8
FTDの濃度[log M]
% of Control
150 
100 
50 
0 
-7
-6
-5
-4
-3
FTDの濃度[log M]
% of Control
150 
100 
50 
-8
0 
-7
-6
-5
-4
-9
FTD concentration 
FTD concentration 
Control 
Panitumumab 
Panitumumab 
Panitumumab 
Panitumumab 
Control 
Panitumumab 
Panitumumab 
Panitumumab 
Panitumumab 


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using colorectal cancer cell strain, FTD which is an active component of TAS-102 activates the 
phosphorylation of EGFR and AKT or MAPK protein that is located downstream from EGFR, and 
also erlotinib which is a tyrosine kinases inhibitor showed synergy effect of inhabitation of cell 
proliferation by simultaneous action with FTD and also indicated that erlotinib down regulates 
phosphorylation of AKT or MAPK protein by FTD.21) From these reasons, it was considered that a 
higher effect may be expected from combination use of TAS-102 and panitumumab compared to 
using them alone. 
As mentioned earlier, for third-line treatment for colorectal cancer with treatment history of 
FOLFOX therapy or FOLFIRI therapy, taking in account of the results, etc. of the 20020408 study4) 
in which treatment with panitumumab alone and BSC were compared, the ASPECCT study17) in 
which panitumumab monotherapy and cetuximab monotherapy were compared, the NCIC CTG 
CO.17 study22) in which treatment with cetuximab alone and BSC were compared, the BOND 
study18) in which treatment groups of cetuximab alone and cetuximab and IRI combination use were 
compared and the GERCOR study19) in which effect of combination use of IRI + panitumumab was 
assessed, treatment with either cetuximab or panitumumab alone or combination use of IRI + 
cetuximab or IRI + panitumumab are recommended by the “Guidelines for Treatment of Colorectal 
Cancer (2014)”.2) Actually, for subjects who did not show serious adverse event in IRI among 
patients with treatment history with fluropyrimidines, IRI, OXA, it is expected that IRI + anti-EGFR 
antibody combination therapy will be a treatment option, although it has not been proven that IRI + 
anti-EGFR antibody combination therapy has longer survival period compared to cetuximab or 
panitumumab monotherapy. If panitumumab + TAS-102 combination therapy has higher 
effectiveness than anti-EGFR antibody monotherapy and similar effect as IRI + anti-EGFR antibody 
in the same patient group, there will be major benefits for the patient such as avoidance of adverse 
event in IRI. 
Comparison of adverse events in treatments with TAS-102 alone and panitumumab alone is shown 
in the table below. Adverse events for TAS-102 are from Japanese phase II study and for 
panitumumab are from Specified drug use surveillance results (all patients surveillance) in Japan, 
incidence of ≥ 10% has been extracted and presented Table 4.f and Table 4.g. As adverse events in 
both drugs do not hardly overlap besides stomatitis, and adverse events besides stomatitis from 
TAS-102 were all ≤ Grade 2, both drugs are considered usable in combination fairly safely. 


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Table 4.f Comparison of rate of adverse events 
in panitumumab alone among common adverse events (incident ≥ 10%) in treatments with TAS-102 
Common adverse events in 
TAS-102 
(incident ≥ 10%) 
TAS-102 
(n = 119) 
Panitumumab alone 
(n = 1254) 
n 
% 
n 
% 
Hematocrit decreased 
34 
28.6 
- 
- 
Haemoglobin decreased 
76 
63.9 
1 
0.1 
Lymphocyte count decreased 
40 
33.6 
0 
0 
Neutrophil count decreased 
87 
73.1 
0 
0 
Platelet count decreased 
49 
41.2 
4 
0.3 
Red blood cell count decreased 
38 
31.9 
- 
- 
White blood cell count decreased 
91 
76.5 
5 
0.4 
Diarrhoea 
40 
33.6 
24 
1.9 
Nausea 
75 
63.0 
9 
0.7 
Stomatitis 
18 
15.1 
123 
9.8 
Vomiting 
34 
28.6 
4 
0.3 
Fatigue 
63 
52.9 
9 
0.7 
Blood albumin decreased 
13 
10.9 
0 
0 
Blood bilirubin increased 
23 
19.3 
1 
0.1 
Weight decreased 
14 
11.8 
1 
0.1 
Protein urine present 
14 
11.8 
2 
0.2 
Decreased appetite 
66 
55.5 
25 
2.0 
Table 4.g Comparison of rate of adverse events 
in TAS-102 among common adverse events (incident ≥ 10%) in treatment with panitumumab alone 
Common adverse events in 
panitumumab alone 
(incident ≥ 10%) 
Panitumumab alone 
(n = 1254) 
TAS-102 
(n = 119) 
n 
% 
n 
% 
Paronychia 
272 
21.7 
1 
0.8 
Hypomagnesaemia 
223 
17.8 
- 
- 
Dermatitis acneiform 
619 
49.4 
- 
- 
Dry skin 
265 
21.1 
1 
0.8 
From the above, this study was planned as it was determined that assessment of recommended dose, 
efficacy and safety of panitumumab in combination with TAS-102 was necessary in RAS wild-type, 
unresectable, advanced/recurrent colorectal cancer. For combination therapy, panitumumab and 
TAS-102 were used as alone treatment and combined. Therefore, panitumumab will be given at a 
dose of 6 mg/kg every 2 weeks, TAS-102 will be given 35 mg/m2/dose for 5 consecutive days orally 
followed by 2 days of washout and after repeating this twice, 14 days of washout will be 
implemented and if safety is confirmed in the phase I part, the dosage and administration will be the 


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recommended dose for the combination therapy and the same dosage and administration will be 
adopted in the phase II part. If it is determined intolerable in the phase I part, continuation of study 
will be considered and dose reduction will be assessed when necessary. 


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5.0 
OBJECTIVE AND ENDPOINTS OF THE STUDY 
5.1 
Objective 
Phase I part 
To assess the recommended dose (RD) of panitumumab in combination with TAS-102 in patients 
with RAS wild-type, unresectable, advanced/recurrent colorectal cancer. 
Phase II part 
To assess the efficacy and safety of panitumumab in combination with TAS-102 in RAS wild-type, 
unresectable, advanced/recurrent colorectal cancer. 
 
5.2 
Definition of endpoints 
5.2.1 Definition of endpoints for phase I part 
Primary endpoint: 
Incidence of DLT in panitumumab treatment in combination with TAS-102 
 
5.2.2 Definition of endpoints for phase II part 
(Including subjects who received RD in phase I part) 
Primary endpoint: 
Efficacy 
Progression-free survival rate at 6 months (PFS rate) 
Secondary endpoints: 
Safety 
Percentage of subjects with adverse events 
Efficacy 
Overall survival (OS) 
Progression-free survival (PFS) 
Response rate (RR) 
Duration of response (DOR) 
Disease control rate (DCR) 
Time to treatment failure (TTF) 
Additional endpoints: 


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Follow-up therapy and its rate 
 
5.3 
Rationale for the endpoints 
5.3.1 Primary endpoint 
In the phase I part, incidence of DLT was set as primary endpoint to assess the tolerability and safety 
of panitumumab in combination with TAS-102 in patients with unresectable, advanced/recurrent 
colorectal cancer and determine RD. 
In the phase II part, PFS rate at 6 months was set as primary endpoint as an important criteria in 
assessing the efficacy of combination use of TAS-102 with panitumumab monotherapy in patients 
with unresectable, advanced/recurrent colorectal cancer. 
 
5.3.2 Secondary endpoints 
The OS, PFS, RR, DOR, DCR, and TTF were selected as the secondary endpoint, because they 
reflect the anti-tumor efficacy. In addition, adverse events were selected as the secondary endpoint, 
because safety is also an important factor in treatment selection in phase II part. 


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6.0 
CLINICAL STUDY DESIGN 
6.1 
Clinical study design 
This phase I/II study is a multi-center, open-label single-arm study that consists of a phase I part 
(dose de-escalation) which will assess the tolerability and RD of Panitumumab in combination with 
TAS-102 as primary objective, and a phase II part which will assess the efficacy and safety of 
Panitumumab in combination with TAS-102 as primary objective in patients with RAS wild-type 
unresectable, advanced/recurrent colorectal cancer. In the phase I part, the subjects will be included 
sequentially into Cohort 1 and 2, 3 subjects each with the same dosage and administration. In the 
phase II part, 46 subjects will be included additionally for RD confirmed in the phase I part. 
 
 
Figure 6.a Outline of study design 
In the phase I part, each cohort will be conducted with 3 subjects, the sponsor will assess tolerability 
of the dosage and administration based on the incidence of Dose Limiting Toxicity (hereinafter 
referred to as DLT) during the assessment period and determine whether or not to move on to the 
next cohort (opinion from the Data Monitoring Committee [hereinafter referred to as DMC] will be 
confirmed appropriately upon determination). Therefore, in Cohort 1, if occurrence of DLT is ≤ 2 
subjects out of 3, the dosage and administration will be determined tolerable and will move on to 
Cohort 2. However, if DLT is observed in 2 subjects during DLT assessment period in Cohort 1, 
subjects will be included one at a time in Cohort 2 in consideration for safety to assess DLT. 


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Similarly 3 subjects will be included in Cohort 2 and DLT will be assessed in a total of 6 subjects of 
Cohort 1 and 2 at most. If DLT is observed in 3 subjects included in Cohort 1, or DLT is observed in 
3 subjects from a total of 6 subjects of Cohort 1 and 2, the sponsor will promptly request to postpone 
new enrollment of subjects to each site and after consultation with the Research Steering Committee 
and DMC on the continuation of the study, will determine whether or not to continue the study. 
If study is to be continued, taking in account of the adverse event that occurred, either panitumumab 
or TAS-102 or both drugs will be reduced one step and re-conducting the phase I part similarly will 
be considered. If DLT is observed in 3 subjects after reducing 1 step of panitumumab or TAS-102 or 
both drugs, the study will be discontinued. 
If DLT is observed in ≤ 2 subjects from a total of 6 subjects of Cohort 1 and 2, the sponsor will 
comprehensively assess with the Research Steering Committee based on the safety data of the phase 
I part, and after confirming the opinion of DMC, will determine the transit to phase II part. 
In the phase II part, in addition to the 6 subjects who received RD dose in the phase I part, a target of 
46 subjects are to be accumulated (a total of 52 subjects). 
 
6.2 
Rationale for study design 
6.2.1 Study population 
Survival period for unresectable, advanced/recurrent colorectal cancer patients is approximately two 
and a half years and still prognostic is poor. Although systemic chemotherapy is used for 
unresectable cases as first-line treatment, recovery is difficult and PFS after initial chemotherapy is 
about one year, second-line chemotherapy PFS is about half a year, and in most cases third-line, 
fourth-line treatment is necessary. Therefore, this became the object of this clinical research as 
development of appropriate treatment for unresectable cases that have become refractory/intolerant 
to existing chemotherapy is an important issue. The patients should also be RAS wild-type, because 
the above mentioned analysis results in the PRIME study5) suggest that panitumumab may be the 
most effective in these patients. 
KRAS/NRAS test will be performed using the in vitro diagnostic that has been approved for 
marketing. 
 


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6.2.2 Treatment regimens and planned number of subjects 
6.2.2.1 Reasons for selecting panitumumab + TAS-102 combination therapy as the 
treatment regimen 
As described in Section 4.1.2, the following regimens using FOLFOX and FOLFIRI treatment and 
methods to use bevacizumab, panitumumab and cetuximab in combination, are shown in the 
Guidelines for Treatment of Colorectal Cancer (2014)2) as the first-line treatment and second-line 
treatment for patients with unresectable, advanced/recurrent colorectal cancer. 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. Further, if it becomes refractory or 
intolerant to these first-line treatment, FOLFIRI+ bevacizumab is used widely as second-line 
treatment (in-house document). Furthermore, if it becomes refractory or intolerant to these 
second-line treatments, the following regimens are for third-line treatment and onwards. 
1. 
Panitumumab monotherapy or cetuximab monotherapy 
2. 
IRI + panitumumab combination therapy or IRI + cetuximab combination therapy 
3. 
Regorafenib monotherapy 
4. 
TAS-102 monotherapy 
5. 
Symptomatic therapies 
On the other hand, from the results of  the  randomized, double blinded, placebo controlled 
comparative study (Japanese phase II control study) in which unresectable, advanced/recurrent 
colorectal cancer that have received previous treatment of 2 regimens including fluoropyrimidine 
agents, OXA, and IRI and became refractory or intolerant was assessed, and it was reported that 
overall survival prolonged significantly compared to placebo administration and TAS-102 obtained 
approval in March 2014 for “unresectable, advanced/recurrent colorectal cancer (restricted to where 
standard treatment is difficult)” as indication. Also, from the results of the phase III global study 
(RECOURSE study11)) in which colorectal cancer patients had no change to standard therapy, it was 
reported that overall survival prolonged significantly compared to placebo and TAS-102 has become 
one of the options for third-line treatment as indication was changed and approved to “unresectable, 
advanced/recurrent colorectal cancer” in March 2015. 
As mentioned in Section 4.2, anti-EGFR antibody agents and chemotherapy has shown that it also 
has anti-tumor effect in patients that have become resistant to chemotherapy. As for panitumumab 
and TAS-102 also, further anti-tumor effect can be expected from combination use. For combination 


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therapy to be assessed in this clinical research, panitumumab and TAS-102 were used as alone 
treatment and combined. Therefore, panitumumab will be given at a dose of 6 mg/kg every 2 weeks, 
TAS-102 will be given 35 mg/m2/dose for 5 consecutive days orally followed by 2 days of washout 
and after repeating this twice, 14 days of washout will be implemented and if safety and tolerability 
is confirmed, the dosage and administration will be the RD for the combination therapy. 
6.2.2.2 Rationale for planned number of subjects 
In the phase I part for the assessment of tolerability and RD of panitumumab and TAS-102 
combination therapy, 6 to 12 subjects were included according to the “Guidelines for clinical 
evaluation methods of anti-cancer drugs” (PFSB/ELD notification No. 1101001, 01/Nov/2005). 
Also, in this study as efficacy will be assessed on PFS rate as primary endpoint, according to the 
above guideline and precedent overseas clinical trial results, number of subjects were set as to 
confirm the expected PFS rate to overwhelm the PFS rate threshold. 
In the panitumumab monotherapy vs. BSC as third-line treatment control trial in patients with 
unresectable, advanced/recurrent colorectal cancer (20020408 study4)), the PFS median were 8.0 
weeks for the panitumumab group and 7.3 weeks for the BSC group. In retrospectively conducted 
KRAS wild-type population and KRAS/NRAS wild-type population, PFS median were 12.3 weeks 
and 14.1 weeks respectively in the panitumumab group. On the other hand, in the panitumumab 
monotherapy vs. cetuximab monotherapy control study (ASPECCT study) in patients with KRAS 
wild-type unresectable, advanced/recurrent colorectal cancer that became resistant to 
fluoropyrimidine agents, OXA, and IRI17), the secondary endpoint PFS were 4.1 months for 
panitumumab and 4.4 months for cetuximab and showed no difference (hazard ratio [HR], 1.00; 
two-sided 95% confidence interval [CI], 0.88–1.14).  Further, PFS rate at 6 months was 33% 
(two-sided 95% CI, 29% to 37%) for the panitumumab group. 


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Figure 6.b ASPECCT study Progression-free survival 
On the other hand, for TAS-102, in the domestic phase II study in previously treated subjects with 
metastatic, unresectable, colorectal cancer refractory or intolerant to fluoropyrimidine agents, OXA, 
and IRI, and has treatment history of 2 regimens of standard chemotherapy, the secondary endpoint 
PFS median assessed by the Investigator were 1.0 months in the placebo group but significantly 
prolonged to 2.7 months in the TAS-102 group (HR = 0.35, two-sided 95% CI 0.25–0.50, p<0.0001) 
As increased anti-tumor effect can be expected by using TAS-102 in combination with panitumumab 
treatment which is the standard treatment for patients with unresectable, advanced/recurrent 
colorectal cancer, the PFS rate at 6 months in this study was assumed to be 48% and this was set as 
the expected value for the panitumumab treatment in combination with TAS-102 therapy in patients 
with RAS wild-type unresectable, advanced/recurrent colorectal cancer. Also, for the threshold 
where further development for panitumumab treatment in combination with TAS-102 may be 
considered not necessary, it was assumed to be 29% from the CI lower limit of the PFS rate at 6 
months in the ASPECCT study. 17) 
For the main analysis, based on the observed PFS rate at 6 months from start of treatment, binomial 
test will be conducted on the null hypothesis “the true PFS rate at 6 months from start of treatment 
will be not more than the PFS threshold rate where value is determined invalid”. With the PFS 
threshold rate at 29%, PFS expected rate at 48% at 6 months from start of treatment, and one-sided 
significant level at 5%, power at 80%, the necessary number of subjects will be 47. Taking into 
consideration of ineligible or discontinued subjects at approximately 10%, the target number of 
subjects was set to 52 (including subjects that received RD in the phase I part). 
PFS rate at 6 month in panitumumab arm is: 33% (95% CI: 29% - 37%) 


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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 sponsor should immediately discontinue the study when at least one of the following criteria is 
applicable. 
 
When new information or other evaluation on the safety or efficacy of protocol treatment 
becomes available which shows a change in the known risk/benefit profile of the concerned 
compound, and risks/benefits are no longer tolerable for subject participation in the study. 
 
When suspension or discontinuation of the clinical study is notified by the DMC. 
 
Occurrence of serious violation of Ethical Guideline for Clinical Research or ICH-GCP which 
may endangers safety of subjects. 
 
6.3.2 Criteria for discontinuation of clinical study at a study site 
A study site may be notified to discontinue clinical study if the site (including the investigator) is 
found in significant violation of Ethical Guideline for Clinical Research, 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 sponsor, the study site director or the investigator decides to suspend or 
discontinue the entire clinical study or clinical study at a study site, a study-specific procedure will 
be provided by the sponsor. The procedure will be followed by applicable study sites during the 
course of clinical study suspension or discontinuation. 
6.4 
Procedures for protocol amendment 
When protocol amendment is required, the sponsor and the research steering committee chairman 
will assess and determine the propriety of the amendment. 
The protocol will be amended when the following purposes are applicable, and when an amendment 
is made, the content will be notified to all study site investigators. Then, investigators should 
confirm the content of the amendment of the protocol and submit a letter of agreement to the sponsor 
to prove agreement for protocol amendment. 


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[When amendment of protocol is required] 
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 subject 
4. 
Dose alteration (including addition of treatment group) 
5. 
Critical change or addition to inclusion/exclusion criteria 
6. 
Change in planned number of subjects 
7. 
Change of plan or description of content due to occurrence of serious adverse event, etc. 
8. 
Following discussion between the sponsor and the research steering committee chairman, 
that it is determined to be applicable to critical change 
Upon receiving the above notification, investigators of the study sites will be reviewed by the ethics 
review board again and must obtain approval from the study site director according to the 
regulations at each site when necessary. 


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7.0 
SELECTION OF STUDY SUBJECTS 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 based on the following criteria. 
1. 
In the opinion of the investigator* or the subinvestigator, the patient is capable of understanding 
and complying with protocol requirements. 
*: A personnel taking part in conducting the study and presides over the study related activities 
within the belonging study site. 
2. 
Patients who signs and dates a written ICF prior to the initiation of any study procedures 
3. 
Patients aged ≥ 20 to < 75 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 who have measurable lesion (refer to Appendix A) according to Response Evaluation 
Criteria in Solid Tumors (hereinafter referred to as RECIST) ver 1.1 
6. 
Patients with colorectal cancer refractory or intolerant* to chemotherapy including 
fluropyrimidines, oxaliplatin (OXA), irinotecan (IRI) and angiogenesis inhibitors (bevacizumab, 
aflibercept, ramycirumab, etc.) 
*: Refractory or intolerant if applicable to any of the following 
1) If recurrence is observed during supportive chemotherapy before or after surgery or from 
imaging diagnosis within 6 months of completion. 
2) If imaging or clinical progression is observed during or within 3 months from the last 
administration of chemotherapy for advanced cancer 
3) When it is determined that resumption is not possible due to intolerable adverse event 
toxicities (serious allergic reaction, accumulative neuropathy, etc.) 
7. 
Patients classified as KRAS/NRAS wild-type** by KRAS/NRAS testing*. 
*: KRAS/NRAS test will be performed using 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 


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8. 
Patients who may receive oral administration 
9. 
Patients who satisfy the following criteria for the major organ function in tests performed 
within two weeks (14 days) prior to enrollment. 
(1) Neutrophil count 1.5 × 103/L 
(2) Platelet count 10.0 × 104/L 
(3) Hemoglobin 8.0 g/dL 
(4) Total blood bilirubin 1.5 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 
10. Eastern Cooperative Oncology Group (hereinafter referred to as ECOG) performance status 
(P.S.) has been determined as 0-1. 
11. 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 treatment history of anti-EGFR antibody drugs (cetuximab, panitumumab), 
regorafenib and TAS-102 
2. 
Patients who have received radiotherapy and chemotherapy for primary disease as previous 
treatment and ≥ 2 weeks (14 days) have not passed since the last treatment at scheduled start 
day of treatment. However, excluding therapy received for pain relief of bone metastasis site 
3. 
Patients with known brain metastasis or strongly suspected of brain metastasis 
4. 
Patients with synchronous cancers or metachronous cancers with a disease-free period of 5 
years (excluding colorectal cancer) excluding mucosal cancers cured or be possibly cured by 
regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, 
bladder cancer, etc.) 
5. 
Patients with body cavity fluid that requires treatment (pleural effusion, ascites, pericardial 
effusion, etc.) 
6. 
Patients who do not want to use contraception to prevent pregnancy, and women who are 
pregnant or breast-feeding, or test positive for pregnancy 
7. 
Patients who have received other study drugs and ≥ 4 weeks (28 days) have not passed since at 
scheduled start day of treatment. 
8. 
Patients with disease requiring systemic steroids for treatment (excluding topical steroids) 
9. 
Patients with history or obvious and extensive computerized tomography (hereinafter referred 
to as CT) findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, 


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etc.) 
10. Patients with serious concurrent medical condition (intestinal paralysis, gastrointestinal 
obstruction, intestinal obstruction, uncontrollable diarrhoea, diabetes mellitus being treated with 
continuous use of insulin or that is difficult to control, renal failure, hepatic failure, psychiatric 
disorder, cerebrovascular disorder, gastrointestinal ulceration requiring blood transfusion) 
11. Patients with serious drug hypersensitivity (excluding allergic reaction to OXA) 
12. Patients with local or systemic active infection requiring treatment, or fever indicating infection 
13. Patients with heart failure or serious heart disease of class II by New York Heart Association 
(NYHA). 
14. Patients with active hepatitis B 
15. Patients with known HIV infection 
16. Patients who have adverse event from previous treatment that has not recovered to at least 
Grade 1 (Grade 2 for peripheral sensory neuropathy) by Common Terminology Criteria for 
Adverse Events (hereinafter referred to as CTCAE, Japanese edition JCOG version v4.03) 
(excluding hemoglobin content) 
17. Patients with known BRAF mutation. 
18. 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 protocol treatment 
7.3.1 Procedures for registration and initiation of protocol treatment 
The investigator or subinvestigator will register subjects according to the following procedure. 
1. The investigator, subinvestigator or study collaborator should pre-register the subject who has 
been given written information on informed consent by entering the identification code and date 
of informed consent discussion into the Web case registration system. * 
*: The study collaborator may enter data into the Web case registration system by instruction of 
the investigator or the subinvestigator. 
2. After pre-registration, the investigator, subinvestigator or study collaborator should enter the 
necessary items into the Web case registration system (formal registration) for a subject who has 
given consent. After formal registration, eligibility of a prospective subject is judged by the Web 
case registration system and the registration will be completed. 
3. The investigator, subinvestigator and study collaborator will check the registration result on the 
Web case registration system. The registration result will be sent via e-mail from the Web case 
registration system to the investigator, subinvestigator and study collaborator. 
PPD


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4. The investigator or the subinvestigator should start the protocol treatment within 2 weeks (14 
days) of registration (including the same day of week as the day of enrollment). However, if 
protocol treatment cannot be initiated within 4 weeks of registration or predicted that the 
initiation of protocol will be after 4 weeks from registration, this must be reported to the study 
office before protocol treatment initiation. See Section 1.3 for study office contacts. 
 
7.3.2 Contacts for enrollment procedure 
Case enrollment center:
 
 E-mail: 
 
[E-mail receipt confirmation] 
 Tel: 
 
[Reception hours] 
PPD
PPD
PPD
PPD
PPD


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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. The drugs used for this study 
should be ethical drugs used by the study site. See the latest package insert for details and handling 
of each drug. 
8.1 
Definition of protocol treatment 
With protocol treatment in principle, combination therapy with panitumumab and TAS-102 
stipulated in the “8.2 treatment regimen” will be conducted, and 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 (such as in case of PD). 
Protocol treatment in principle will be initiated within 14 days of entry. 
 
8.2 
Treatment regimen 
The treatment regimen shown below should be administered (28 days [Day1-28] as one course) until 
any of the criteria specified in “8.7 Criteria for discontinuation of protocol treatment for each subject” 
is met. For administration of each drug, see “8.3 Recommended dose of protocol treatment”, “8.4 
Criteria for administration” and “8.5 Criteria for protocol treatment change”. 
Table 8a Treatment regimen of combination therapy with panitumumab + TAS-102 
Drug 
Dose 
Method of 
administration 
Date of 
administration 
Panitumumab 
6 mg/kg 
IV drip infusion 60 
min* 
Day 1, 15 
TAS-102 
35 mg/m2 
Oral 
administration 
(twice daily**) 
Day 1-5 
Day 8-12 
*: When the dose at one time exceeds 1,000 mg, intravenously administer it over 90 min or longer 
after dilution with JP physiological saline to make approximately 150 mL. 
**: Within 1 hour of breakfast and dinner as reference. When TAS-102 is given at fasting state, 
elevation of Cmax of trifluridine (FTD) is observed, therefore fasting should be avoided. 
***: Oral drug intake will start from Day 1 after dinner or the next morning and to oral drug intake 
on Day 6 after breakfast or after dinner will be the 5 day intake (however, in the phase I part, 
after dinner on Day 1 will be the start). 
****: Oral drug intake will start from Day 8 after dinner or the next morning and to oral drug intake 
on Day 13 after breakfast or after dinner will be the 5 day intake (however, in the phase I part, 
after dinner in Day 8 will be the start). 




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Table 8.c TAS-102 dosage when dose is adjusted 
TAS-102 dosage 
(twice daily) 
Body 
surface 
area 
(m2) 
One dose 
(mg) 
Dose per day 
(mg) 
One dosage 
15 mg tablet 
20 mg tablet 
Drug reduction (35 mg/m2 to 30 mg/m2) 
30 mg/m2 
(60 mg/m2/day) 
< 1.09 
30 
60 
2 
0 
1.09 – 1.24 
35 
70 
1 
1 
1.25 – 1.39 
40 
80 
0 
2 
1.40 – 1.54 
45 
90 
3 
0 
1.55 – 1.69 
50 
100 
2 
1 
1.70 – 1.94 
55 
110 
1 
2 
1.95 – 2.09 
60 
120 
0 
3 
2.10 – 2.28 
65 
130 
3 
1 
2.29 
70 
140 
2 
2 
Drug reduction (30 mg/m2 to 25 mg/m2) 
25 mg/m2 
(50 mg/m2/day) 
< 1.10 
25 
50 
2 (after dinner) 
1 (after 
breakfast) 
1.10 – 1.29 
30 
60 
2 
0 
1.30 – 1.49 
35 
70 
1 
1 
1.50 – 1.69 
40 
80 
0 
2 
1.70 – 1.89 
45 
90 
3 
0 
1.90 – 2.09 
50 
100 
2 
1 
2.10 – 2.29 
55 
110 
1 
2 
2.30 
60 
120 
0 
3 
Drug reduction (25 mg/m2 to 20 mg/m2) 
20 mg/m2 
(40 mg/m2/day) 
< 1.14 
20 
40 
0 
1 
1.14 – 1.34 
25 
50 
2 (after dinner) 
1 (after 
breakfast) 
1.35 – 1.59 
30 
60 
2 
0 
1.60 – 1.94 
35 
70 
1 
1 
1.95 – 2.09 
40 
80 
0 
2 
2.10 – 2.34 
45 
90 
3 
0 
2.35 
50 
100 
2 
1 
*: If TAS-102 is to be given 50 mg/day, 20 mg will be given after breakfast, 30 mg after dinner. 
 
8.4 
Criteria for administration 
In principle, the day (Day 29) that is 4 weeks after the starting day of treatment (Day 1) in the 
previous course will be Day 1 of the subsequent course (however, if the actual starting day is the 
next morning, the day before the starting day will be Day 1). Postponement or acceleration due to 
holidays is allowed. See ”Table 9c. Allowance range for protocol treatment and laboratory tests”. 


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It should be confirmed that all of the criteria for initiation of protocol treatment (Table 8.d, Table 
8.e) are satisfied on the starting day of treatment of each course. However, the latest data obtained 
from 2 days before treatment to the starting day of treatment may be used as test value. 
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, and if only one drug 
satisfies the criteria for start of treatment then monotherapy with that drug may be allowed. However, 
at the starting point of the second course of the phase I part, both drugs are required to meet the 
treatment initiation criteria. If start of treatment with TAS-102 is postponed, the starting day 
thereafter (if the actual staring day is  next morning, the day before) will be Day 1 of the course and 
that will be the schedule starting point, and if treatment with TAS-102 is determined to be 
discontinued and monotherapy with panitumumab is to be continued, the starting day of 
monotherapy with panitumumab will be defined as the start of course (Day 1), and the course will be 
defined as to give panitumumab on Day 1 and Day 15 between Day 1 and Day 28. However, while 
monotherapy with panitumumab is ongoing and treatment does not start beyond 42 days from 
scheduled start of treatment (starting day of treatment of previous course as Day 1, if treatment does 
not start by Day 57), protocol treatment will be discontinued. Postponement of start of treatment due 
to holidays is allowed. 
 
Also, if start of treatment with panitumumab is postponed or discontinued, the starting day of 
treatment with TAS-102 (if the actual staring day is next morning, the day before) will be Day 1 of 
the course and that will be starting point for the schedule thereafter. However, while monotherapy 
with TAS-102 is ongoing and treatment does not start beyond 28 days from scheduled start of 
treatment (starting day of treatment of previous course as Day 1, if treatment does not start by Day 


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57), protocol treatment will be discontinued. Postponement of start of treatment due to holidays is 
allowed. 
 


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Table 8.d. Criteria for initiation of treatment with panitumumab 
Item 
Criteria for initiation 
Skin symptom (e.g., rash acneiform, dry skin, 
paronychia) 
≤ Grade 2 
Hypomagnesaemia * 
≤ Grade 2 
Treatment may be postponed when suspension is needed at the discretion of the investigator or 
the subinvestigator due to adverse events not listed above. 
*: When accompanied by abnormal ECG findings requiring treatment such as significant QTc 
prolongation, discontinuation or suspension of panitumumab should be considered irrespective of 
the severity of hypomagnesaemia. 
Table 8.e Criteria for initiation of treatment with TAS-102 
Item 
Criteria for initiation 
Hemoglobin concentration 
≥8.0 g/dL 
Neutrophil count 
≥ 1.5 × 103 μL 
Platelet count 
≥ 7.5 × 104/μL 
Total bilirubin 
≤ 1.5 mg/dL 
AST 
≤ 100 IU/L 
(≤ 200 IU/L with liver metastasis) 
ALT 
Serum creatinine 
≤ 1.5 mg/dL 
Periphial sensory neuropathy 
≤ Grade 2 
Other non-hematological toxicity 
(excluding 
alopecia, 
dygeusia, 
pigmentation, underlying disease related 
symptoms) ≤ Grade 1 
Treatment may be postponed when suspension is needed at the discretion of the investigator or the 
subinvestigator due to adverse events not listed above. 
8.5 
Criteria for protocol treatment change 
8.5.1 Criteria for suspension/dose reduction of panitumumab 
The criteria for suspension/dose reduction and doses of panitumumab are shown in Table 8.f and 
Table 8.g, respectively. 


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Table 8.f Criteria for suspension/dose reduction of panitumumab 
Item 
Grade 
Dose adjustment for the next dose of panitumumab 
Skin disorder 
≥ 3 
Dose reduction by 1 level after suspension 
However, treatment at a dose of 6 mg/kg is allowed 
without dose reduction when it recovers to Grade 2 or 
less within 6 weeks (42 days). 
Hypomagnesaemia * 
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 due to adverse events not listed above. 
*: When accompanied by abnormal ECG findings requiring treatment such as significant QTc 
prolongation, discontinuation or suspension of panitumumab should be considered irrespective of the 
severity of hypomagnesaemia. 
**: Allergic reaction, anaphylactoid reaction, and chills, fever, and dyspnea occurring within 24 hours 
after the initial dose 
***: 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.g Doses 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) 
The administration of panitumumab may be postponed (skipped) and only TAS-102 therapy 
performed when the subject meets the panitumumab suspension criteria (in this case, the day of 
starting the next course (Day 1) will be the day of starting TAS-102 therapy). When the actual day of 
initiating administration starts on the morning of the next day, the day before starting administration 
will be Day 1. For the next dose of panitumumab, treatment will be resumed after it is confirmed that 
the subject does not meet the criteria for suspension of panitumumab, but if panitumumab cannot be 
administered for more than 28 days after the scheduled day of treatment initiation, panitumumab 
treatment will be discontinued. 
 
8.5.2 Criteria for suspension/dose reduction of TAS-102 
The criteria for suspension/dose reduction and doses of TAS-102 are shown in Tables 8.h-j. 


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Table 8.h Criteria for suspension of TAS-102 
Item 
Suspension criteria 
Hemoglobin concentration 
< 7.0 g/dL 
Neutrophil count 
< 1.0 × 103/Λ 
Platelet count 
< 5.0 × 104/Λ 
Total bilirubin 
> 2.0 mg/dL 
AST 
> 100 U/L 
(> 200 U/L with liver metastasis) 
ALT 
Serum creatinine 
> 1.5 mg/dL 
Periphial sensory neuropathy 
Grade 3 or higher 
Other non-hematologic toxicity 
Grade 3 or higher 
Dose suspension is allowed as necessary at the discretion of the investigator or the subinvestigator 
due to adverse events not listed above. 
 
If adverse events meeting the criteria for dose reduction of TAS-102 shown in Table 8.i occur during 
the previous course (including the suspension period), dose will be reduced in course units, with a 
daily dose unit of reduction of 10 mg/day, when TAS-102 is resumed. However, the minimum dose 
will be 40 mg/ m2/day (Table 8.j). 
Table 8.i Criteria for dose reduction of TAS-102 
Item 
Criteria for dose reduction 
Neutrophil count 
< 0.5 × 103/Λ 
Platelet count 
< 5.0 × 104/Λ 
Dose reduction is allowed as necessary at the discretion of the investigator or the subinvestigator due 
to adverse events not listed above. 
 
Table 8.j Doses of TAS-102 
Dose reduction 
level 
TAS-102 
Initial dose 
35 mg/m2 (70 mg/m2/day) 
-1 
30 mg/m2 (60 mg/m2/day) 
-2 
25 mg/m2 (50 mg/m2/day) 
-3 
20 mg/m2 (40 mg/m2/day) 
-4 
Discontinuation (no resumption) 
When the subject meets the criteria for suspension of TAS-102, administration of TAS-102 will be 
suspended, and only panitumumab therapy will be administered. For the next dose of TAS-102, 


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TAS-102 treatment will be resumed after it is confirmed that the subject meets the criteria for 
initiation of TAS-102 treatment (however, when the subject satisfies the criteria for initiation of 
treatment from Day 13 to Day 28 of the suspension period, treatment will be resumed on Day 29). 
However, if TAS-102 cannot be administered for more than 28 days from the scheduled day of 
initiation of treatment, treatment with TAS-102 will be discontinued. (At this time, the day of 
initiating panitumumab monotherapy after it is determined that treatment with TAS-102 will be 
discontinued will be defined as the day for starting the course (Day 1), and the course will be defined 
as the administration of panitumumab between Day 1 and Day 28 on Days 1 and 15.) 
 
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 each subject 
The number of doses is not specified. 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. For 
subjects discontinuing before enrollment, see 9.3 Records of subjects who discontinued before 
enrollment. 
1. Lack of efficacy (exacerbation) 
When PD is evident in the clinical or imaging evaluation 
2. Adverse event 
Discontinuation of treatment due to 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 “4. Death during protocol treatment” and not in 
this item. 
Protocol treatment is postponed due to adverse event for 58 days or more after the day of 
starting the last course. However, postponement due to holidays is allowed. 
3. Voluntary discontinuation 
A subject wishes to discontinue study participation. The reason for discontinuation should be 
recorded in CRF when it is clarified. 


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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 
Death before discontinuation of protocol treatment is decided. Date of death, reason of death 
(protocol treatment related, primary disease, others) should be described in the CRF. 
5. Significant deviation from the protocol 
When study continuation may cause intolerable risk to the health of a subject because the 
subject was found not to satisfy the inclusion criteria specified in the protocol after enrollment 
or the protocol has not been observed. 
6. Lost to follow-up 
When subject fails to make visits and cannot be contacted. The attempts that were made to 
contact the subject should be recorded in the source documents. 
7. Discontinuation of the entire study 
For example, when the sponsor decides to discontinue the clinical study upon the 
recommendation of the DMC. See 6.3.1 Criteria for discontinuation of entire clinical study for 
details. 
8. Pregnancy 
When a female subject is found to be pregnant. 
Note: Study participation should be immediately discontinued when pregnancy is known. See 
“9.2.13 Pregnancy” for procedures. 
9. Others 
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 Subject 
The investigator or the subinvestigator may discontinue a subject’s study participation at any time 
during the study when the subject meets the study termination criteria described in Section 8.7. In 
addition, a subject may discontinue his or her participation without giving a reason at any time 
during the study. Should a subject’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/evaluation scheduled at the time of discontinuation. 
 


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8.9 
DLT 
In this study, DLT will be assessed based on the toxicity in 6 subjects at maximum enrolled in phase 
I part. The sponsor will confirm the opinion of the DMC in a suitable manner when evaluating DLT. 
8.9.1 DLT Evaluation Period 
The DLT evaluation period will be the period from Day 1 of Course 1 of protocol treatment to Day 1 
of Course 2. However, it is mandatory that the treatment initiation criteria for both panitumumab and 
TAS-102 be satisfied in order to start Course 2 of protocol treatment. Furthermore, the DLT 
evaluation period will be the period until the test day at discontinuation of protocol treatment for 
subjects who could not start Course 2 of protocol treatment until Day 57 due to adverse events and 
discontinued the protocol treatment. 
 
8.9.2 Subjects Included in the DLT Evaluation 
Subjects enrolled in the phase I part of the study will be included in the DLT evaluation. Subjects 
will be excluded from the DLT evaluation if at least the designated dose of protocol treatment is not 
administered by the end of Course 1 (except when the protocol treatment is discontinued due to 
DLT), if there are major protocol deviations such as the use of contraindicated drugs, or if the 
subject is determined to be unsuitable for the DLT evaluation. The designated dose is 75% (15 
doses) of the total number of doses (20 doses) of panitumumab (2 doses of 6 mg/kg) and TAS-102 (2 
doses daily of 35 mg/m2) on Days 1-5 and Days 8-12. 
 
8.9.3 DLT Criteria 
DLT is defined as any adverse event for which a causal relationship with protocol treatment cannot 
be denied falling in the following categories. Adverse events will be graded according to the 
“Common Terminology Criteria for Adverse Events (CTCAE), ver. 4.03.” Further, DLT will be 
assessed from Day 1 of course 1 of protocol treatment, and if DLT does not occur by Day 1 of 
course 2, it will be handled as no occurrence of DLT in the subject. Adverse events that can clearly 
be denied of causal relationship with the protocol treatment will not be considered DLT. If serious 
adverse event or unexpected adverse event occurs which causal relationship with the protocol 
treatment cannot be denied other than the following, it may be determined as to whether or not to 
handle it as DLT in consultation with the Investigator, the Research Steering Committee and the 
sponsor. 
1. 
Persistent Grade 4 neutropenia for more than 7 days under maximum supportive therapy 


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2. 
Febrile neutropenia 
3. 
Blood platelete decreased of Grade 3 requiring platelet transfusion or blood platelete decreased 
of Grade 4 
4. 
If start of second course is delayed for more than 14 days due to adverse event related to 
protocol treatment 
5. 
Grade 3 or higher non-hematologic toxicity that is clinically problematic however the following 
will not be applicable as DLT. 
- Grade 3 gastrointestinal symptoms that can be controlled with supportive care (appropriate 
use of antiemetics, antidiarrheals, etc.) 
- Grade 3 or higher electrolyte abnormalities that are not deemed clinically problematic 
 
8.10 
Replacement/Addition of Subjects 
Should there be, during the DLT evaluation period in the phase I part of the study, a major deviation 
from the protocol affecting the DLT evaluation for a reason other than an adverse event classified as 
a DLT or if DLT cannot be evaluated appropriately, that subject can be excluded from the DLT 
evaluation and a new subject can be enrolled and added to that cohort. 
 
8.11 
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 
subjects 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 (BRM) therapy 
- 
Antibody therapy 
- 
Gene therapy 
 
Other antibody therapy (except for denosumab) 
 
Flucytosine (antifungal) 


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 
Radiotherapy for primary disease 
Except for treatment for pain relief of bone metastasis site is allowed. 
 
Hyperthermia therapy for primary disease 
 
Study drug and unapproved drug 
 
8.12 
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 The type of G-CSF products administered should depend on the insurance 
coverage. 
 
Nausea/vomiting 
Premedication including prophylactic administration of antiemetics is allowed. Premedication 
with 5-HT3 (serotonin) receptor antagonists, NK1 (neurokinin 1) receptor antagonists, steroids, 
and antihistamines may be carried out using the method employed at each study site. 
 
Diarrhoea 
Fluids and electrolyte balance will be followed adequately, and suitably supplemented, as 
necessary. If careful observation suggests that it is necessary, administration of an antidiarrheal 
such as loperamide hydrochloride may be considered. 
 
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 by slowing the infusion speed may be considered. 
 
Pulmonary fibrosis (interstitial pneumonia) 
If it 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 which have been continued from 
before the start of this study are allowed. 
In addition, it is recommended that the supportive care shown below be performed at the discretion 
of the investigator 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) 


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- 
External salicylic acid petrolatum (10%) 
- 
External steroid therapy (example) 
 
Face: hydrocortisone butyrate (0.1%) 
 
Trunk: difluprednate (0.05%) 
- 
Moisturizer (example): heparin analog lotion 
- 
Sunscreen (example): not containing 4-aminobenzoic acid, SPF (Sun Protection Factor) 30, 
PA (Protection grade of UVA)++. Apply before going out to block ultraviolet rays (UVA 
and UVB). 
Dermatopathy prevention with humectants, suntan lotion, antibiotic or external steroids may be 
carried out using the method employed at each study site, based on non-Japanese29) and 
Japanese reports30), etc. 
 
Electrolyte abnormality (e.g., hypomagnesaemia, hypocalcaemia) 
- 
ECG: ECG may be performed to determine whether there are abnormal ECG findings 
requiring treatment such as significant QTc prolongation. When any abnormal ECG 
findings requiring treatment are observed, suspension of panitumumab should be 
considered irrespective of the serum magnesium concentration. 
- 
Magnesium supplementation (example): intravenous infusion of magnesium sulfate 
(10 mmol) over 60 min 
 
8.13 
Recommended follow-up therapy 
Approved drugs (e.g., regorafenib) should be used as appropriately 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 
(phase I part of the study)” in the phase I part of the study and “Table 9.b Study calendar (phase II 
part of the study)” in the phase II part of the study. The same investigator or the subinvestigator 
should perform tests/observations/evaluation of subjects in principle. For the allowance range of 
protocol treatment and various laboratory tests, see “Table 9.c. Allowance range for protocol 
treatment and laboratory tests” 
 
 


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Table 9.a Study calendar (phase I part of the study) 
Item 
At 
enrollme
nt 
Protocol treatment period 
Follow-up 
period# 
Course 1 
Second and later 
courses 
Discontinuat
ion 
of protocol 
treatment † 
Reference day: 
Number of days 
counted from the first 
day of each course 
-14, -1 
1 
8 
15 
22 
1 
15 
Informed 
consent 
obtained*1 
● 
 
 
 
 
 
 
 
 
Patient Background 
● 
 
 
 
 
 
 
 
 
RAS status*2 
● 
 
 
 
 
 
 
 
 
Clinical findings*3 
● 
● 
● 
● 
● 
● 
● 
● 
 
Height*2 
● 
 
 
 
 
 
 
 
 
Body weight*4 
●*7 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
ECOG P.S. *3 
●*7 
● 
○ 
○ 
○ 
● 
○ 
● 
 
Compliance*3 
 
● 
○ 
○ 
 
● 
○ 
 
 
Hematology*5 
●*7 
● 
● 
● 
● 
● 
● 
● 
 
Serum chemistry*5 
●*7 
● 
● 
● 
● 
● 
● 
● 
 
Immunology 
(HBs antigen)*6 
● 
 
 
 
 
 
 
 
 
Tumor marker 
 
●*8 
 
 
 
<- ●*9-> 
● 
 
Imaging tests 
(thoracoabdominal-pel
vic CT/MRI) 
●*10 
 
 
 
 
<- ●*9-> 
○*11 
○ 
Follow-up treatment 
 
 
 
 
 
 
 
 
● 
Survival survey 
 
 
 
 
 
 
 
 
● 
Adverse events 
- 
<-     ●     -> 
○ 
●: Mandatory, ○: Perform as necessary 
†: Perform within 28days of discontinuation or earlier date than start of follow-up treatment. 
#: Perform every 6 months as a guide with protocol discontinuation date as starting point. 
*1: Consent must be obtained before enrollment. Further, consent should be obtained after RAS status has been 
identified. 
*2: Values obtained after the diagnosis of colorectal cancer may be used. 
*3: When the visit day is the treatment day, this will be done before administration. 
*4: Measurement is not mandatory during protocol treatment period. Even if measured, it is unnecessary to record 
in the CRF. 
*5: Testing will be performed from 2 days before to the day of the visit during each course. 
*6: Test results from up to one year before obtaining consent may be used. It is unnecessary to record this in the 
CRF. However, follow JSH Guidelines for the Management of Hepatitis B virus infection for the measurement 
of HBs antibody, HBc antibody and HBV-DNA. 
*7: If done within 14 days before enrollment, results from before obtaining informed consent may be used. 


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*8: If it has been performed within 28days before treatment day, the test for Course 1 may be omitted. 
*9: Measure once every 8 weeks (56 days) with Day 1 of Course 1 as starting point. However, reduce the frequency 
to once every 12 weeks (84 days) when one year has passed since initiation of protocol treatment. 
*10: 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 is performed within 4 weeks (28 days) prior to enrollment. 
*11: This is only done when the subject is discontinued for a reason other than imaging results (PD). 
Table 9.b Study calendar (phase II part of the study) 
Item 
At 
enrollme
nt 
Protocol treatment period 
Follow-up 
period# 
Course 1 
Second and later 
courses 
Discontinuation 
of protocol 
treatment † 
Number of days 
counted from the first 
day of each course 
-14, -1 
1 
15 
22 
1 
15 
Informed 
consent 
obtained*1 
● 
 
 
 
 
 
 
 
Patient Background 
● 
 
 
 
 
 
 
 
RAS status*2 
● 
 
 
 
 
 
 
 
Clinical findings*3 
● 
● 
● 
● 
● 
● 
● 
 
Height*2 
● 
 
 
 
 
 
 
 
Body weight*4 
●*7 
○ 
○ 
○ 
○ 
○ 
 
 
ECOG P.S. *3 
●*7 
● 
○ 
○ 
● 
○ 
● 
 
Compliance*3 
 
● 
○ 
 
● 
○ 
 
 
Hematology*5 
●*7 
● 
● 
● 
● 
● 
● 
 
Serum chemistry*5 
●*7 
● 
● 
● 
● 
● 
● 
 
Immunology 
(HBs antigen)*6 
● 
 
 
 
 
 
 
 
Tumor marker 
 
●*8 
 
 
<-●*9-> 
● 
 
Imaging tests 
(thoracoabdominal-pel
vic CT/MRI) 
●*10 
 
 
 
<-●*9-> 
○*11 
○ 
Follow-up treatment 
 
 
 
 
 
 
 
● 
Survival survey 
 
 
 
 
 
 
 
● 
Adverse events 
- 
<-      ●      -> 
○ 
●: Mandatory, ○: Perform as necessary 
†: Perform within 28days of discontinuation or earlier date than start of follow-up treatment. 
#: Perform every 6 months as a guide with protocol discontinuation date as starting point. 
*1: Consent must be obtained before enrollment. Further, consent should be obtained after RAS status has been 
identified. 
*2: Values obtained after the diagnosis of colorectal cancer may be used. 
*3: When the visit day is the treatment day, this will be done before administration. 


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*4: Measurement is not mandatory during protocol treatment period. Even if measured, it is unnecessary to record 
in the CRF. 
*5: Testing will be performed from 2 days before to the day of the visit during each course. 
*6: Test results from up to one year before obtaining consent may be used. It is unnecessary to record this in the 
CRF. However, follow JSH Guidelines for the Management of Hepatitis B virus infection for the measurement 
of HBs antibody, HBc antibody and HBV-DNA. 
*7: If done within 14 days before enrollment, results from before obtaining informed consent may be used. 
*8: If it has been performed within 28 days before treatment day, the test for Course 1 may be omitted. 
*9: Measure once every 8 weeks (56 days) with Day 1 of Course 1 as starting point. However, reduce the frequency 
to once every 12 weeks (84 days) when one year has passed since initiation of protocol treatment. 
*10: 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 is performed within 4 weeks (28 days) prior to enrollment. 
*11: This is only done when discontinuation is for a reason other than imaging results (PD). 
Table 9.c Allowance range for protocol treatment and laboratory tests 
Performed items 
Protocol specification 
Allowance range 
Clinical Laboratory test values 
(During protocol treatment) 
Course 1: Day 1, 8, 15, 22 
(phase I part of the study) or 
Day 1, 15, 22 (phase II part of 
the study) 
Course 2: Day 1, 15 
From Day -2 before scheduled 
day 
(However, Mg is tested once 
per course.) 
Protocol treatment 
From treatment day (Day 1) of 
previous course to 4 weeks later 
(Day 29) 
Scheduled day ±3 days 
Tumor markers and imaging 
tests (during protocol treatment) 
Protocol treatment ≤ 1 year: 8 
weeks (56 days) 
Scheduled day ±1 week (7 
days) 
Protocol treatment > 1 year: 12 
weeks (84 days) 
Scheduled day ±2 week (14 
days) 
9.2 
Collection/test/observation items and procedures during the clinical 
study 
The investigator or the subinvestigator will perform the following as scheduled in “ 9.1 Study 
calendar” or “Table 9.b Study calendar”. 
9.2.1 Informed consent procedure 
Consent should be obtained from subject before initiation of study procedures. 
A unique subject ID code to anonymize the subject will be assigned to each subject at the time of 
obtaining consent. The subject ID code will be used throughout the study period and not changed. 
The method for obtaining consent is described in Section “15.3 Written information and subject’s 
consent.” 
 


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9.2.2 Enrollment and protocol treatment 
For procedures and storage of enrollment and initiation of protocol treatment, see: “7.3 Procedures 
for Enrollment and Protocol Treatment.” 
 
9.2.3 Subject demographics 
For demographic data of the subject, 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 
 
Solitary/Multiple 
 
Primary tumor site (cecum, ascending colon, transverse colon, descending colon, sigmoid 
colon, rectosigmoid, rectum) 
(2) Information on metastasis 
• 
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 “1 organ”. For example, even if it is observed in cervical lymph 
node and thoracic lymph node, it will be counted as 1 organ. 
• 
Organs with metastasis (liver, lung, peritoneum, lymph node*, bone, adrenal gland, skin, 
and others**) 
*: Does not include regional lymph node, other lymph nodes in several sites will be 
counted as “1 organ”. For example, even if it is observed in cervical lymph node and 
thoracic lymph node, it will be counted as 1 organ. 
**: Name of organ to be recorded in CRF 
(3) History of treatment 
• 
History of surgery in primary tumor site/palliative metastasis site and history of colostomy 
/bypass surgery 
- 
Subjects with history, the date of surgery 
However, endoscopic surgery, which is not considered a history of surgery, should 
not be entered into the CRF. 
• 
History of radiotherapy (radical irradiation) 
- 
Subjects with history, the date of final dose 
However, irradiation for pain relief (palliative irradiation) in the bone metastasis site, 
which is not considered as radiotherapy, should not be entered into the CRF. 
• 
Treatment history for subjects with unresectable lesions 
- 
Description of first-, second-, and third-line treatment (FOLFOX, FOLFOX + 
anti-angiogenic agent (e.g., bevacizumab); CapeOX, CapeOX + anti-angiogenic agent 
(e.g., bevacizumab); FOLFIRI, FOLFIRI + anti-angiogenic agent (e.g., 
bevacizumab); IRIS, IRIS + anti-angiogenic agent (e.g., bevacizumab); IRI, IRI + 
anti-angiogenic agent (e.g., bevacizumab); FOLFOXIRI, FOLFOXIRI + 
anti-angiogenic agent (e.g., bevacizumab); SOX, SOX + anti-angiogenic agent (e.g., 


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bevacizumab); SOX, SOX + anti-angiogenic agent (e.g., bevacizumab); other), date 
of initiation of first-line treatment 
• 
History of preoperative and/or postoperative adjuvant chemotherapy 
- 
Subjects with history, history of preoperative and/or postoperative adjuvant 
chemotherapy with OXA, date of final treatment 
 
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. 
 
9.2.5 Clinical findings 
Medical examination will be performed prior to protocol treatment. In particular, the following 
symptoms at the medical examination will be confirmed. 
Allergic reaction, rash acneiform, cutaneous dryness, paronychia, infusion reaction (infusion related 
reaction), anorexia, diarrhoea, nausea, vomiting, oral mucositis, hypomagnesemia, blood neutrophil 
count decreased, febrile neutropenia, reduced blood platelet count, peripheral sensory neuropathy, 
thromboembolism, gastrointestinal perforation, interstitial pneumonia, fatigue. 
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 “10.0 Adverse event” for definition of adverse event. 
 
9.2.6 Body weight, height 
Body weight at enrollment should be measured within 2 weeks (14 days) before enrollment 
(including the same day of week as the day of enrollment) and recorded in the CRF. Height obtained 
after the diagnosis of colorectal cancer may be used. 
 


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9.2.7 Eastern Cooperative Oncology Group Performance Status (ECOG) 
Performance Status 
ECOG Performance Status (P.S.) will be assessed according to Table 9.d. P.S. at enrollment will be 
determined within 2 weeks (14 days) prior to enrollment (including same day of the week as the day 
of enrollment). P.S. before initiation of each course will be determined before administration on 
treatment day. P.S. at discontinuation will be determined as much as possible within 4 weeks (28 
days) after discontinuation or before the initiation of follow-up treatment whichever date is earlier. 
Table 9.d Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) 
P.S. 
Definition 
0 
Fully active, 
able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair 
 
9.2.8 Compliance 
The investigator or the subinvestigator should record the compliance with protocol treatment in the 
CRF as follows: 
• 
Doses and treatment days for panitumumab 
• 
Doses, treatment initiation day, and number of doses of TAS-102 
 
9.2.9 Clinical laboratory tests 
In principle, 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). 
Testing will be performed from 2 days before to the day of the visit during the protocol treatment 
period. 
Tests at discontinuation will be conducted as much as possible within 4weeks (28 days) after 
discontinuation or before the initiation of follow-up treatment whichever date is earlier. 
Test items and notes are listed in Table 9e to Table 9. g. 




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immunosuppressive therapy for autoimmune diseases such as rheumatological diseases in view of the risk of 
reactivation of HBV. The frequency of reactivation of HBV and the occurrence and progression to fulminant 
status of hepatitis with standard chemotherapy and immunosuppressive therapy is not known, and there is 
insufficient evidence related to guidelines. In addition, treatment with nucleotide analogues does not 
completely guarantee prevention of progression to a fulminant status. 
Note 1) Screening will be conducted for HBV carriers and subjects with previous infections prior to 
immunosuppressive therapy or chemotherapy. First, HBs antigen will be measured to identify HBV carriers. In 
HBs antigen-negative subjects, HBc antibody and HBs antibody will be measured to identify subjects with 
previous infections. Highly sensitive techniques should be used to measure HBs antigen, HBc antibody, and 
HBs antibody. In subjects positive for HBs antibody only (HBs antigen-negative and HBc antibody-negative), 
HBV reactivation will be reported, and action should be taken according to guidelines, except when the subject 
is known to have been vaccinated. 
Note 2) When a subject is HBs antigen-positive, consult with a hepatologist. A hepatologist should be consulted when 
administering nucleotide analogues to any subjects. 
Note 3) Antibody titers may decrease when initially starting chemotherapy in subjects who are being retreated but 
have not been measured for HBc antibody and HBs antibody and subjects who have already been started on 
immunosuppressive therapy, and detailed examinations should be performed, e.g., measuring HBV DNA 
levels. 
Note 4) Screening for HBV DNA will be performed by real time PCR in subjects with previous infections. 
Note 5) 
a. Caution is required with subjects receiving chemotherapy with rituximab, a steroid, and fludarabine and 
hematopoietic stem cell transplantation because they are at high risk of HBV reactivation from previously 
infected people. HBV DNA should be monitored once a month during and for a period of at least 12 months 
after completion of therapy. Subjects receiving hematopoietic stem cell transplantation require long-term 
monitoring after transplantation. 
b. There is also a risk of HBV reactivation with combination therapy using standard chemotherapy and 
molecularly targeted drugs having an immunological effect, although the frequency of reactivation is low. As 
a general guideline, HBV DNA levels should be monitored every 1 to 3 months, but the frequency and time of 
monitoring should take the nature of the treatment into consideration. Action should be taken prudently in the 
case of hematological malignancies. 
c. There is also a risk of HBV reactivation with immunosuppressive therapy using corticosteroids, 
immunosuppressives, and molecularly targeted drugs having an immunosuppressive or immunomodulating 
effect. With immunosuppressive therapy, HBV DNA levels should be monitored monthly for at least 6 
months after staring or changing the therapy. After the first 6 months, the frequency and time of monitoring 
should take the nature of the treatment into consideration. 
Note 6) Administration of nucleotide analogues should be started as early as possible before starting 
immunosuppressive therapy or chemotherapy. However, deaths from fulminant hepatitis during prophylactic 
nucleotide analogue therapy have been reported in HBs antigen-positive patients with a high viral load, and the 
viral load should therefore be reduced before starting immunosuppressive therapy or chemotherapy. 
Note 7) Administration of nucleotide analogues should be started immediately when HBV DNA has reached 2.1 log 
copies/mL or higher during or after completion of immunosuppressive therapy or chemotherapy. During 
immunosuppressive therapy or chemotherapy, a hepatologist should be consulted about the action to be taken 
without immediately discontinuing the immunosuppressive agent or anti-neoplastic agent with an 
immunosuppressive action. 
Note 8) The recommended nucleotide analogue is entecavir. 
Note 9) Termination of nucleotide analogue treatment may be considered when the following conditions are satisfied. 
In subjects who are HBs antigen-positive at screening: when the criteria for terminating nucleotide analogue 
treatment in chronic hepatitis B are satisfied. In subjects who are HBc antibody-positive or HBs 
antibody-positive at screening: (1) Nucleotide analogue treatment should continue for at least 12 months after 
completing immunosuppressive therapy or chemotherapy. (2) Normalization of ALT (GPT) should be 
achieved during this period of continued treatment. (unless ALT is abnormal for a reason other than HBV). 
(3) Sustained negative HBV DNA should be maintained during this period of continued treatment. 
Note 10) Subjects should be followed vigilantly, including HBV DNA monitoring, for at least 12 months after 
terminating nucleotide analogue treatment. The follow-up should be based on the Precautions for Use in the 
package insert of the nucleotide analogue used. Nucleotide analogue treatment should be resumed 
immediately when HBV DNA reaches 2.1 log copies/mL or higher in subjects being followed. 


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Table 9.f Clinical laboratory tests performed during the protocol treatment period 
Hematology 
Serum chemistry 
Tumor markers 
Neutrophil count * 
Platelet count * 
Hemoglobin content 
* 
Total bilirubin * 
ALT* 
AST* 
Creatinine * 
Mg *** 
Albumin * 
Na* 
K* 
Ca* 
CEA**, † 
*: 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. 
**: If it had been conducted within 28 days before treatment day, it may be omitted. 
***: May be measured once during each course. 
†: Measure every 8 weeks (56 days) with Day 1 of Course 1 as starting point. However, when 1 year has passed since 
initiation of protocol treatment, once every 12 weeks (84 days). 
Table 9.g Laboratory tests performed at the time of discontinuation 
Hematology 
Serum chemistry 
Tumor markers 
Neutrophil count 
Platelet count 
Hemoglobin content 
Total bilirubin 
ALT 
AST 
Creatinine 
Mg 
Albumin 
Na 
K 
Ca 
CEA* 
*: If ≥ 28days has not passed since the last measurement, the test can be omitted. 
 
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 is 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 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 CRF. 


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After initiation of protocol treatment, imaging test will be performed every 8 weeks (56 days) with 
protocol treatment initiation date (Day 1) of Course 1 as the starting point. However, when 1 year 
has passed since initiation of protocol treatment, imaging may be performed once every 12 weeks 
(84 days), counting from the point in time at which 1 year has passed. (For details, see “Table 9.a 
Study calendar (phase I part of the study)” or “Table 9.b Study calendar (phase II part of the study).” 
Thoracoabdominal-pelvic CT (in principle, contrast CT; a slice width of 5 mm or less is 
recommended, 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, brain MRI / CT and a neck CT will 
be performed. 
In principal, the same modality should be used for imaging test during protocol treatment throughout 
the study period. 
The investigator or the subinvestigator should evaluate the test results according to the RECIST v1.1 
(see Appendix A) and enter the determined results into the CRF. 
Furthermore, for subjects withdrawn from the study for any reason other than imaging test results 
such as clinical PD, imaging test specified at the time of discontinuation should be performed within 
4 weeks (28 days) including the day of decision (including the same day of week as the day of 
decision). 
If the subject is not determined to have PD on imaging up to the time of withdrawal, the following 
information should be collected until the subject dies or the sponsor terminates the study, even after 
follow-up treatment has been started. 
 
Day of decision on clinical PD (only when the subject is not determined to have clinical PD by 
the time of discontinuation) 
 
It will not be necessary to collect information if the subject is determined to have 
radiological PD before the subject is determined to have clinical PD. 
 
Day of decision on radiological PD 
 
The day of decision on radiological PD will be collected, regardless of the state of clinical 
PD. The final imaging test date will be collected in subjects not determined to have 
radiological PD during the follow-up period as well. 
 
Date of last confirmed progression-free survival 
 
The date of last confirmed progression-free survival will be collected in subjects not 
determined to have either clinical PD or radiological PD during the follow-up period as 
well. 
However, when follow-up is not possible due to withdrawal of consent, loss to follow-up, etc., the 
date of the last visit will be entered in the CRF as the date of last confirmed progression-free 
survival. 


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9.2.11 Follow-up treatment 
The following information will be collected when follow-up treatment is performed after 
discontinuation of protocol treatment. If several types of follow-up treatment are performed, 
information will only be collected on the follow-up treatment immediately following discontinuation 
of protocol treatment. 
- 
Name of drugs used (regorafenib, other) 
- 
Initiation date 
9.2.12 Survival survey 
After discontinuation of protocol treatment, every subject will be followed-up to confirm survival of 
subjects 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 subject dies or 
the sponsor terminates the study. 
• 
Survival survey date 
• 
Date of death or last confirmed date of survival 
- 
If deceased, the reason of death (death from primary disease/others) 
 
9.2.13 Pregnancy 
When it becomes apparent that a female subject is pregnant, with consent from female subject, the 
investigator or the subinvestigator should notify the primary care physician (obstetrician and 
gynecologist, etc.) that the female subject was participating in a clinical study at the time she became 
pregnant and provide details of protocol treatment. 
For every female subject reported to have become pregnant, the investigator or subinvestigator 
should follow-up to delivery including result of premature delivery with consent from the female 
subject and report to the sponsor using the specified follow-up form. Evaluation after delivery will 
also be conducted. 
 
9.3 
Records of subjects who discontinued before enrollment 
Every subject who has signed the ICF and dropped-out before enrollment should be registered in the 
Web registration center and a CRF should be prepared. 
The following items are to be entered in the CRF. 
• 
Date of consent obtained 


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• 
Date of birth (the age at enrollment) 
• 
Sex 
• 
Eligibility 
• 
Reason for discontinuation 
For subjects who drop-out from the study before enrollment, the main reason for dropping-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 subject ID code of a subject withdrawn from the study before enrollment should not be reused. 
 
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
Adverse events are any unfavorable medical events encountered in a subject treated with a drug. 
They are not limited to the events with clear causal relationship with treatment with the concerned 
drug. 
In other words, adverse events are any unfavorable or unintended sign (including clinically 
problematic abnormalities of laboratory test data), symptoms or diseases that develop after 
administration of a drug irrespective of a causal relationship with the relevant drug. 
 
10.1.2 Items to be considered concerning adverse events 
Generally unfavorable findings are shown below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent event of 
the existing symptom is not considered an adverse event) 
• 
Requiring action or medical practice 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation of protocol treatment (panitumumab + TAS-102 combination 
therapy) or of combination therapy or change in dose 
• 
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, 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 judges the change to 
have exceeded the normal physiological variation range of the subject). Retest and/or continued 
monitoring of abnormality are not considered medical practice. Also, repeated or additional conduct 


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of non-invasive 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 CRF that the adverse event 
is an aggravation of the concurrent disease (e.g., “aggravation of hypertension”, etc.). 
When a subject has an existing symptom that is transient (e.g., asthma, epilepsy) and incidence of 
the symptom is increased, or the symptom becomes serious or severe, it should be recorded as an 
adverse event. When a subject has a chronic disease (e.g., cataract, rheumatoid arthritis) and the 
symptom is aggravated more than anticipated, it should be recorded as an adverse event. The 
investigator 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 which resulted 
from previously planned surgery is reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a subject 
(cosmetic surgery, etc.) is not considered an adverse event. However it should be recorded in the 
source documents. Complications due to a non-urgent surgery should be reported as an adverse 
event. 


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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 or on imaging 
progression of pre-existing cancer (including new metastasis) is confirmed, 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 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), serious adverse event is an event that: 
1. 
Results in death during protocol treatment* and all deaths irrespective of a causal relationship 
with protocol treatment. 
*: Period from initiation of protocol treatment up to 4 weeks (28 days) after discontinuation of 
protocol treatment or initiation of follow-up 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 follow-up 
treatment 
3. 
Is life-threatening. The term “life-threatening” refers to an event in which the subject was at 
risk of death during onset of the adverse event; it does not refer to an event which 
hypothetically might have caused death if it were severer. 
4. 
Requiring hospitalization or prolongation of hospitalization 
However, hospitalization or prolongation of hospitalization for the following reasons will not 
be handled as a serious adverse event. 
(1) Preplanned inpatient hospitalization or prolongation of existing hospitalization 


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(2) Inpatient hospitalization or prolongation of existing hospitalization unrelated to an adverse 
event 
5. 
Results in persistent or significant disability/incapacity. 
6. 
Leads to a congenital anomaly/birth defect. 
7. 
Other medically significant condition: medically important event which causes a risk to a 
subject even if it is not immediately life-threatening, nor does it result in death or 
hospitalization, or requires an action or treatment to prevent the results shown in 1 to 6 above. 
 
10.1.4 Special interest adverse event for sponsor 
Adverse events listed in Table 10.a “Takeda Medically Significant AE List” will be handled as 
“special interest adverse event” for sponsor irrespective of severity determined by the investigator or 
the subinvestigator. Further, any adverse events listed in Table 10.a that has been determined as 
serious by the investigator or the subinvestigator will be handled as serious adverse event. 
Table 10.a Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion and 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of infection 
by a medicinal product 
Confirmed or suspected endotoxin shock 
 
10.1.5 Severity of adverse events 
The severity of adverse event is classified into 5 grades (Grade 1-5) as follows based on the 
Common Terminology Criteria for Adverse Events (hereafter referred to as CTCAE, Japanese 
edition JCOG version 4.03), of the National Cancer Institute, USA. Furthermore, the grade for 
adverse events not listed in CTCAE will be classified according to the following criteria. 


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Table 10.b CTCAE (Japanese edition JCOG version 4.03) Grade 
Grade 1 
Mild; asymptomatic or slightly symptomatic; only clinical or test findings; or 
requiring no treatment 
Grade 2 
Moderate; requiring the least treatment or local or non-invasive treatment; or 
interfering with age-appropriate activities of daily living except for self-care 
activities* 
Grade 3 
Severe or medically critical, but not immediately life-threatening; requiring 
hospitalization or prolongation of existing hospitalization; disabling/incapacitating; 
or interfering with self-care activities of daily living** 
Grade 4 
Life-threatening; or requiring emergent treatment 
Grade 5 
Death due to an adverse event 
AE: Adverse Event, “;” stands for “or” 
*: Activities of daily living except for self-care activities include meal preparation, shopping for daily necessities and 
clothings, phone call, and financial management. 
**: Self-care activities of daily living include bathing, dressing, eating, toilet, and oral drug intake, and indicate that a 
person is not confined to bed. 
 
10.1.6 Causality of adverse events 
Causal relationship between protocol treatment (panitumumab + TAS-102 combination therapy) and 
adverse events, and causal relationship between panitumumab and adverse events (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 or panitumumab although other 
factors such as underlying disease, complications, concomitant drugs/treatment are 
also presumed. 
Not 
related 
An adverse event with no chronological correlationship with protocol treatment 
(chemotherapy, 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 Date of onset of adverse events 
The date of onset of adverse events will be determined according to the following criteria. 
Adverse event, etc. 
Date of onset 
Signs, symptoms, and 
diseases (diagnoses) 
The subject, investigator, or subinvestigator will record the date on 
which the sign or symptom of an adverse event is first noticed. 
Asymptomatic diseases 
The date on which diagnosis is confirmed by testing will be 
recorded. 
Even if testing reveals old findings or if the time of occurrence can 
generally be estimated, the date on which diagnosis is confirmed 
will be recorded. 
Aggravation of concurrent 
medical conditions 
The subject, investigator, or subinvestigator will record the date on 
which a disease or aggravation of a disease is first noticed. 
Test results that became 
abnormal after initiation of 
protocol treatment 
The test date on which abnormal test results determined to be 
clinically problematic were observed will be recorded. 
Test results that are abnormal 
at initiation of protocol 
treatment and aggravated in 
later testing 
The date on which the time profile of a laboratory value shows a 
clear increase or decrease, based on medical judgment, will be 
recorded. 
 
10.1.8 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”. 


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10.1.9 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 has not returned to normal or baseline 
 
when the subject 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 aggravated compared with the date of onset 
 
irreversible congenital anomaly 
 
when a subject died where the concerned adverse event is not a direct cause 
of death and the concerned adverse event remained not recovered 
Recovered 
with sequelae 
 
disability which disturbs daily life 
Death 
 
direct relationship between death and the concerned adverse event 
 
“Direct relationship” means that the concerned adverse event was the cause 
of death, or the concerned adverse event was clearly responsible for death. 
 
Outcome of an adverse event which was not determined (judged, presumed) a 
direct cause of death observed in the same subject 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. 
 
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 follow-up treatment, whichever 
date is earlier. In addition, adverse event causal relationship cannot be ruled out of protocol 
treatment collected later 4 weeks (28 days) after discontinuation of protocol treatment or initiation of 
follow-up treatment. 


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10.2.1.2 Reporting of adverse events 
At each visit of subject, 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 a question such as “how has your condition been since the last 
visit?” to a subject. 
The investigator or the subinvestigator should follow up all subjects who developed adverse events 
irrespective of a causal relationship with protocol treatment until disappearance of symptoms or 
abnormal laboratory values, 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, date of onset, 
severity, seriousness, causal relationship with protocol treatment (unrelated or related), further if 
event 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 as well as date of resolution 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. 
When the investigator or the subinvestigator judges that a serious adverse event has occurred based 
on the reporting by a subject, etc., or results of various tests, imaging findings or definitive diagnosis, 
etc., it should be reported immediately to the director of the study site. 
Also, the investigator or the subinvestigator should report to the sponsor (see attached sheet for 
contact information) within 72 hours of recognition of onset of event. Further, the investigator 
should submit a formal report within 10 calendar days to the sponsor. 
Furthermore, the content below which is to be reported to the sponsor within 72 hours is mandatory, 
and other items should be reported as much as possible. 
• 
Brief description of adverse event and the reason for why it was determined as serious 
• 
Study title 


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• 
Subject ID code 
• 
Name of study site 
• 
Name of investigator or the subinvestigator 
• 
Name of protocol treatment being conducted 
• 
Determined causal relationship 
 
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 the 
director of study site and the sponsor. When requested by the sponsor or the study site committee 
such as the ethics review committee, related data of the study site (e.g., ECG, laboratory test values, 
summary of discharge report, result of autopsy, etc.) should be provided. 
 
10.2.4 Reporting of additional information concerning adverse events 
If the sponsor requests 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 in the EDC system or submit a report within the period specified by 
the sponsor. 
 
10.2.5 Dissemination of unknown serious adverse event to joint research 
institutions 
If the director of the study site receives a report of an unexpected serious adverse event, for which a 
direct causal relationship with protocol treatment cannot be denied, from the investigator or 
subinvestigator, the director should ask the opinion of a study site committee such as the ethics 
review committee and add the items below to the report submitted by the investigator, and 
disseminate it to the monitoring committee and research institutions that are jointly conducting 
clinical study through the sponsor. 


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• 
Date of review, summery of review, result, necessary action, etc., related to the study site 
committee such as ethics review committee. 
 
10.2.6 Reporting of serious adverse events, etc., to ethics review committee, etc., 
and regulatory authorities 
If the director of the study site receives report of serious adverse event from the investigator, the 
director should ask opinion of the ethics review committee, etc., and disseminate the study sites that 
are conducting clinical study through the sponsor or the CRO (research secretariat office) consigned 
by the sponsor. 
If the director of the study site receives report of unexpected serious adverse event, the director 
should add the items below to the report submitted by the investigator, and prepare unexpected 
serious adverse event report and report to the Minister of Health, Labour and Welfare, and 
disseminate the study sites that are conducting clinical study (report to the Minister of Health, 
Labour and Welfare, and dissemination to study sites through sponsor is also possible). 
• 
Action taken for serious adverse event 
(discontinuation of new enrollment, revision of ICF, re-consent from other subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to ethics review 
committee, etc. 
• 
Dissemination to joint research institutions. 
The sponsor should report according to regulations, unexpected serious adverse drug reactions and 
other serious adverse events that are subject to emergency reporting to regulatory authorities, the 
investigator and director of study site. 
From the time point of first acknowledging the event or receiving additional information, the 
sponsor or the CRO (research secretariat office) consigned by the sponsor should comply with 
regulatory required time frame for reporting, and make emergency report concerning unexpected 
serious adverse drug reactions and expected serious adverse drug reactions to regulatory authorities. 
Also, the sponsor 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 clinical study. The study site should submit copies of emergency 
report documents to the ethics review committee, etc. 
 
 


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11.0 
COMMIITTEES 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 sponsor, research steering committee chairman, 
research steering committee members and statistics representative, and the sponsor or its designee 
will act as the secretariat. 
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 
Data monitoring committee 
The Data Monitoring Committee (hereinafter referred to as DMC) will be established according to 
the ICH E6 (1.25), and the sponsor or its designee will serve as the secretariat of the DMC. 
The purpose of the DMC is to evaluate safety report data (including DLT occurring during the DLT 
evaluation period of the phase I part of the study) independent of the research steering committee 
concerning the appropriateness of continuing the study, or changing, discontinuing, suspending, or 
other measures regarding the study, and to submit the results to the sponsor. The sponsor will 
determine whether to continue, discontinue, or change the study based on the results. 
The sponsor will prepare the DMC procedures (DMC charter) specifying the details such as the 
objective, roles, and responsibilities of the DMC, and management procedure. DMC members are 
listed in Section 1.2. 
 
 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
The sponsor's Data Management Group will perform data management activities independent of the 
Medical Affairs Division in accordance with standard operating procedures. Adverse events and 
concurrent conditions should be coded using MedDRA. 
12.1 
Case report form 
The investigator or the subinvestigator should prepare the case report form (CRF) for all subjects 
who have given consent. 
The sponsor or its designee should provide study sites with access authorization to the electronic 
data capture (hereinafter referred to as EDC). The sponsor should provide the investigator, 
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 the sponsor. The CRF will be prepared 
in Japanese. Data will be directly entered in preparing the CRF. 
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, date of 
change or correction, and its reason. 
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 bear 
full responsibility for the accuracy and reliability of all the 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 and 
“panitumumab” 
When the investigator or the subinvestigator makes a change or correction in the data entered into 
the CRF after fixation of clinical data base, a record (Data Clarification Form) of change or 
correction in the CRF provided by the sponsor should be used. The investigator should confirm that 
the record of change or correction in the CRF is accurate and complete, and sign or write name/ affix 
a seal, and date it. 
The sponsor or its designee should confirm CRF has been prepared appropriately. The sponsor or its 
designee should have access to the medical records of study subjects and in-house records to ensure 
the accuracy of the CRF as necessary. The completed CRF is the property of the sponsor, and the 
investigator or the subinvestigator should not disclose the information to a third party without a 
written permission from the sponsor. 


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12.2 
Time limit for data input into the EDC 
The sponsor or its designee should request the investigator or the subinvestigator to promptly enter 
EDC during the period from enrollment of subject to the end of follow-up. 
It is recommended that after consent has been obtained from subject, 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 much as possible. 
1. 
At enrollment: within 2 weeks (14 days) after enrollment (within 1 week (7 days) of course 1 of 
the phase I part of the study (the DLT evaluation period)) 
2. 
During protocol treatment: within 2 weeks (14 days) after the final day of each course (the 
starting day of the next course) (within 1 week (7 days) of course 1 of the phase I part of the 
study (the DLT evaluation period)) 
3. 
At discontinuation of protocol treatment: within 4 weeks (28 days) after the day of 
discontinuing protocol treatment (within 2 weeks (14 days) of course 1 of the phase I part of the 
study (the DLT evaluation period)) 
4. 
Imaging test results: within two weeks (14 days) after evaluation of efficacy 
5. 
Follow-up period: within two weeks (14 days) after request for follow-up 
6. 
Inquiry about data input items: within two weeks (14 days) from inquiry 
 
12.3 
Storage of records 
The investigator or the director of study site should store the following materials including those 
specified in Section 14.1 and study specific documents to be used by the sponsor or its designee for 
investigation and audit. The materials include a list of subject screening, medical records, signed and 
dated original consent form, and a record of change and correction of the CRF (copy)/electronic 
copy of electronic CRF containing audit trail. Also, the investigator and the director of study site 
should store the essential documents until the date that passes five years after discontinuation or 
completion of the study. However, when the sponsor requires a longer storage period, the director of 
the study site will discuss the period and methods of storage with the sponsor. 
Further, the investigator and the director of the study site will store the essential documents until the 
sponsor notifies that storage is no longer necessary. 


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13.0 
STATISTICAL ANALYSIS METHODS 
The statistics representative or his/her designee (a personnel belonging to an institution independent 
from sponsor, analysis personnel) will conduct analysis. Sponsor will not be involved in analysis. 
13.1 
Statistical and analytical plans 
The statistics representative or analysis personnel should start preparing the statistical analysis plan 
(SAP) (first version) and establish the SAP (first version) before conducting the final analysis. The 
SAP (first version) should be finalized before data fixation. 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, subject evaluability, and appropriateness of the 
planned analysis methods. 
 
13.2 
Statistical analysis of the phase I part of the study 
13.2.1 Analysis set 
Two analysis sets will be created for the phase I part of the study: “enrolled subjects who received at 
least one dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT 
evaluation set.” The “DLT evaluation set” will be based on the definition subjects included in the 
DLT evaluation in Section 8.9.2. 
 
13.2.2 Analysis of demographic and other baseline characteristics 
The following analyses will be performed in “enrolled subjects who received at least one dose of 
protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
Demographic factors will be tabulated for each subject. Frequency will be tabulated for discrete data, 
and summary statistics will be calculated for continuous data. 
 
13.2.3 Safety analysis 
13.2.3.1 Primary endpoint and analysis method 
[Primary endpoint] 
Incidence of DLT with panitumumab + TAS-102 combination therapy 


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[Analysis method] 
The incidence of DLT will evaluated in the DLT evaluation set according to Section 6.1 Study 
Design (Figure 6.a Outline of study design). In addition, a table listing each DLT event that occurs 
will be prepared. 
 
13.3 
Statistical analysis of the phase II part of the study 
13.3.1 Analysis sets 
In the phase II part of the study, statistical analysis will be performed in a “full analysis set” and 
“safety analysis set”. The “full analysis set” is the main efficacy analysis set, and is defined as 
“subjects enrolled in phase I and 2 who received at least one dose of protocol treatment (RD) and 
satisfied all of the enrollment criteria”. Detailed definitions of analysis sets are separately specified 
in the SAP. 
The analysis personnel should finalize the definition of analysis sets and appropriateness of 
analytical handling rules of the subject data in the analysis sets before data fixation in discussion 
with the statistics representative. 
 
13.3.2 Analysis of demographic and other baseline characteristics 
Perform the following analysis in the “full analysis set”. 
In the analysis of the main subject demographic factors, frequency will be tabulated for discrete data, 
and summary statistics will be calculated for continuous data. 
 
13.3.3 Efficacy analysis 
13.3.3.1 Primary endpoint and analysis method 
[Primary endpoint] 
PFS rate 6 months after enrollment 
The PFS rate 6 months after enrollment, the primary endpoint, is the gross proportion of surviving 
subjects without documented progression up to 6 months after enrollment, counting from the day of 
enrollment. Subjects with no imaging data on progression at 6 months after enrollment and subjects 
lost to follow-up will be included in the denominator, but will not be handled as progression-free. 


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The criteria for determining progression are described in “13.3.3.2 Secondary Endpoints and 
Analytical Methods for Them”. 
[Main analysis] 
The following analysis will be performed in the “full analysis set”. 
TBased on the observed PSF rate at 6 months from the day of enrollment, binomial test will be 
conducted on the null hypothesis “value will be determined invalid at PSF rate ≤ 29%”. Significant 
level will be 2.5% (one-sided) in main analysis. For interval estimation, accurate 90% confidence 
interval (two-sided) based on binomial distribution will be used. 
13.3.3.2 Secondary endpoints and analysis method 
[Secondary endpoints] 
• 
Progression-free survival (PFS) 
PFS is the period from the day of enrollment until the day of documented PD or the day of 
death due to all causes whichever comes earlier. 
Progression will include both PD based on diagnostic imaging assessed according to RECIST 
ver 1.1 (see Appendix A) and primary disease progression that cannot be confirmed by 
diagnostic imaging (clinical progression). When progression is documented by diagnostic 
imaging, the day that the diagnostic imaging is performed will be the progression date. For 
clinical progression, the day of the clinical determination will be the progression date. In a case 
where, for example, tumor diameter has become extremely small, if the status is determined to 
be “not definite progression” clinically, although the assessment is PD according to the 
response criteria, the assessment of PD according to the response criteria will take precedence 
and the status will be considered progression. (In this case, the clinical determination on 
continuing protocol treatment will take precedence.) Even if the assessment is not PD according 
to the response criteria, if there is definite clinically documented progression, the clinical 
determination will take precedence and the status will be considered progression. For surviving 
subjects without documented progression, the period will be cut off on the final day when a 
progression-free status is confirmed (final day of confirming progression-free survival). 
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 by 
telephone only will not be allowed.) Events and the cut-off will also be handled the same way 
in subjects who have discontinued protocol treatment for reasons such as toxicity and refusal of 
treatment, even if another (follow-up) therapy is added. Thus, the time of treatment 
discontinuation or the day of follow-up treatment initiation will not be the cut-off. 


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[Analysis method] 
Show the Kaplan-Meier survival curve until the onset of event in the “full analysis set” and 
calculate the quartiles for PFS and their 95% confidence intervals (two-sided). The Log-Log 
conversion of Brookmeyer and Crowley23) will be used to calculate the 95% confidence 
intervals of the quartiles for PFS. 
• 
Overall survival (OS) 
OS is the period from the day of enrollment until death by all causes. For surviving subjects, the 
period is terminated on the final day of confirming survival or data cut-off date, whichever 
occurs earlier. 
[Analysis method] 
The analysis will be performed in the same manner as for PFS in the “full analysis set”. 
 
Response rate (RR) 
RR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver 1.1 (see Appendix A) is either CR or PR. Overall response will be graded by 
favorability in the order of CR, PR, SD, PD, and NE. 
[Analysis method] 
RR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set”. 
 
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 
subjects without documented PD, the period will be cut off on the final day when specified 
diagnostic imaging reveals no PD (final day of confirming progression-free survival). For 
surviving subjects 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 progression-free survival). 
[Analysis method] Show the Kaplan-Meier survival curve until the onset of event for the 
subjects who showed response among the “full analysis set” and calculate the point estimation 
value of survival rate and its 95% confidence interval (two-sided) at the quantile of survival 
period and specified time points. 
 
Disease control rate (DCR) 
DCR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver 1.1 (see Appendix A) is CR, PR, or SD. Overall response will be graded by 
favorability in the order of CR, PR, SD, PD, and NE. 


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[Analysis method] 
DCR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set”. 
 
Time to treatment failure (TTF) 
TTF is the period from the day of enrollment until the day of the decision to discontinue 
protocol treatment, the day of documented progression during protocol treatment, or the day of 
death due to all causes whichever comes earlier. 
[Analysis method] 
The analysis of TTF will be performed in the same manner as for PFS in the “full analysis set”. 
13.3.3.3 Data conversion method and handling of missing data 
Details are separately determined in the SAP. 
13.3.3.4 Level of significance, confidence coefficient 
 
Significance level: Main analysis only, 10% (two-sided); other analyses, 5% (two-sided) 
 
Confidence coefficient: Main analysis only, 90% (two-sided); other analyses, 95% (two-sided) 
 
13.3.4 Safety analysis 
The following analysis will be performed in the “full analysis set” and “safety analysis set”. 
13.3.4.1 Treatment-Emergent Adverse Events 
Treatment-Emergent Adverse Events (TEAE) are adverse events which develop after initiation of 
protocol treatment. 
Perform the following analysis for TEAE. Code TEAE using MedDRA and summarize by Preferred 
Term (PT) and System Organ Class (SOC). 
 
Frequency tabulation of all TEAE 
 
Frequency tabulation of TEAE for which the causal relationship with protocol treatment was 
“related” 
 
Frequency tabulation of all TEAE by severity 
 
Frequency tabulation of TEAE by severity for which the causal relationship with protocol 
treatment was “related” 
 
Frequency tabulation of TEAE for action taken for protocol treatment was “discontinuation” 
 
Frequency tabulation of serious TEAE 
 


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13.4 
Criteria for interim analysis and premature discontinuation 
No interim analyses are scheduled. 
 
13.5 
Determination of the planned number of subjects 
See “6.2.2.2 Rationale for planned number of subjects“. 
 
 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of study sites 
The sponsor or its designee will perform periodic monitoring of study sites during the study to 
confirm that the study is carried out in accordance with all specifications in the protocol. Central 
monitoring and site visit monitoring, when necessary, will be performed in this study. 
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, based on the data collected by EDC. Central 
monitoring will be conducted twice a year in principle, and periodic monitoring report will be 
prepared. Periodic monitoring report will be evaluated by research steering committee and feedback 
will be given to study sites when necessary. 
Detailed procedures for central monitoring will be determined in the separately prepared procedures. 
 
14.1.2 Site visit monitoring 
Site visit monitoring is conducted to confirm that the study is carried out safely and in compliance 
with the protocol and the data are accurately collected by checking the data entered into the EDC 
against source documents. Source documents are the original documents, data and records. The 
investigator and the director of study site will ensure that the sponsor or its designee and the ethics 
review committee, etc., have access to the source documents. 
The sponsor or its designee will access the records including the list of subject screening, medical 
records, signed and dated original consent forms to confirm that the study is appropriately conducted 
in compliance with the protocol. Also, confirm the consistency between CRF and the related source 
documents. The investigator and the subinvestigator and other personnel involved in the study will 
spare sufficient time to facilitate monitoring procedures during visits to the study site. 
Prior to site visit monitoring, study sites will be randomly selected to perform Source Documents 
Verification (SDV) for the enrolled subjects. 
The frequency and procedures of study site visit monitoring should follow separately prepared 
procedure manual. 


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14.1.3 Deviations from Ethical Guideline for Clinical Research, ICH-GCP, and 
Protocol 
The investigator or the subinvestigator should record all deviations from Ethical Guideline for 
Clinical Research, ICH-GCP, and protocol. 
The investigator or the subinvestigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a prior 
written agreement with the sponsor or a prior approval from ethics review committee, etc. In the 
event of a deviation or change, the investigator should notify the sponsor and the director of the site 
of the deviation or change as well as its reason in a written form, and retain a copy of the written 
form. When necessary, the investigator may consult and agree with the sponsor on a protocol 
amendment. If the protocol is to be amended, the amendment proposal should be submitted to the 
director of the site as soon as possible and an approval should be obtained from site committee such 
as ethics review committee. 
 
14.2 
Quality assurance 
The sponsor or its designee and site committee such as ethics review committee will perform audit at 
the study site when necessary. In such a case, the auditor designated by the sponsor should contact 
the study site in advance to determine the date of audit. The auditor may request a visit to other sites 
that will be used during the study. The investigator and the director of 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., subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
Ethical Guideline for Clinical Research and the ICH-GCP. Each investigator will conduct the study 
according to regulatory requirements and in accordance with Appendix B “Responsibilities of the 
Investigator”. 
 
15.1 
Approval by the study site committee such as the ethics review 
committee 
The study site committee such as the ethics review committee is constituted according to regulations. 
The sponsor or its designee should obtain the document listing the name and title of each committee 
member. 
The sponsor or its designee should provide related documents to the study site committee such as the 
ethics review committee for review and approval of the protocol. In addition to the protocol, a copy 
of informed consent form, written materials related to subject recruitment, advertisement, and other 
documents required by regulation, when necessary, should be submitted to the central committee or 
the study site committee such as the ethics review committee to obtain approval. The sponsor should 
notify the study site, the investigator and the subinvestigator after confirming the appropriateness of 
the regulatory documents of the study site. Protocol procedures such as obtaining consent should not 
be started until the study site, the investigator and the subinvestigator receive the notification. 
The study site should comply with all the requirements specified by the study site committee such as 
the ethics review committee. The requirements include notifications to committees such as the ethics 
review committee, for instance, revision of the protocol, revision of the informed consent form, 
revision of materials related to subject recruitment, report on safety in accordance with the 
regulatory requirement, report on study implementation state at intervals determined by the study 
site committee such as the ethics review committee, and study completion report. The sponsor or its 
designee should obtain written approval from the study site committee such as the ethics review 
committee related to the above mentioned items and all related materials. 
 
15.2 
Conflict of interests 
This study will be conducted with support from sponsor. Prior to conduct of the study, the 
investigator should appropriately manage according to the study site regulation, that this study has 
no conflict of interests (hereinafter referred to as COI). 24)~28) 


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The study site should comply with all the requirements specified by the ethics review committee, etc. 
The requirements include the COI self-declaration, protocol, and informed consent form. 
15.3 
Written information and subject’s consent 
The informed consent form contains specific requirements of the Declaration of Helsinki, Ethical 
Guideline for Clinical Research and the ICH-GCP and all applicable laws and regulations. The 
informed consent form specifies the use of personal information and medical information of subjects 
in this study (both in and outside Japan: supply to a third party), and disclosure. Written explanation 
explains in detail the general idea and purpose of the study, and its possible risks and benefits. The 
informed consent form also clarifies the conditions for study participation and states the fact that 
subjects can discontinue study participation at any time without giving reasons and without loss of 
benefits in treatment. In principal, the items below are described. 
1) Clinical study and informed consent form 
2) Disease and 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 
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 subject) 
and study duration 
8) The estimated number of patients participating in the study 
9) The reason for being selected as subject 
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 


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18) Status related to funding of study, etc., study site related conflict of interest and personal 
benefits upon study, etc., study staff related conflict of interest upon study 
19) Intellectual property rights 
20) Possibility that the data is 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 they consist 
26) Issues to be followed 
27) Notification of new information and study discontinuation 
28) Explanation that on the premises of patients privacy being preserved, monitoring personnel, 
audit personnel and ethic review committee will have access to sample/information of 
subjects in the study within the scope of necessity. 
29) Explanation that informed consent cannot be obtained from anyone but the patient him or 
herself. 
The investigator is responsible for preparation, content, and the site committee such as ethics review 
committee approval of the informed consent form. The informed consent form should be approved 
by the site committee such as ethics review committee before use. 
The informed consent form should be written in a language easily understood by subjects. The 
investigator or the subinvestigator is responsible for providing detailed explanation of the informed 
consent form to subjects. Information should be provided orally and in writing as much as possible 
by the method deemed appropriate by the site committee such as ethics review committee. 
The investigator or the subinvestigator should ensure that the subjects have (1) an opportunity to 
inquire about the study and (2) sufficient time to determine study participation. When a subject 
decides to participate in the study, the subject should sign or write name/affix seal, and date the 
consent form prior to study participation. The investigator and the subinvestigator should request the 
subject to sign or write name/affix seal using a legal name and not a popular name with black or blue 
ballpoint pen. The investigator or the subinvestigator should also sign or write name/affix seal, and 
date the consent form prior to subject 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 which was signed or 
contains name/ affixed seal. The investigator or the subinvestigator should document in the subject’s 
medical record the date when the subject signed or wrote name/ affixed seal on the consent form. A 


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copy of the consent form with signature or name typed with seal affixed should be provided to the 
subject. 
The investigator or the subinvestigator should take the same procedures taken for obtaining the 
initial consent for newly obtaining consent from the concerned subject when the informed consent 
form is revised. The date of obtaining new consent should be recorded in the subject’s medical 
record, and a copy of the revised consent form should be provided to the subject. 
 
15.4 
Subject confidentiality 
The sponsor and its designee should comply with the principles of protection of the subject’s right 
against invasion of privacy. The subject ID code in this study is used to connect the clinical study 
database and related study documents of the sponsor with the source data of subjects. The limited 
information of subjects such as sex, age, and date of birth may be used within the scope of all 
applicable laws and regulations for identification of subjects and confirmation of accuracy of subject 
ID code. 
In compliance with Ethical Guideline for Clinical Research and the ICH-GCP, the sponsor should 
request the investigator for the access to the original laboratory test data, ECG, record of 
hospitalization/discharge during study period, and the original medical records such as autopsy 
report (source data or materials) by a monitor or the person designated by the sponsor, auditor 
designated by the sponsor, and the ethical committee, etc. The investigator or the subinvestigator 
should obtain approval from subject concerning access to the original medical records by a monitor 
when obtaining consent from a subject (see Section 15.3). 
When providing a copy of source documents to the sponsor, the investigator or the subinvestigator 
should delete the information leading to identification of an individual (name and address of subject, 
other personal information not recorded in CRF of subject). 
 
15.5 
Contacts for inquiries from subjects and concerned people 
The investigator should establish a contact service to respond to inquiries concerning this study from 
subjects or concerned people. Details of the contacts for inquiries will be described in the ICF. 
 


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15.6 
Advantages and disadvantages to subjects 
15.6.1 Advantage to subjects 
This study is performed as part of normal medical practice, and no advantage is expected by 
participating in this study. 
 
15.6.2 Disadvantage to subjects 
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 the sponsor. The intellectual property 
rights regarding the pharmaceutical products manufactured and/or distributed by Takeda 
Pharmaceutical Company Limited also belong to Takeda Pharmaceutical Company Limited. Data 
generated from this study may be made available for secondary use (e.g., meta-analysis) without any 
link to personally identifying information only with approval from the research steering committee 
chairman 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 the sponsor. 
 
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 director of the study site written summary of results of the 
study and provide the sponsor with all the results and data obtained from the study. Only the sponsor 
may disclose the study information to other investigators or subinvestigators during the study period 
except for a case required by laws and regulations. The sponsor will be responsible for publication of 


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the protocol and study-related results (including the public web site) except for other cases permitted 
in the study contract. 
During study period and after the end of study, the sponsor or its designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. 
The sponsor may publish the data and information obtained from the study (including the data and 
information provided by the investigator) based on the agreement with the research steering 
committee chairman. 
The investigator or the subinvestigator should obtain the prior written approval from the sponsor 
when publishing the information obtained in this study at an academic conference, etc. 
The sponsor should report to the director of the study site that final publication of the study result 
has been made. 
 
15.8.2 Clinical study registration 
Takeda Pharmaceutical Company Limited will ensure timely publication of the information of a 
clinical study and registration of all clinical researches in patients under way all over the world, prior 
to study initiation, with ClinicalTrials.gov, JAPIC, and UMIN to comply with the applicable 
laws/regulations and guidelines. The city and country where a study is performed, and the subject 
recruitment status should be registered as well as the contact information of Takeda Pharmaceutical 
Company Limited to enable general access. 
 
15.8.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited will post the results of a clinical study on 
ClinicalTrials.gov, JAPIC, and UMIN as specified by the applicable laws and/or regulations 
irrespective of results. 
 
15.8.4 Method of storage and destruction of material/information concerning 
clinical study 
The director of the study site should appropriately retain the material/information related to this 
study for at least to the date passing 5 years from the date of reporting of the ending of the study 
from the investigator or to the date passing 3 years from the date of reporting of final publication of 
the study result, whichever date is later. 


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15.9 
Insurance and compensation for injury 
The subjects participating in this study will be compensated for any injury resulting from 
participation in the study according to local regulations applicable to the study site. It should be 
noted that any treatment provided will be covered by health insurance, and no monetary 
compensation will be provided. 


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16.0 
REFEREnCES 
1) The Editorial Board of Cancer Statistics in Japan. Cancer Statistics in Japan 2014. 
Foundation for Promotion of Cancer Research: 2014. 
2) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines for the 
treatment of colorectal cancer 2014. Kanehara & CO., LTD. 
3) Pharmaceutical interview form. Panitumumab (genetical recombination) injection, latest 
version. 
4) Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label 
phase III trial of panitumumab plus best supportive care compared with best supportive 
care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin 
Oncol. 2007;25(13):1658-64. 
5) Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, 
phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin 
(FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously 
untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 
2010;28(31):4697-705. 
6) Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized 
phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) 
compared with FOLFIRI alone as second-line treatment in patients with metastatic 
colorectal cancer. J Clin Oncol. 2010;28(31):4706-13. 
7) Muro K, Yoshino T, Doi T, Shirao K, Takiuchi H, Hamamoto Y, et al. A phase 2 clinical 
trial of panitumumab monotherapy in Japanese patients with metastatic colorectal cancer. 
Jpn J Clin Oncol. 2009;39(5):321-6. 
8)  Boku N, Sugihara K, Kitagawa Y, Hatake K, Gemma A, Yamazaki N, et al. 
Panitumumab in Japanese Patients with Unresectable Colorectal Cancer: A Post-marketing 
Surveillance Study of 3085 Patients. Jpn J Clin Oncol. 2014;44(3):214-223. 
9)  Pharmaceutical interview form. Lonsurf combination tablets, latest version. 
10) Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated 
metastatic colorectal cancer: a doubleblind, randomised, placebo-controlled phase 2 trial. 
Lancet Oncol 2012; 13: 993, 1001  
11) Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et 
al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 
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12) Kuboki Y, Nishina T, Shinozaki E, Yamazaki K, Shitara K, Wataru Okamoto W, et al. 
An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for 
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Oncol 2015; 33 suppl; abstr 3544 
13) Patterson SD, Marc P, Salvatore S, Eric VC, Yves H, Jean-Luc VL, et al. Comprehensive 
analysis of KRAS and NRAS mutations as predictive biomarkers for single agent 
panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer 
(mCRC) study (20020408). J Clin Oncol 31, 2013 (suppl; abstr 3617) 


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14) Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. 
Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J 
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15) Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. 
Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in 
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16) Japanese Society of Medical Oncology. Guidance for measuring RAS (KRAS/NRAS) 
mutations in colorectal cancer patients, ver.2, April 2014. 
17) Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. Panitumumab versus 
cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic 
colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority 
phase 3 study. Lancet Oncol, 15 2014;15:569–579 
18) Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab 
monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal 
cancer. N Engl J Med 2004; 351: 337-45. 
19) Andre T, Blons H, Mabro M, Chibaudel B, Bachet JB, Tournigand C, et al. Panitumumab 
combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer 
refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational 
molecular study. Ann Oncol 2013; 24: 412-9. 
20) Tsukihara H, Nakagawa F, Sakamoto K, Ishida K, Tanaka N, Okabe H, et al. Efficacy of 
combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together 
with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. 
Oncol Rep. 2015;33(5):2135-42. 
21) Bijnsdorp IV, Kruyt FA, Fukushima M, Smid K, Gokoel S Peters GJ. Molecular 
mechanism underlying the synergistic interaction between trifluorothymidine and the 
epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. 
Cancer Sci 2010;101: 440 -7 
22) Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. 
K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer. N Eng J 
Med 2008; 359 (17);1757-65 
23) Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics 1982; 38:  29-41. 
24) Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, 
Sports, Science and Technology dated November 1, 2002) 
25) Guidelines for determining the conflict of interest polity for clinical researches (Review 
group for ethical aspects of clinical researches and conflict of interest, March 2006) 
26) Guidelines on the Management of Conflict of Interest (Conflict of Interest: COI) in 
Health and Labour Sciences Research (March 31, 2008) 
27) Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
28) Common guidelines for conflict of interest (COI) in clinical research (Japanese Society 
of Internal Medicine, Japan Society of Hepatology, Japanese Circulation Society, Japan 
Endocrine Society, Japan Diabetes Society, Japanese Respiratory Society, Japanese 


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Society of Hematology, Japanese Society of Allergology, Japanese Association for 
Infectious Diseases, Aug 2011) 
29) Lacouture ME, Mitchell EP, Piperdi B et al. Skin toxicity evaluation protocol with 
panitumumab (STEPP), a Phase II, open-label, randomized trial evaluating the impact of a 
pre-Emptive Skin treatment regimen on skin J. Clin. Oncol. 28, 1351–1357 (2010). 
30) Kobayashi Y, Komatsu Y, Yuki S, Fukushima H, Sasaki T, Iwanaga I, et al. Randomized 
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colorectal cancer: HGCSG1001 study; J-STEPP. Future Oncol. 2015 Feb;11(4):617-27. 
 


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Appendix A 
Evaluation according to RECIST ver 1.1 
Evaluation will be conducted according to RECIST ver 1.1 as follows. 
1. 
Definition of measurable lesion 
Lesion that fulfills any of the conditions below will be considered as a measurable lesion. 
(1) Lesions other than malignant lymph node (non-nodal lesion) that meet either of the below 
1) 
CT scan slice thickness no greater than 5 mm or MRI largest diameter at least10 mm 
2) 
CT scan slice thickness greater than 5 mm or MRI largest diameter is 2 folds or more 
the slice thickness 
(2) Malignant lymph node CT scan slice thickness 5 mm or less and short diameter at least 15 
mm 
(Malignant lymph node with short diameter at least 10 mm and less than 15 mm will be a 
non-target lesion, lymph node with short diameter of less than 10 mm will not be 
considered as a lesion) 
Any other lesion besides the above will be considered as non-measurable lesions. 
Note that lesions below will be considered as non-measurable lesions irrespective of test 
method or size of lesion: 
 
Bone lesions 
 
Cystic lesions 
 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy 
 
Leptomeningeal disease lesion 
 
Ascites, pleural effusion, pericardial effusion 
 
Lymphangitic involvement of skin or lung 
 
Abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques 
2. 
Baseline documentation of target lesions 
From measurable lesions observed before initiation of protocol treatment, select 5 
lesions highest in diameter (long diameter for non-nodal lesion and short diameter 
for malignant lymph node), 2 lesions at most for 1 organ and determine them as 
target lesions. Upon selection, organs with measurable lesions should be included evenly, and 
select in consideration of those that lend themselves to reproducible repeated measurements 
(lesions with large diameter but difficult to measure should be avoided). 
For chosen target lesion, in order from head to tail, record site, lesion diameters (long diameter 
for non-nodal target lesions, short axis for nodal target lesion) and a sum of diameters 
(hereinafter referred to as SoD) of all target lesions should be recorded. 
3. 
Baseline documentation of non-target lesions 
Lesions not selected for target lesion should be recorded as present or absent non-target lesion 
irrespective of whether measurement is possible or not. Multiple non-target lesions in the same 


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CONFIDENTIAL 
organ can be recorded as 1 lesion (e.g. multiple enlarged pelvic lymph nodes, multiple liver 
metastases) 
4. 
Tumor response criteria 
Evaluate target lesion and non-target lesion using the same method as at enrollment according 
to “9.2.10 Imaging test (thoracoabdominal-pelvic CT/MRI)“, and record diameter of target 
lesion, presence or absence of non-target lesion or onset of new lesion. 
5. 
Response criteria of target lesion 
 
CR (Complete Response): 
Disappearance of all non-nodal target lesions and all lymph node target lesions short axis 
<10mm If nodal target lesion is selected at baseline, response criteria may be CR even 
though SoD is not 0 mm. 
 
PR (Partial Response): 
At least a 30% decrease in the SoD of target lesions, taking as reference the baseline SoD. 
 
PD (Progressive Disease): 
Taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study), at least a 20% increase in the SoD of target lesions, and the sum must 
also demonstrate an absolute increase of at least 5 mm. 
 
SD (Stable Disease): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest SoD while on study. 
 
Not all Evaluated: 
When test cannot be conducted for some reason, or cannot be determined as CR, PR, PD 
or SD. 
SoD before treatment – SoD at evaluation 
Reduction ratio of SoD =   ――――――――――――――――――  × 100% 
SoD before treatment 
 
SoD at evaluation – Smallest SoD 
Increase ratio of SoD  =  ――――――――――――――――――  × 100% 
Smallest SoD 
 
* 
Diameter of target lesion is recorded with actual measurements (e.g., even if under 5 
mm) as much as possible, but when target lesion is determined as “too small to 
measure”, irrespective of CT slice thickness, if it is determined that tumor lesion no 
longer exists and the diameter will be recorded as 0 mm, whereas if it is determined 
to exist the diameter will be 5 mm. 


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* 
If reduction ratio meets the PR criteria and increase ratio meets the PD criteria at the 
same time, criteria will be determined as PD. 
* 
If one lesion is divided during treatment, each diameter should be added to the SoD. 
* 
If multiple lesions agglutinate and the border cannot be distinguished, the diameter of 
the agglutinated lesion should be added to the SoD. 
* 
Whenever lesions are in contact, if the borders of the lesions are distinguishable, the 
diameter of each lesion should be added to the SoD. 
6. 
Response criteria of non-target lesion 
 
CR (Complete Response): 
Disappearance of all non-nodal non-target lesions and all lymph nodes short axis <10mm 
 
Non-CR/non-PD: 
Persistence of one or more non-target lesion(s) including lymph nodes short axis ≥ 10 mm 
and/or maintenance of tumor marker either of which the level is above the common normal 
limits. 
 
PD (Progressive Disease): 
“Unequivocal progression” of existing non-target lesions (including recurrence). 
When the patient has measurable lesion: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. When response criteria for target lesion is SD or PR, an increase of non-target 
lesion that will overwhelm the tumor burden decrease will be determined as “unequivocal 
progression”, and if not it will be Non-CR/non-PD. 
When the patient has only non-measurable lesion: a 20% increase diameter in a 
non-measurable lesion, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ will be determined as “unequivocal progression”. 
 
Not all Evaluated: 
When test cannot be conducted for some reason, or cannot be determined as CR, 
Non-CR/non-PD, or PD. 
7. 
Appearance of new lesions 
When a lesion that was not present at baseline has been observed after initiation of treatment, 
this will be determined as appearance of “new lesion”. However, “new lesion” should not 
attributable to differences in scanning technique, change in imaging modality or findings 
thought to represent something other than tumor. For example, necrosis of a liver lesion may be 


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CONFIDENTIAL 
reported as a “new” cystic lesion, which it is not. A newly identified lesion in a location by test 
that was not mandatory at baseline (evaluation before enrollment) is considered a new lesion 
If a lesion disappears and reappears later, measurement will be continued. However, the 
response at the time of reappearance of the lesion will be different depending on other lesions. 
If lesion has reappeared after CR, it will be determined as PD at the time of reappearance. On 
the other hand, if it was PR or SD, when the once disappeared lesion reappears, in order to 
calculate the response, the diameter of the lesion will be added to the rest of the lesions. Thus, 
when there are a number of lesions still existing, if one lesion apparently “disappears” and 
reappears later, from that alone, it will not be determined as PD but if the SoD of all the lesions 
meet the PD criteria, it will be determined as PD. The reason for this is that there is an 
understanding that most of the lesions do not truly “disappear” and yet it cannot be extracted 
due to the limit to resolution of imaging modality. 
If there is a possibility of new lesion but cannot be confirmed, it should not be determined as a 
new lesion but re-examination by imaging test should be conducted after clinically appropriate 
interval. If new lesion is confirmed by imaging test re-examination, the date of the imaging test 
that confirmed the new lesion will be the time point for appearance of new legion. 
8. 
Overall Response 
Overall Response will be determined with combination of target lesion response, non-target 
lesion response, appearance of new lesion according to Tables A.1 and A.2 below. 
Table A.1 Overall response at each time point: When patient has target lesion (with or without 
non-target lesion) 
Target lesion 
Non-target lesion 
New lesion 
Overall 
response 
CR 
CR 
Absent 
CR 
CR 
Non-CR/non-PD 
Absent 
PR 
CR 
Not determined 
Absent 
PR 
PR 
Non-PD or defect in evaluation Absent 
PR 
SD 
Non-PD or defect in evaluation Absent 
SD 
Defect in 
evaluation 
Non-PD 
Absent 
NE 
PD 
Any 
Present or 
absent 
PD 
Any 
PD 
Present or 
absent 
PD 
Any 
Any 
Yes 
PD 


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CONFIDENTIAL 
9. 
Best Overall Response 
Response will be more favorable in the following order: CR>PR>SD>PD>NE. The most 
favorable overall response through the entire course will be the best overall response. 
When response could not be determined by imaging due to an obvious aggression of disease or 
death before the first response determination, it will be determined as PD. When response could 
not be determined by imaging due to discontinuation from toxicity or rejection by subject 
before the first response determination, it will be determined as NE. 


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CONFIDENTIAL 
Appendix B 
 
Responsibilities of the investigator 
1. 
To appropriately conduct the study in accordance with the protocol, Ethical Guideline for 
Clinical Research and the ICH-GCP considering the human rights, safety, and wellbeing of 
human subjects. 
2. 
When assigning a part of important duties related to this study to subinvestigators or study 
collaborators, prepare a list of subinvestigators or study collaborators, which will be submitted 
to the director of study site as necessary. 
3. 
To prepare the informed consent form and revise it as necessary. 
4. 
To check the contents of the study contract. 
5. 
To provide sufficient information on the protocol, drug and duties of each personnel to 
subinvestigators and study collaborators, and give guidance and supervision. 
6. 
To select subjects who satisfy the protocol, give explanation using written information, and 
obtain consent in writing. 
7. 
To be responsible for all medical judgments related to the study. 
8. 
Corresponding to request from the director of the study site, report the latest progress status at 
least once a year to the director of the study site. 
9. 
To request COI committee of each study site to review and approve that there is no COI issues 
in conducting this study. 
10. To ensure together with the director of study site that sufficient medical care is provided to 
subjects for all study-related clinically problematic adverse events throughout the period of 
subject’s study participation and thereafter. 
11. When a subject is treated at another medical institution or department, inform a physician of the 
medical institution or department in writing of the subject’s study participation and study 
completion/discontinuation after obtaining the subject’s consent, and prepare the record. 
12. When emergency report of serious adverse events, etc. is required, immediately report it in 
writing to the director of the study site and the sponsor. 
13. To prepare accurate and complete CRF and submit it to the sponsor with an electronic 
signature. 
14. To inspect and check the contents of CRF prepared by subinvestigators, or transcribed by study 
collaborators from the source data, and submit it to the sponsor with an electronic signature. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 
16. To report the study completion in writing to the director of study site. 

SAP_000.pdf: 
 
 
Title: A phase I/II study for the safety and efficacy of Panitumumab in combination with 
TAS-102 
for 
patients 
with 
RAS 
(KRAS, 
NRAS) 
wild-type, 
unresectable, 
advanced/recurrent colorectal cancer 
 
NCT Number: NCT02613221 
Statistical analysis plan Approve Date: 10-Jul-2018 
 
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). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


Page 1 of 25 
 
 
 
APOLLON study 
(A phase I/II study for the safety and efficacy of Panitumumab in 
combination with TAS-102 for patients with RAS wild-type metastatic 
colorectal cancer refractory to standard chemotherapy) 
(Protocol number: Panitumumab-1501) 
 
Statistics Analysis Plan 
 
Version 4.0 
 
 
 
 
 
PPD
PPD
PPD


Page 2 of 25 
 
 
Table of Contents 
1. History of preparation and revision ......................................................................................... 3 
2. Analysis Plan Objectives ........................................................................................................ 4 
3. Time period for Analysis ........................................................................................................ 4 
4. Analysis data set .................................................................................................................... 5 
4.1 Handling of cases/data ...................................................................................................... 5 
4.2 Number of significant figures in analysis results ................................................................. 6 
5. Software used for analysis ...................................................................................................... 6 
6. Statistical analysis of the phase I part of the study .................................................................... 7 
6.1 Analysis set ..................................................................................................................... 7 
6.2 Analysis of demographic and other baseline characteristics ................................................. 7 
6.3 Safety analysis ................................................................................................................. 8 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy ................ 8 
6.3.2 Listing of DLT events ................................................................................................ 8 
6.3.3 Frequency tabulation of adverse events ....................................................................... 8 
7. Statistical analysis of the phase II part of the study ................................................................. 10 
7.1 Analysis set ................................................................................................................... 10 
7.2 Evaluation of analysis set ............................................................................................... 10 
7.2.1 Eligibility and analysis set ........................................................................................ 10 
7.2.2 Analysis of demographic and other baseline characteristics .......................................... 11 
7.2.3 Medication status ...................................................................................................... 11 
7.2.4 Efficacy analysis ...................................................................................................... 13 
7.2.5 Safety analysis......................................................................................................... 19 
7.2.6 Other safety analysis items ....................................................................................... 20 
7.2.7 Table listing ............................................................................................................ 21 
7.3 Criteria for interim analysis and premature discontinuation ............................................... 24 
7.4 Sensitivity analysis ......................................................................................................... 24 
8. References .......................................................................................................................... 25 
 
 
 
 


Page 3 of 25 
 
 
1. History of preparation and revision 
Version 
Date of approval 
Author 
Reason for revision 
1.0 
June 3, 2016 
 
 
Not applicable, because it is the first 
version 
2.0 
February 28, 2017 
 
 
(1) Addition of definition of protocol 
treatment and acceptable range  
(2) Addition of analysis plan for phase II 
part 
3.0 
December 28, 2017 
 
 
(1) Addition of analysis items associated 
with the protocol revision (ver. 2.0) 
(2) 7.2.3 Completion of administration 
(3) 7.2.3.3 Dose reduction status 
4.0 
July 10, 2018 
 
 
(1) 3. Time Period for Analysis is 
clarified. 
(2) MedDRA version is stated. 
(3) Addition of following analysis items: 
7.2.3.2 
7.2.3.3 
7.2.4.3 1) and 2) 
7.2.4.4 
7.2.6.3 
7.2.6.4 
7.2.6.5 
 
 
 
PPD
PPD
PPD
PPD




Page 5 of 25 
 
 
treatment is met (Section 8.7 of protocol). Protocol treatment in principle will be initiated within 14 
days of entry. 
4. Analysis data set 
4.1 Handling of cases/data 
(1) Handling of laboratory values/subjective and objective findings of adverse events 
Adverse events recorded on the adverse event form will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) (ver.21.0) and summarized by system organ class (SOC) and 
preferred terms (PTs). Skin disorders will be regarded as events classified into “Skin and 
subcutaneous tissue disorders” of SOC or “Paronychia” by PT. The PTs classified as skin toxicity 
(Rash acneiform, Paronychia, Dry skin, Pruritus) are defined in Table 4.1. 
 
Table 4.1 Events classified as skin toxicity 
Rash acneiform 
Acne, Dermatitis acneiform, Folliculitis, Rash, Dermatitis, Drug eruption, 
Rash pruritic, Eczema, Skin disorder, Rash generalized, Seborrhoeic dermatitis  
Paronychia 
Paronychia, Nail avulsion, Onychoclasis, Onychomadesis, Nail disorder, 
Ingrowing nail, Excessive granulation tissue, Pyogenic granuloma  
Dry skin 
Dry skin, Skin fissures, Xeroderma, Skin exfoliation, Skin chapped, Eczema 
asteatotic, Hyperkeratosis 
Pruritus 
Pruritus, General pruritus 
 
(2) Handling of adverse event grade 
If an AE is assessed multiple times in the same subject, the highest grade among all AE 
assessments shall be reported as the worst grade of the AE. 
(3) Handling of missing/ejected data 
Missing data will not be complemented unless the details of individual analysis items are specified. 
When rejecting data, the corresponding data will be indicated and the reason for rejection clarified in 
a table. However, handling of patients with no occurrence of events related to Progression-Free 
Survival (PFS), Overall Survival (OS), or Time to Treatment Failure (TTF) will be described in each 
section. 
(4) Protocol treatment and acceptable range for tests 
Performed items 
Protocol specification 
Allowance range 
Protocol treatment 
From the date of treatment of 
the previous course (Day 1) to 
after 4 weeks (Day 29) 
Scheduled day ± 3 days 
 
 


Page 6 of 25 
 
 
4.2  Number of significant figures in analysis results 
Percentages (%) expressing frequency distribution will be rounded to one decimal place unless the 
details of individual analysis items are specified. 
Among summary statistics (number of cases, the mean, standard deviation, minimum, maximum, 
and inclusive quartiles), the mean, standard deviation, and quartiles will be rounded to one decimal 
place lower than the original data. 
P-values will be indicated to 4 decimal places rounded from the 5th decimal. However, a p-value 
less than 0.0001 will be expressed as “p < 0.0001.” Hazard ratios and their 95% confidence intervals 
will be indicated to 2 decimal places rounded from the 3rd decimal. 
 
5.  Software used for analysis 
The statistical software used for analysis will be 
 
 
 
CCI


Page 7 of 25 
 
 
6.  Statistical analysis of the phase I part of the study 
6.1  Analysis set 
Two analysis sets will be created for the phase I part of the study: “set of enrolled subjects who 
received at least one dose of protocol treatment and satisfied all of the enrollment criteria” and the 
“DLT evaluation set.” The DLT evaluation set will be based on the following definition from the 
protocol, Section 8.9.2:  
Subjects enrolled in the phase I part of the study will be included in the DLT evaluation set. 
Subjects will be excluded from the DLT evaluation if at least the designated dose of protocol 
treatment is not administered by the end of Course 1 (except when the protocol treatment is 
discontinued due to DLT), if there are major protocol deviations such as the use of contraindicated 
drugs, or if the subject is determined to be unsuitable for the DLT evaluation. The designated dose is 
75% (15 doses) of the total number of doses (20 doses) of panitumumab (2 doses of 6 mg/kg) and 
TAS-102 (2 doses daily of 35 mg/m2) on Days 1-5 and Days 8-12. 
 
6.2  Analysis of demographic and other baseline characteristics 
The following analyses will be conducted in the “set of enrolled subjects who received at least one 
dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
(1) Discrete data:  
A frequency distribution for the discrete data will be computed indicating the percentage (%) with 
the analysis set as a denominator. Aggregation items are as follows: 
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
tumor (solitary, multiple), primary tumor location [colon (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon), rectum (rectosigmoid, rectum)], [right side, left side], information 
on metastasis (number of organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, 
peritoneum, lymph node, bone, adrenal gland, skin, and others), ECOG Performance status (P.S.) 
[before treatment on Day 1 of Course 1 (0, 1)], resection of primary tumor (yes, no), adjuvant 
chemotherapy (yes, no), number of previous treatments (1, 2, 3), complications (absence, presence) 
Determination of primary tumor location: 
Right side: in the case of solitary or multiple lesions in the cecum, ascending colon, and transverse 
colon 
Left side: in the case of solitary or multiple lesions in the descending colon, sigmoid colon, 
rectosigmoid, and rectum 
 
(2) Continuous data:  
Summary statistics (number of cases, mean, standard deviation, minimum, maximum, and 


Page 8 of 25 
 
 
inclusive quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment), period 
from the start date of first-line treatment to the date of enrollment (months) (One month is 
considered as 28 days in calculations).  
 
6.3  Safety analysis 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy 
In accordance with the protocol, Section 8.9.3., the number of cases determined as DLTs among 
subjects in the DLT evaluation set will be shown and the percentage (%) will be indicated with the 
total number of cases in the DLT evaluation set as a denominator. 
 
6.3.2 Listing of DLT events 
A table listing events determined as DLTs in the DLT evaluation set will be prepared. 
Display items:  
Subject No., sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment initiation date, DLT 
event name (event name recorded by physician, Lowest Level Terms [LLT] code, LLT (English, 
Japanese), PT code, PT (English, Japanese), SOC code, SOC (English, Japanese), date of onset, 
severity, causal relationship of adverse event with protocol treatment, causal relationship with 
panitumumab, seriousness, discontinuation of protocol treatment, outcome, date of resolution 
 
6.3.3  Frequency tabulation of adverse events 
The following analyses regarding treatment-emergent adverse events (TEAEs) will be performed 
on the “set of enrolled subjects who received at least one dose of protocol treatment and satisfied all 
of the enrollment criteria” and the “DLT evaluation set.” 
TEAEs are adverse events that develop after initiation of protocol treatment. 
Skin toxicity are events meeting the definitions of TEAEs in Table 4.1. 
TEAEs will be coded using MedDRA and summarized by SOC and PTs.  
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
6.3.3.1 Frequency tabulation of all TEAEs 
6.3.3.2 Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
6.3.3.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 


Page 9 of 25 
 
 
6.3.3.4 Frequency tabulation of all TEAEs by severity 
6.3.3.5 Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
6.3.3.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
6.3.3.7 Frequency tabulation of TEAEs for action taken for protocol treatment was 
“discontinuation” 
6.3.3.8 Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 
6.3.3.9 Frequency tabulation of serious TEAEs 
6.3.3.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
6.3.3.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
6.3.3.12 Frequency tabulation of non-serious TEAEs with > 5% incidence 
6.3.3.13 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with protocol treatment was “related” 
6.3.3.14 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with panitumumab was “related” 
6.3.3.15 Frequency tabulation of TEAEs with ≥ Grade 3 
6.3.3.16 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
protocol treatment was “related” 
6.3.3.17 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
6.3.3.18 The incidence rate of TEAEs of Grade ≥ 3 
6.3.3.19 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with protocol 
treatment was “related” 
6.3.3.20 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
 
The following analyses will be performed on the “set of enrolled subjects who received at least 
one dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation 
set.” 
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 


Page 10 of 25 
 
 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 
confidence intervals will be calculated using the following formula:  
 
95% confidence interval of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
Skin toxicity will be analyzed similarly as described above (6.3.3.1 to 6.3.3.20) 
 
7.  Statistical analysis of the phase II part of the study 
7.1  Analysis set 
In the phase II part of the study, statistical analysis will be performed on a “full analysis set” and 
“safety analysis set.” The “full analysis set” will be the main efficacy analysis set, and is defined as 
“subjects enrolled in phase I and II who received at least one dose of protocol treatment (RD) and 
satisfied all of the enrollment criteria.” RD is the recommended dose that is confirmed in the phase I 
part. The "safety analysis set" is defined as “subjects enrolled in phase I and II who received at least 
one dose of either panitumumab orTAS-102.” Additionally, the set of all subjects who are enrolled in 
this study is defined as "all enrolled subjects." 
The statistics representative and analysis personnel should finalize a statistical analysis plan 
before data fixation based on confirmation of the definition of analysis sets and appropriateness of 
analytical handling rules of the subject data in the analysis sets, and additional handling rules for the 
issues that are not determined at planning before data fixation. 
 
7.2  Evaluation of analysis set 
7.2.1  Eligibility and analysis set 
A flow chart showing the breakdown of “all enrolled subjects,” “full analysis set,” and “safety 
analysis set,” and reasons for patients not being included in the analysis set will be tabulated and 
shown with a flow chart. 
Reason for exclusion of safety analysis set: 
• 
Never received panitumumab or TAS-102 
 
Reason for exclusion of the full analysis set 
• 
Not meeting enrollment criteria 
• 
Never received protocol treatment (RD) 
 


Page 11 of 25 
 
 
7.2.2  Analysis of demographic and other baseline characteristics 
7.2.2.1  Demographic and other baseline characteristics 
The following analyses will be performed on “all enrolled subjects,” the “full analysis set,” and 
the “safety analysis set”:  
(1) Discrete data 
A frequency distribution will be tabulated for discrete data, and the percentage (%) will be 
indicated with the analysis set as a denominator. Tabulation items are as follows:  
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
tumor (solitary, multiple), primary tumor location [colon (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon), rectum (rectosigmoid, rectum)], [right side, left side], information 
on metastasis (number of organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, 
peritoneum, lymph node, bone, adrenal gland, skin, and others), ECOG Performance status (P.S.) 
[before treatment on Day 1 of Course 1 (0, 1)], resection of primary tumor (yes, no), adjuvant 
chemotherapy (yes, no), number of previous treatments (1, 2, 3), complications (absence, presence). 
 
(2) Continuous data 
Summary statistics (number of cases, the mean, standard deviation, minimum, maximum, 
quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment), period 
from the start date of first-line treatment to the date of enrollment (months) (One month is 
considered as 28 days in calculations).  
. 
 
7.2.2.2  Breakdown of complications 
The frequency distribution of complications in “all enrolled subjects,” “full analysis set,” and 
“safety analysis set” will be tabulated, and the percentage (%) will be indicated with the analysis set 
as the denominator. Complications will be coded using MedDRA and summarized by SOC and PTs. 
 
7.2.3 Medication status 
7.2.3.1  Completion of administration 
The summary statistics (number of cases, mean, median, standard deviation, minimum, maximum, 
quartiles) of the cumulative dose and relative dose intensity (RDI) up to 6 months after the start of 
protocol treatment (168 days) or until the completion date of the course over the period of 6 months 
(168 days) will be calculated by drug for the “full analysis set” and “safety analysis set.” The RDI 
will be calculated using the following formulae:  


Page 12 of 25 
 
 
 
 
Total RDI (%) = (all actual dose/all planned dose) x (168/actual number of days of all courses) × 
100 
 
7.2.3.2  Completion of administration by worst grade of stomatitis 
The cumulative dose and summary statistics of RDI (number of cases, mean, SD, minimum, 
maximum, quartile) will be calculated for the “full analysis set” and “safety analysis set” by the 
presence/absence of stomatitis, worst grade, and by drug up to 6 months (168 days) after the start of 
protocol treatment or to the date of completion of the course across 6 months (168 days). 
 
7.2.3.3  Initial onset of stomatitis and cumulative dose 
Kaplan-Meier method will be used to estimate survival curve until the onset of event in the “safety 
analysis set,” and the point estimation value of incidence and its 95% confidence interval 
(two-sided) will be calculated at the quartile of the cumulative dose to the initial onset of event and 
specified time points.  
Cumulative dose is to be the dose accumulated by the time of initial onset of event for each drug. 
For cases without event occurrence, the cumulative dose to the date of death, date of 
discontinuation/dropout, date of last survival confirmation, or the date of data cut-off, whichever is 
earlier, will be used. 
First onset of event: ≥ Grade 1 stomatitis, ≥ Grade 2 stomatitis, ≥ Grade 3 stomatitis 
 
7.2.3.4 Reason for discontinuation of protocol treatment 
Reasons for discontinuation of patients who withdraw up to 6 months (168 days) and during the 
entire study period in the “full analysis set” and “safety analysis set” will be tabulated, and the 
percentage (%) will be indicated with the respective analysis set as the denominator. 
Reasons for discontinuation of protocol treatment:  
• 
Lack of efficacy (progression) 
• 
Adverse event 
• 
Voluntary discontinuation 
• 
Death during protocol treatment 
• 
Significant deviation from the protocol 
• 
Lost to follow-up 
• 
Discontinuation of the entire study 
• 
Pregnancy 
• 
Others 


Page 13 of 25 
 
 
 
7.2.3.5  Dose reduction status 
The frequency and percentage (%) of the subjects with dose reduction from the initial dose of the 
treatment period up to 6 months after the start of protocol treatment (168 days), or until the 
completion date of the course over the period of 6 months (168 days), and over the entire study 
period will be tabulated for each drug for the “full analysis set” and “safety analysis set.” Drug 
withdrawal or treatment discontinuation will not be regarded as dose reduction. 
 
7.2.3.6  Follow-up status 
The quartiles of follow-up period will be calculated in the “full analysis set” and “safety analysis 
set.” The follow-up period is the period from the day of enrollment until the day of completion of 
follow-up. The reverse Kaplan-Meier method will be used to calculate the quartiles of the follow-up 
period.1) The final date of follow-up is the date before the date of death for the case of death, and on 
the final day on which survival is confirmed for surviving subjects 
 
7.2.4  Efficacy analysis 
7.2.4.1  Primary endpoint and analysis method 
[Primary endpoint] 
Progression-free survival (PFS rate) at 6 months after enrollment  
The PFS rate 6 months after enrollment, the primary endpoint, is the gross proportion of surviving 
subjects without documented progression up to 6 months after enrollment (date of enrollment + 24 
weeks ± 2 weeks), counting from the day of enrollment. Subjects with no imaging data on 
progression at 6 months after enrollment and subjects lost to follow-up will be included in the 
denominator, but will not be handled as progression-free. 
 
Definition of progression:  
Progression will include both progressive disease (PD) based on diagnostic imaging assessed 
according to RECIST ver. 1.1 and primary disease progression that cannot be confirmed by 
diagnostic imaging (clinical progression). When progression is documented by diagnostic imaging, 
the day on which the diagnostic imaging is performed will be the progression date. For clinical 
progression, the day of the clinical determination will be the progression date. In a case in which, for 
example, tumor diameter has become extremely small, if the status is determined to be “not definite 
progression” clinically, although the assessment is PD according to the response criteria, the 
assessment of PD according to the response criteria will take precedence and the status will be 
considered progression. (In this case, the clinical determination on continuing protocol treatment will 
take precedence.) Even if the assessment is not PD according to the response criteria, if there is 


Page 14 of 25 
 
 
definite clinically documented progression, the clinical determination will take precedence and the 
status will be considered progression. For surviving subjects without documented progression, the 
period will be cut off on the final day when a progression-free status is confirmed (final day of 
progression-free survival confirmation). 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 by telephone only will not be allowed. Events and the cut-off will also be 
handled the same way in subjects who have discontinued protocol treatment for reasons such as 
toxicity and refusal of treatment, even if another (follow-up) therapy is added. Thus, the time of 
treatment discontinuation or the day of follow-up treatment initiation will not be the cut-off. 
 
[Main analysis] 
The following analysis will be performed on the “full analysis set.” 
PFS rate at 6 months is calculated by counting of subjects with progression, without progression, 
and unconfirmed at 6 months. Based on the observed PFS rate at 6 months from the day of 
enrollment, binomial test will be conducted on the null hypothesis “value will be determined invalid 
at PFS rate ≤ 29%.” Significant level will be 2.5% (one-sided) in the main analysis. For interval 
estimation, accurate 90% confidence interval (two-sided) based on binomial distribution will be 
used. 
 
7.2.4.2  Secondary endpoints and analysis method 
[Secondary endpoints] 
1) Progression-free survival (PFS) 
PFS is the period from the day of enrollment until the day of documented PD (radiological 
decision or clinical decision) or the day of death due to any cause, whichever comes earlier. 
For surviving subjects without documented progression, the period will be cut off on the final 
day on which progression-free status is confirmed (final day of progression-free survival 
confirmation). Events and the cut-off will also be handled the same way in subjects who have 
discontinued protocol treatment for reasons such as toxicity and refusal of treatment, even if 
another (follow-up) therapy is added. Thus, the time of treatment discontinuation or the day of 
follow-up treatment initiation will not be the cut-off. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of PFS and specified time points. The 


Page 15 of 25 
 
 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for PFS. 
 
2) Overall survival (OS) 
OS is the period from the day of enrollment until death by any cause. For surviving subjects, 
the period is terminated on the final day of survival confirmation or data cut-off date, whichever 
occurs earlier. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of OS and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for OS. 
3) Response rate (RR) 
RR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is either complete response or partial response. Overall response will be 
graded by favorability in the order of complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), and not evaluable (NE). Best overall response is the 
best response recorded throughout all courses. 
 
[Analysis method] 
RR of target lesion and its 95% confidence interval (two-sided) will be calculated in the “full 
analysis set.” 
Further, the maximum tumor reduction rate will be calculated for each subject, and a waterfall 
plot will be created by arranging the maximum tumor reduction rate in ascending order. Lines 
of reference at -30% indicating PR and at + 20% indicating PD will be drawn. 
 
Reduction ratio of SoD = SoD at evaluation point −SoD before treatment 
SoD before treatment
 × 100% 
 
4) Duration of response (DOR) 


Page 16 of 25 
 
 
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 any cause, whichever occurs earlier. For surviving 
subjects without documented PD, the period will be cut off on the final day of progression-free 
survival confirmation. 
[Analysis method] 
The Kaplan-Meier survival curve will show the subject status until the onset of event for the 
subjects who showed response among the “full analysis set,” and the point estimation value of 
survival rate and its 95% confidence interval (two-sided) will be calculated at the quartile of 
DOR and specified time points. 
 
5) Disease control rate (DCR) 
DCR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is CR, PR, or SD. 
[Analysis method] 
DCR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set.” 
 
6) Time to treatment failure (TTF) 
TTF is the period from the day of enrollment until the day of the decision to discontinue 
protocol treatment, the day of documented progression during protocol treatment (day of 
decision on clinical PD or radiological PD), or the day of death due to any cause, whichever 
comes earlier. Subjects not included in the above criteria will be censored at the dose starting 
date in the final course. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of TTF and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for TTF. 
 
7.2.4.3 Subgroup analysis of efficacy 


Page 17 of 25 
 
 
1) Subgroup analysis on the following items will be performed for each background factor 
described below. The same analysis method will be used as in Sections 7.2.4.1 and 7.2.4.2. 
Using all background factors as explanatory variables, multivariate analysis will be performed 
using the Cox proportional hazard model for PFS, OS, and TIF. Similarly, using all background 
factors as explanatory variables, logistic regression analysis will be performed for PFS rate and 
DCR.  
 7.2.4.3.1.1 PFS rate  
 7.2.4.3.1.2 PFS 
 7.2.4.3.1.3 OS 
 7.2.4.3.1.4 RR 
 7.2.4.3.1.5 DCR 
 7.2.4.3.1.6 TTF 
 
Background factors: 
Age (≥ 20 years ˂ 65 years, ≥ 65 years ˂ 75 years), sex, ECOG Performance status (P.S.) 
[before dosing on Day 1 of Course 1 (0, 1)], information on primary tumor location [right, left], 
adjuvant chemotherapy (yes, no), resection of primary lesion (yes, no), number of days since 
the start of first-line treatment (˂ 600 days, ≥ 600 days) 
 
2) A landmark analysis for PFS, OS, and TIF will be performed for each landmark point after 
enrollment. Patients developing applicable events by the landmark point after enrollment and 
those who have been discontinued will be excluded from the analysis. The same analysis 
method will be used as in Section 7.2.4.2. 
7.2.4.3.2.1 PFS 
7.2.4.3.2.2 OS 
7.2.4.3.2.3 TTF 
Factor 
Landmark point 
Category 
Skin Toxicity, 
Week 6 
≤G1, ≥G2 
Skin Toxicityr 
Week 10 
≤G1, ≥G2 


Page 18 of 25 
 
 
Factor 
Landmark point 
Category 
Stomatitis 
Week 6 
≤G1, ≥G2 
Stomatitis 
Week 10 
≤G1, ≥G2 
Neutropenia 
Week 6 
≤G0, ≥G1 
Neutropenia 
Week 6 
≤G2, ≥G3 
Early Tumor Shrinkage (ETS)* 
Week 8 
Yes,  No 
*ETS refers to the case of tumor shrinkage by at least 20% within 8 weeks after enrollment. 
 
7.2.4.4  Other efficacy analysis items 
1) ETS 
The presence/absence of cases with tumor shrinkage by at least 20% within 8 weeks after 
enrollment, the number of patients who dropped out (discontinued protocol treatment) within 8 
weeks after enrollment in the full analysis set, and the dropout rate will be shown. 
2) Administration of each drug and the change from the onset of response to death or completion 
of observation 
Swimmers plot will be created to illustrate the change from the onset of response to death or 
completion of observation. 
Date of response onset: the date CR or PR is first confirmed 
Vertical axis: case 
Horizontal axis: duration (days) 
Administration status: A bar graph showing the duration of TAS administration (from Day 1 of 
TAS-102 to the date of last administration of TAS-102, with “x” indicating administration of 
panitumumab. 
     ▲ will indicate the date of discontinuation of protocol treatment.  
     Therapeutic effect: ○ will indicate the date of response onset  
■ will indicate the confirmation date of PD. 
Survival: The OS part after discontinuation of protocol treatment will be indicated as ---- 
(survivors will be distinguished by color) 
Post treatment: ● will indicate the start date of post treatment. 


Page 19 of 25 
 
 
 
3) Time-course change in the reduction rate of the sum of target lesion diameters 
A spider plot will be created to describe the reduction rate of the sum of target lesion 
diameters in all patients by best overall response of PR, SD, and PD. 
 
7.2.4.5 Level of significance, confidence coefficient 
Significance level: Main analysis only, 5% (one-sided); other analyses, 5% (two-sided) 
Confidence coefficient: Main analysis only, 90% (two-sided); other analyses, 95% (two-sided) 
 
7.2.5  Safety analysis 
The following analyses regarding TEAEs will be performed on the “full analysis set” and “safety 
analysis set.” 
TEAEs will be coded using MedDRA and summarized by SOC and PTs. 
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
7.2.5.1 Frequency tabulation of all TEAEs 
7.2.5.2 Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
7.2.5.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 
7.2.5.4 Frequency tabulation of all TEAEs by severity 
7.2.5.5 Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
7.2.5.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
7.2.5.7 Frequency tabulation of TEAEs for action taken for protocol treatment was 
“discontinuation” 
7.2.5.8 Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 
7.2.5.9 Frequency tabulation of serious TEAEs 
7.2.5.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
7.2.5.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
7.2.5.12 Frequency tabulation of non-serious TEAEs with > 5% incidence 


Page 20 of 25 
 
 
7.2.5.13 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with protocol treatment was “related” 
7.2.5.14 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with panitumumab was “related” 
7.2.5.15 Frequency tabulation of TEAEs with ≥ Grade 37.2.5.16 Frequency tabulation of TEAEs 
with ≥ Grade 3 for which the causal relationship with protocol treatment was “related” 
7.2.5.17 Frequency tabulation of TEAEs with ≥ Grade 3 for which the causal relationship with 
panitumumab was “related” 
7.2.5.18 The incidence rate of TEAEs with ≥ Grade 3 
7.2.5.19 The incidence rate of TEAEs with ≥ Grade 3 for which the causal relationship with 
protocol treatment was “related” 
7.2.5.20 The incidence rate of TEAEs with ≥ Grade 3 for which the causal relationship with 
panitumumab was “related” 
 
The following analyses will be performed on the “full analysis set” and “safety analysis set”:  
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 
confidence intervals will be calculated using the following formula:  
The 95% confidence intervals of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
Skin toxicity will be analyzed similarly as described above (7.2.5.1 to 7.2.5.20) 
 
7.2.6  Other safety analysis items 
7.2.6.1  ECOG P.S. 
The frequency distribution of ECOG P.S. in the “full analysis set” and “safety analysis set” will 
be tabulated for each course, and the percentage (%) will be indicated with the analysis set at Day 1 
of each course (excluding withdrawal cases) as the denominator. 
 
7.2.6.2  Laboratory tests 
A shift table will be prepared by performing a cross tabulation (number of cases and the 
percentages) of the results of CTCAE grading based on laboratory values for each test item in the 
“full analysis set” and “safety analysis set,” using the worst grade at the start and after the start of 
treatment. The percentage (%) will be indicated with the respective analysis set as the denominator. 


Page 21 of 25 
 
 
Test items: 
Neutrophil count, platelet count, hemoglobin level, total bilirubin, ALT (GPT), AST (GOT), 
creatinine, Mg, albumin, Na, K, Ca 
 
 
7.2.6.3  Number of days to the onset of specific event 
Summary statistics will be calculated for the number of days from the start date of protocol 
treatement to the onset of the events below in the “full analysis set” and “safety analysis set.” 
Target events: 
≥ Grade 1 stomatitis, worst Grade stomatitis, ≥ Grade 3 stomatitis, ≥ Grade 3 dermatitis acneiform, 
≥  Grade 3 hypomagnesaemia, ≥  Grade 2 skin toxicity 
 
7.2.6.4  Subsequencet therapy 
With regard to the implementation status of Subsequencet therapy in the “full analysis set” and 
“safety analysis set,” the frequency distribution of the following items will be shown, as well as the 
percentages (%) with analysis set as the denominator:  
Implementation status of Subsequencet therapy 
No 
Patients with continuous treatment 
 
Deaths within 4 weeks of discontinuation of protocol treatment 
 
BSC after 4 weeks of discontinuation of protocol treatment 
Yes 
Regorafenib 
 
Other 
 
 
7.2.6.5  Effects between specific events 
Cross-tabulation by the presence/absence of occurrence and cross-tabulation by grade will be 
performed for events 1 and 2, below, in the “full analysis set” and “safety analysis set.” Cases of no 
event will be counted as Grade 0. The percentages (%) will be shown with analysis set as the 
denominator. 
Event 1 
Event 2 
Neutropenia 
Stomatitis 
Dermatitis acneiform 
Stomatitis 
 
7.2.7 Table listing 
The following tables will be created for the “enrolled subjects” in section 7.2.7.2 and for the 
“safety analysis set” in other sections 


Page 22 of 25 
 
 
 
7.2.7.1  List of subjects who discontinued protocol treatment  
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, date of discontinuation, reason for discontinuation, adverse 
event name (event name recorded by physician, LLT code, LLT (English, Japanese), PT code, PT 
English, Japanese), SOC code, SOC (English, Japanese), date of onset, severity, causal relationship 
of adverse event with protocol treatment, causal relationship with panitumumab, seriousness, 
discontinuation of protocol treatment, outcome, date of resolution  
 
7.2.7.2  List of subjects/data excluded from analysis 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, reason for exclusion 
 
7.2.7.3  List of fatal cases 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, date of death, reason for death, adverse event name (event 
name recorded by physician, LLT code, LLT (English, Japanese), PT code, PT (English, Japanese), 
SOC code, SOC (English, Japanese), date of onset, seriousness, causal relationship of adverse event 
with protocol treatment, causal relationship with panitumumab, seriousness, discontinuation of 
protocol treatment, outcome, date of resolution  
 
7.2.7.4  List of treatments 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, primary lesion (information on primary organ, site, 
with/without resection, date of surgery), metastatic lesion (number of organs with metastases, site, 
with/without resection, date of surgery), performing a palliative colostomy (with/without, date of 
surgery), bypass surgery (with/without, date of surgery), radiation therapy (radical irradiation) 
(with/without, date of surgery, date of final dose), first-line treatment (start date, treatment details), 
second-line treatment (treatment details), third-line treatment (with/without, treatment details), 
preoperative/postoperative adjuvant chemotherapy (with/without, time period, oxaliplatin-containing 
regimen, date of final dose) 
 


Page 23 of 25 
 
 
7.2.7.5  List of protocol treatment status 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, start date of TAS-102 by course, dose, number of doses, date 
of panitumumab administration, dose, presence or absence of discontinuation of protocol treatment, 
date of discontinuation, reason for discontinuation 
 
7.2.7.6  List of complications 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, name of complication (name of complication recorded by 
physician, LLT code, LLT (English, Japanese), PT code, PT (English, Japanese), SOC code, SOC 
(English, Japanese)  
 
7.2.7.7  Table of MedDRA-coded AEs 
Display items: 
Name of AE recorded by physician LLT code, LLT (English, Japanese), PT code, PT (English, 
Japanese), SOC code, SOC (English, Japanese) 
 
7.2.7.8  List of TEAEs 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, adverse event name (event name recorded by physician, LLT 
code, LLT (English, Japanese), PT code, PT (English, Japanese), SOC code, SOC (English, 
Japanese), date of onset, severity, causal relationship with protocol treatment, causal relationship 
with panitumumab, seriousness, discontinuation of protocol treatment, outcome, date of resolution.  
 
7.2.7.9  List of Deaths and other serious adverse events 
Display items: 
Same as “List of TEAEs” 
 
7.2.7.10  List of skin toxicity 
Display items: 
Same as “List of TEAEs” 
 
7.2.7.11  List of RECIST response evaluations 


Page 24 of 25 
 
 
Display items:  
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, evaluation period, sum of target lesion diameter (before 
treatment, at evaluation), reduction rate of sum of target lesion diameter, results of response 
evaluation of target lesion, results of response evaluation of non-target lesion, development of new 
lesion, site of new lesion, results of overall response evaluation 
 
Reduction ratio of SoD = SoD at evaluation point −SoD before treatment 
SoD before treatment
 × 100% 
 
7.2.7.12  List of determinations of PD 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, day of decision on clinical PD, day of decision on 
radiological PD, final day of imaging test, final day on which progression-free survival is confirmed, 
start date of follow-up treatment 
 
7.2.7.13  List of survival survey results 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, survival survey results, last confirmed date of survival, date 
of death, reason of death (other details) 
 
7.2.7.14  List of laboratory test values 
Display items: 
 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, laboratory test items, test date, measured values (SI), Unit 
(SI), site reference values (SI) (lower limit – upper limit) 
Test items: Same as 7.2.6.2. 
 
7.3  Criteria for interim analysis and premature discontinuation 
No interim analyses are scheduled. 
 
7.4  Sensitivity analysis 
Sensitivity analysis of primary endpoint 


Page 25 of 25 
 
 
For the PFS rate at 6 months (the primary endpoint), results will be calculated for the case in 
which the period is terminated at the point follow-up treatment is initiated, and the difference 
between major analysis results will be confirmed. 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the “full 
analysis set,” and the point estimation value of survival rate and its 95% confidence interval 
(two-sided) will be calculated at the quartile of PFS and specified time points. The Log-Log 
conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence intervals of the 
quartiles for PFS. 
In evaluating PFS, results will be calculated for the case of termination at the point follow-up 
treatment is initiated (start date of follow-up treatment), and the difference between that and the 
results for the case in which the period is cut off on the last confirmed date of progression-free 
status. 
 
8.  References 
1) Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials 1996; 17: 343–46. 


Page 1 of 22 
 
 
 
APOLLON study 
(A phase I/II study for the safety and efficacy of Panitumumab in 
combination with TAS-102 for patients with RAS wild-type metastatic 
colorectal cancer refractory to standard chemotherapy) 
(Protocol number: Panitumumab-1501) 
 
Statistics Analysis Plan 
 
Version 3.0 
 
 
 
 
 
PPD
PPD
PPD


Page 2 of 22 
 
 
Table of Contents 
1. History of preparation and revision ......................................................................................... 3 
2. Analysis Plan Objectives ........................................................................................................ 4 
3. Time period for Analysis ........................................................................................................ 4 
4. Analysis data set .................................................................................................................... 5 
4.1 Handling of cases/data ...................................................................................................... 5 
4.2 Number of significant figures in analysis results ................................................................. 5 
5. Software used for analysis ...................................................................................................... 6 
6. Statistical analysis of the phase I part of the study .................................................................... 7 
6.1 Analysis set ..................................................................................................................... 7 
6.2 Analysis of demographic and other baseline characteristics ................................................. 7 
6.3 Safety analysis ................................................................................................................. 8 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy ................ 8 
6.3.2 Listing of DLT events ................................................................................................ 8 
6.3.3 Frequency tabulation of adverse events ....................................................................... 8 
7. Statistical analysis of the phase II part of the study ................................................................. 10 
7.1 Analysis set ................................................................................................................... 10 
7.2 Evaluation of analysis set ............................................................................................... 10 
7.2.1 Eligibility and analysis set ........................................................................................ 10 
7.2.2 Analysis of demographic and other baseline characteristics ......................................... 10 
7.2.3 Medication status ...................................................................................................... 11 
7.2.4 Efficacy analysis ...................................................................................................... 12 
7.2.5 Safety analysis......................................................................................................... 16 
7.2.6 Other safety analysis items ....................................................................................... 18 
7.2.7 Table listing ............................................................................................................ 18 
7.3 Criteria for interim analysis and premature discontinuation ............................................... 21 
7.4 Sensitivity analysis ......................................................................................................... 21 
8. References .......................................................................................................................... 22 
 
 
 
 


Page 3 of 22 
 
 
1. History of preparation and revision 
Version 
Date of approval 
Author 
Reason for revision 
1.0 
June 3, 2016 
 
 
Not applicable, because it is the first 
version 
2.0 
February 28, 2017 
 
 
(1) Addition of definition of protocol 
treatment and acceptable range  
(2) Addition of analysis plan for phase II 
part 
3.0 
December 28, 2017 
 
 
(1) Addition of analysis items associated 
with the protocol revision (ver. 2.0) 
(2) 7.2.3 Completion of administration 
(3) 7.2.3.3 Dose reduction status 
 
 
 
PPD
PPD
PPD




Page 5 of 22 
 
 
4. Analysis data set 
4.1 Handling of cases/data 
(1) Handling of laboratory values/subjective and objective findings of adverse events 
Adverse events recorded on the adverse event form will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred terms 
(PTs). Skin disorders will be regarded as events classified into “Skin and subcutaneous tissue 
disorders” of SOC or “Paronychia” by PT. The PTs classified as skin toxicity (Rash acneiform, 
Paronychia, Dry skin, Pruritus) are defined in Table 4.1. 
 
Table 4.1 Events classified as skin toxicity 
Rash acneiform 
Acne, Dermatitis acneiform, Folliculitis, Rash, Dermatitis, Drug eruption, 
Rash pruritic, Eczema, Skin disorder, Rash generalized, Seborrhoeic dermatitis  
Paronychia 
Paronychia, Nail avulsion, Onychoclasis, Onychomadesis, Nail disorder, 
Ingrowing nail, Excessive granulation tissue, Pyogenic granuloma  
Dry skin 
Dry skin, Skin fissures, Xeroderma, Skin exfoliation, Skin chapped, Eczema 
asteatotic, Hyperkeratosis 
Pruritus 
Pruritus, General pruritus 
 
(2) Handling of adverse event grade 
If an AE is assessed multiple times in the same subject, the highest grade among all AE 
assessments shall be reported as the worst grade of the AE. 
(3) Handling of missing/ejected data 
Missing data will not be complemented unless the details of individual analysis items are specified. 
When rejecting data, the corresponding data will be indicated and the reason for rejection clarified in 
a table. However, handling of patients with no occurrence of events related to Progression-Free 
Survival (PFS), Overall Survival (OS), or Time to Treatment Failure (TTF) will be described in each 
section. 
(4) Protocol treatment and acceptable range for tests 
Performed items 
Protocol specification 
Allowance range 
Protocol treatment 
From the date of treatment of 
the previous course (Day 1) to 
after 4 weeks (Day 29) 
Scheduled day ± 3 days 
 
 
4.2  Number of significant figures in analysis results 
Percentages (%) expressing frequency distribution will be rounded to one decimal place unless the 


Page 6 of 22 
 
 
details of individual analysis items are specified. 
Among summary statistics (number of cases, the mean, standard deviation, minimum, maximum, 
and inclusive quartiles), the mean, standard deviation, and quartiles will be rounded to one decimal 
place lower than the original data. 
P-values will be indicated to 4 decimal places rounded from the 5th decimal. However, a p-value 
less than 0.0001 will be expressed as “p < 0.0001.” Hazard ratios and their 95% confidence intervals 
will be indicated to 2 decimal places rounded from the 3rd decimal. 
 
5.  Software used for analysis 
The statistical software used for analysis will be 
 
 
 
CCI


Page 7 of 22 
 
 
6.  Statistical analysis of the phase I part of the study 
6.1  Analysis set 
Two analysis sets will be created for the phase I part of the study: “set of enrolled subjects who 
received at least one dose of protocol treatment and satisfied all of the enrollment criteria” and the 
“DLT evaluation set.” The DLT evaluation set will be based on the following definition from the 
protocol, Section 8.9.2:  
Subjects enrolled in the phase I part of the study will be included in the DLT evaluation set. 
Subjects will be excluded from the DLT evaluation if at least the designated dose of protocol 
treatment is not administered by the end of Course 1 (except when the protocol treatment is 
discontinued due to DLT), if there are major protocol deviations such as the use of contraindicated 
drugs, or if the subject is determined to be unsuitable for the DLT evaluation. The designated dose is 
75% (15 doses) of the total number of doses (20 doses) of panitumumab (2 doses of 6 mg/kg) and 
TAS-102 (2 doses daily of 35 mg/m2) on Days 1-5 and Days 8-12. 
 
6.2  Analysis of demographic and other baseline characteristics 
The following analyses will be conducted in the “set of enrolled subjects who received at least one 
dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
(1) Discrete data:  
A frequency distribution for the discrete data will be computed indicating the percentage (%) with 
the analysis set as a denominator. Aggregation items are as follows: 
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
tumor (solitary, multiple), primary tumor location [colon (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon), rectum (rectosigmoid, rectum)], [right side, left side], information 
on metastasis (number of organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, 
peritoneum, lymph node, bone, adrenal gland, skin, and others), ECOG Performance status (P.S.) 
[before treatment on Day 1 of Course 1 (0, 1)], resection of primary tumor (yes, no), adjuvant 
chemotherapy (yes, no), number of previous treatments (1, 2, 3), complications (absence, presence) 
Determination of primary tumor location: 
Right side: in the case of solitary or multiple lesions in the cecum, ascending colon, and transverse 
colon 
Left side: in the case of solitary or multiple lesions in the descending colon, sigmoid colon, 
rectosigmoid, and rectum 
 
(2) Continuous data:  
Summary statistics (number of cases, mean, standard deviation, minimum, maximum, and 


Page 8 of 22 
 
 
inclusive quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment), period 
from the start date of first-line treatment to the date of enrollment. 
 
6.3  Safety analysis 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy 
In accordance with the protocol, Section 8.9.3., the number of cases determined as DLTs among 
subjects in the DLT evaluation set will be shown and the percentage (%) will be indicated with the 
total number of cases in the DLT evaluation set as a denominator. 
 
6.3.2 Listing of DLT events 
A table listing events determined as DLTs in the DLT evaluation set will be prepared. 
Display items:  
Subject No., sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment initiation date, DLT 
event name (event name recorded by physician, Lowest Level Terms [LLT] code, LLT (English, 
Japanese), PT code, PT (English, Japanese), SOC code, SOC (English, Japanese), date of onset, 
severity, causal relationship of adverse event with protocol treatment, causal relationship with 
panitumumab, seriousness, discontinuation of protocol treatment, outcome, date of resolution 
 
6.3.3  Frequency tabulation of adverse events 
The following analyses regarding treatment-emergent adverse events (TEAEs) will be performed 
on the “set of enrolled subjects who received at least one dose of protocol treatment and satisfied all 
of the enrollment criteria” and the “DLT evaluation set.” 
TEAEs are adverse events that develop after initiation of protocol treatment. 
Skin toxicity are events meeting the definitions of TEAEs in Table 4.1. 
TEAEs will be coded using MedDRA and summarized by SOC and PTs.  
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
6.3.3.1 Frequency tabulation of all TEAEs 
6.3.3.2 Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
6.3.3.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 
6.3.3.4 Frequency tabulation of all TEAEs by severity 


Page 9 of 22 
 
 
6.3.3.5 Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
6.3.3.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
6.3.3.7 Frequency tabulation of TEAEs for action taken for protocol treatment was 
“discontinuation” 
6.3.3.8 Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 
6.3.3.9 Frequency tabulation of serious TEAEs 
6.3.3.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
6.3.3.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
6.3.3.12 Frequency tabulation of non-serious TEAEs with > 5% incidence 
6.3.3.13 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with protocol treatment was “related” 
6.3.3.14 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with panitumumab was “related” 
6.3.3.15 Frequency tabulation of TEAEs with ≥ Grade 3 
6.3.3.16 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
protocol treatment was “related” 
6.3.3.17 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
6.3.3.18 The incidence rate of TEAEs of Grade ≥ 3 
6.3.3.19 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with protocol 
treatment was “related” 
6.3.3.20 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
 
The following analyses will be performed on the “set of enrolled subjects who received at least 
one dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation 
set.” 
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 


Page 10 of 22 
 
 
confidence intervals will be calculated using the following formula:  
 
95% confidence interval of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
Skin toxicity will be analyzed similarly as described above (6.3.3.1 to 6.3.3.20) 
 
7.  Statistical analysis of the phase II part of the study 
7.1  Analysis set 
In the phase II part of the study, statistical analysis will be performed on a “full analysis set” and 
“safety analysis set.” The “full analysis set” will be the main efficacy analysis set, and is defined as 
“subjects enrolled in phase I and II who received at least one dose of protocol treatment (RD) and 
satisfied all of the enrollment criteria.” RD is the recommended dose that is confirmed in the phase I 
part. The "safety analysis set" is defined as “subjects enrolled in phase I and II who received at least 
one dose of either panitumumab orTAS-102.” Additionally, the set of all subjects who are enrolled in 
this study is defined as "all enrolled subjects." 
The statistics representative and analysis personnel should finalize a statistical analysis plan 
before data fixation based on confirmation of the definition of analysis sets and appropriateness of 
analytical handling rules of the subject data in the analysis sets, and additional handling rules for the 
issues that are not determined at planning before data fixation. 
 
7.2  Evaluation of analysis set 
7.2.1  Eligibility and analysis set 
A flow chart showing the breakdown of “all enrolled subjects,” “full analysis set,” and “safety 
analysis set,” and reasons for patients not being included in the analysis set will be tabulated and 
shown with a flow chart. 
Reason for exclusion of safety analysis set: 
• 
Never received panitumumab or TAS-102 
 
Reason for exclusion of the full analysis set 
• 
Not meeting enrollment criteria 
• 
Never received protocol treatment (RD) 
 
7.2.2  Analysis of demographic and other baseline characteristics 
7.2.2.1  Demographic and other baseline characteristics 
The following analyses will be performed on “all enrolled subjects,” the “full analysis set,” and 


Page 11 of 22 
 
 
the “safety analysis set”:  
(1) Discrete data 
A frequency distribution will be tabulated for discrete data, and the percentage (%) will be 
indicated with the analysis set as a denominator. Tabulation items are as follows:  
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
tumor (solitary, multiple), primary tumor location [colon (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon), rectum (rectosigmoid, rectum)], [right side, left side], information 
on metastasis (number of organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, 
peritoneum, lymph node, bone, adrenal gland, skin, and others), ECOG Performance status (P.S.) 
[before treatment on Day 1 of Course 1 (0, 1)], resection of primary tumor (yes, no), adjuvant 
chemotherapy (yes, no), number of previous treatments (1, 2, 3), complications (absence, presence). 
 
(2) Continuous data 
Summary statistics (number of cases, the mean, standard deviation, minimum, maximum, 
quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment), period 
from the start date of first-line treatment to the date of enrollment. 
 
7.2.2.2  Breakdown of complications 
The frequency distribution of complications in “all enrolled subjects,” “full analysis set,” and 
“safety analysis set” will be tabulated, and the percentage (%) will be indicated with the analysis set 
as the denominator. Complications will be coded using MedDRA and summarized by SOC and PTs. 
 
7.2.3 Medication status 
7.2.3.1  Completion of administration 
The summary statistics (number of cases, mean, median, standard deviation, minimum, maximum, 
quartiles) of the cumulative dose and relative dose intensity (RDI) up to 6 months after the start of 
protocol treatment (168 days) or until the completion date of the course over the period of 6 months 
(168 days) will be calculated by drug for the “full analysis set” and “safety analysis set.” The RDI 
will be calculated using the following formulae:  
 
Total RDI (%) = (all actual dose/all planned dose) x (168/actual number of days of all courses) × 
100 
 


Page 12 of 22 
 
 
7.2.3.2  Reason for discontinuation of protocol treatment 
Reasons for discontinuation of patients who withdraw up to 6 months (168 days) and during the 
entire study period in the “full analysis set” and “safety analysis set” will be tabulated, and the 
percentage (%) will be indicated with the respective analysis set as the denominator. 
Reasons for discontinuation of protocol treatment:  
• 
Lack of efficacy (progression) 
• 
Adverse event 
• 
Voluntary discontinuation 
• 
Death during protocol treatment 
• 
Significant deviation from the protocol 
• 
Lost to follow-up 
• 
Discontinuation of the entire study 
• 
Pregnancy 
• 
Others 
 
7.2.3.3  Dose reduction status 
The frequency and percentage (%) of the subjects with dose reduction from the initial dose of the 
treatment period up to 6 months after the start of protocol treatment (168 days), or until the 
completion date of the course over the period of 6 months (168 days), and over the entire study 
period will be tabulated for each drug for the “full analysis set” and “safety analysis set.” Drug 
withdrawal or treatment discontinuation will not be regarded as dose reduction. 
 
7.2.3.4  Follow-up status 
The quartiles of follow-up period will be calculated in the “full analysis set” and “safety analysis 
set.” The follow-up period is the period from the day of enrollment until the day of completion of 
follow-up. The reverse Kaplan-Meier method will be used to calculate the quartiles of the follow-up 
period.1) The final date of follow-up is the date before the date of death for the case of death, and on 
the final day on which survival is confirmed for surviving subjects 
 
7.2.4  Efficacy analysis 
7.2.4.1  Primary endpoint and analysis method 
[Primary endpoint] 
Progression-free survival (PFS rate) at 6 months after enrollment  
The PFS rate 6 months after enrollment, the primary endpoint, is the gross proportion of surviving 
subjects without documented progression up to 6 months after enrollment (date of enrollment + 24 
weeks ± 2 weeks), counting from the day of enrollment. Subjects with no imaging data on 


Page 13 of 22 
 
 
progression at 6 months after enrollment and subjects lost to follow-up will be included in the 
denominator, but will not be handled as progression-free. 
 
Definition of progression:  
Progression will include both progressive disease (PD) based on diagnostic imaging assessed 
according to RECIST ver. 1.1 and primary disease progression that cannot be confirmed by 
diagnostic imaging (clinical progression). When progression is documented by diagnostic imaging, 
the day on which the diagnostic imaging is performed will be the progression date. For clinical 
progression, the day of the clinical determination will be the progression date. In a case in which, for 
example, tumor diameter has become extremely small, if the status is determined to be “not definite 
progression” clinically, although the assessment is PD according to the response criteria, the 
assessment of PD according to the response criteria will take precedence and the status will be 
considered progression. (In this case, the clinical determination on continuing protocol treatment will 
take precedence.) Even if the assessment is not PD according to the response criteria, if there is 
definite clinically documented progression, the clinical determination will take precedence and the 
status will be considered progression. For surviving subjects without documented progression, the 
period will be cut off on the final day when a progression-free status is confirmed (final day of 
progression-free survival confirmation). 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 by telephone only will not be allowed. Events and the cut-off will also be 
handled the same way in subjects who have discontinued protocol treatment for reasons such as 
toxicity and refusal of treatment, even if another (follow-up) therapy is added. Thus, the time of 
treatment discontinuation or the day of follow-up treatment initiation will not be the cut-off. 
 
[Main analysis] 
The following analysis will be performed on the “full analysis set.” 
PFS rate at 6 months is calculated by counting of subjects with progression, without progression, 
and unconfirmed at 6 months. Based on the observed PFS rate at 6 months from the day of 
enrollment, binomial test will be conducted on the null hypothesis “value will be determined invalid 
at PFS rate ≤ 29%.” Significant level will be 2.5% (one-sided) in the main analysis. For interval 
estimation, accurate 90% confidence interval (two-sided) based on binomial distribution will be 
used. 
 
7.2.4.2  Secondary endpoints and analysis method 
[Secondary endpoints] 


Page 14 of 22 
 
 
1) Progression-free survival (PFS) 
PFS is the period from the day of enrollment until the day of documented PD (radiological 
decision or clinical decision) or the day of death due to any cause, whichever comes earlier. 
For surviving subjects without documented progression, the period will be cut off on the final 
day on which progression-free status is confirmed (final day of progression-free survival 
confirmation). Events and the cut-off will also be handled the same way in subjects who have 
discontinued protocol treatment for reasons such as toxicity and refusal of treatment, even if 
another (follow-up) therapy is added. Thus, the time of treatment discontinuation or the day of 
follow-up treatment initiation will not be the cut-off. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of PFS and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for PFS. 
 
2) Overall survival (OS) 
OS is the period from the day of enrollment until death by any cause. For surviving subjects, 
the period is terminated on the final day of survival confirmation or data cut-off date, whichever 
occurs earlier. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of OS and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for OS. 
3) Response rate (RR) 
RR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is either complete response or partial response. Overall response will be 
graded by favorability in the order of complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), and not evaluable (NE). Best overall response is the 
best response recorded throughout all courses. 
 


Page 15 of 22 
 
 
[Analysis method] 
RR of target lesion and its 95% confidence interval (two-sided) will be calculated in the “full 
analysis set.” 
Further, the maximum tumor reduction rate will be calculated for each subject, and a waterfall 
plot will be created by arranging the maximum tumor reduction rate in ascending order. Lines 
of reference at -30% indicating PR and at + 20% indicating PD will be drawn. 
 
Reduction ratio of SoD = SoD at evaluation point −SoD before treatment 
SoD before treatment
 × 100% 
 
4) 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 any cause, whichever occurs earlier. For surviving 
subjects without documented PD, the period will be cut off on the final day of progression-free 
survival confirmation. 
[Analysis method] 
The Kaplan-Meier survival curve will show the subject status until the onset of event for the 
subjects who showed response among the “full analysis set,” and the point estimation value of 
survival rate and its 95% confidence interval (two-sided) will be calculated at the quartile of 
DOR and specified time points. 
 
5) Disease control rate (DCR) 
DCR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is CR, PR, or SD. 
[Analysis method] 
DCR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set.” 
 
6) Time to treatment failure (TTF) 
TTF is the period from the day of enrollment until the day of the decision to discontinue 
protocol treatment, the day of documented progression during protocol treatment (day of 
decision on clinical PD or radiological PD), or the day of death due to any cause, whichever 


Page 16 of 22 
 
 
comes earlier. Subjects not included in the above criteria will be censored at the dose starting 
date in the final course. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of TTF and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for TTF. 
 
7.2.4.3 Subgroup analysis of efficacy 
Subgroup analysis on the following items will be performed for each primary lesion location 
(right side, left side). The same analysis method will be used as in Sections 7.2.4.1 and 7.2.4.2. 
 7.2.4.3.1 PFS rate  
 7.2.4.3.2 PFS 
 7.2.4.3.3 OS 
 7.2.4.3.4 RR 
 7.2.4.3.5 DCR 
7.2.4.4  Level of significance, confidence coefficient 
Significance level: Main analysis only, 5% (one-sided); other analyses, 5% (two-sided) 
Confidence coefficient: Main analysis only, 90% (two-sided); other analyses, 95% (two-sided) 
 
7.2.5  Safety analysis 
The following analyses regarding TEAEs will be performed on the “full analysis set” and “safety 
analysis set.” 
TEAEs will be coded using MedDRA and summarized by SOC and PTs. 
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
7.2.5.1 Frequency tabulation of all TEAEs 
7.2.5.2 Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
7.2.5.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 


Page 17 of 22 
 
 
7.2.5.4 Frequency tabulation of all TEAEs by severity 
7.2.5.5 Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
7.2.5.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
7.2.5.7 Frequency tabulation of TEAEs for action taken for protocol treatment was 
“discontinuation” 
7.2.5.8 Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 
7.2.5.9 Frequency tabulation of serious TEAEs 
7.2.5.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
7.2.5.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
7.2.5.12 Frequency tabulation of non-serious TEAEs with > 5% incidence 
7.2.5.13 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with protocol treatment was “related” 
7.2.5.14 Frequency tabulation of non-serious TEAEs with > 5% for which the causal relationship 
with panitumumab was “related” 
7.2.5.15 Frequency tabulation of TEAEs with ≥ Grade 37.2.5.16 Frequency tabulation of TEAEs 
with ≥ Grade 3 for which the causal relationship with protocol treatment was “related” 
7.2.5.17 Frequency tabulation of TEAEs with ≥ Grade 3 for which the causal relationship with 
panitumumab was “related” 
7.2.5.18 The incidence rate of TEAEs with ≥ Grade 3 
7.2.5.19 The incidence rate of TEAEs with ≥ Grade 3 for which the causal relationship with 
protocol treatment was “related” 
7.2.5.20 The incidence rate of TEAEs with ≥ Grade 3 for which the causal relationship with 
panitumumab was “related” 
 
The following analyses will be performed on the “full analysis set” and “safety analysis set”:  
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 
confidence intervals will be calculated using the following formula:  


Page 18 of 22 
 
 
The 95% confidence intervals of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
Skin toxicity will be analyzed similarly as described above (7.2.5.1 to 7.2.5.20) 
 
7.2.6  Other safety analysis items 
7.2.6.1  ECOG P.S. 
The frequency distribution of ECOG P.S. in the “full analysis set” and “safety analysis set” will 
be tabulated for each course, and the percentage (%) will be indicated with the analysis set at Day 1 
of each course (excluding withdrawal cases) as the denominator. 
 
7.2.6.2  Laboratory tests 
A shift table will be prepared by performing a cross tabulation (number of cases and the 
percentages) of the results of CTCAE grading based on laboratory values for each test item in the 
“full analysis set” and “safety analysis set,” using the worst grade at the start and after the start of 
treatment. The percentage (%) will be indicated with the respective analysis set as the denominator. 
Test items: 
Neutrophil count, platelet count, hemoglobin level, total bilirubin, ALT (GPT), AST (GOT), 
creatinine, Mg, albumin, Na, K, Ca 
 
7.2.7 Table listing 
The following tables will be created for the “enrolled subjects” in section 7.2.7.2 and for the 
“safety analysis set” in other sections 
 
7.2.7.1  List of subjects who discontinued protocol treatment  
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, date of discontinuation, reason for discontinuation, adverse 
event name (event name recorded by physician, LLT code, LLT (English, Japanese), PT code, PT 
English, Japanese), SOC code, SOC (English, Japanese), date of onset, severity, causal relationship 
of adverse event with protocol treatment, causal relationship with panitumumab, seriousness, 
discontinuation of protocol treatment, outcome, date of resolution  
 
7.2.7.2  List of subjects/data excluded from analysis 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 


Page 19 of 22 
 
 
(years), start date of protocol treatment, reason for exclusion 
 
7.2.7.3  List of fatal cases 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, date of death, reason for death, adverse event name (event 
name recorded by physician, LLT code, LLT (English, Japanese), PT code, PT (English, Japanese), 
SOC code, SOC (English, Japanese), date of onset, seriousness, causal relationship of adverse event 
with protocol treatment, causal relationship with panitumumab, seriousness, discontinuation of 
protocol treatment, outcome, date of resolution  
 
7.2.7.4  List of treatments 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, primary lesion (information on primary organ, site, 
with/without resection, date of surgery), metastatic lesion (number of organs with metastases, site, 
with/without resection, date of surgery), performing a palliative colostomy (with/without, date of 
surgery), bypass surgery (with/without, date of surgery), radiation therapy (radical irradiation) 
(with/without, date of surgery, date of final dose), first-line treatment (start date, treatment details), 
second-line treatment (treatment details), third-line treatment (with/without, treatment details), 
preoperative/postoperative adjuvant chemotherapy (with/without, time period, oxaliplatin-containing 
regimen, date of final dose) 
 
7.2.7.5  List of protocol treatment status 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, start date of TAS-102 by course, dose, number of doses, date 
of panitumumab administration, dose, presence or absence of discontinuation of protocol treatment, 
date of discontinuation, reason for discontinuation 
 
7.2.7.6  List of complications 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, name of complication (name of complication recorded by 
physician, LLT code, LLT (English, Japanese), PT code, PT (English, Japanese), SOC code, SOC 
(English, Japanese)  


Page 20 of 22 
 
 
 
7.2.7.7  Table of MedDRA-coded AEs 
Display items: 
Name of AE recorded by physician LLT code, LLT (English, Japanese), PT code, PT (English, 
Japanese), SOC code, SOC (English, Japanese) 
 
7.2.7.8  List of TEAEs 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, adverse event name (event name recorded by physician, LLT 
code, LLT (English, Japanese), PT code, PT (English, Japanese), SOC code, SOC (English, 
Japanese), date of onset, severity, causal relationship with protocol treatment, causal relationship 
with panitumumab, seriousness, discontinuation of protocol treatment, outcome, date of resolution.  
 
7.2.7.9  List of Deaths and other serious adverse events 
Display items: 
Same as “List of TEAEs” 
 
7.2.7.10  List of skin toxicity 
Display items: 
Same as “List of TEAEs” 
 
7.2.7.11  List of RECIST response evaluations 
Display items:  
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, evaluation period, sum of target lesion diameter (before 
treatment, at evaluation), reduction rate of sum of target lesion diameter, results of response 
evaluation of target lesion, results of response evaluation of non-target lesion, development of new 
lesion, site of new lesion, results of overall response evaluation 
 
Reduction ratio of SoD = SoD at evaluation point −SoD before treatment 
SoD before treatment
 × 100% 
 
7.2.7.12  List of determinations of PD 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 


Page 21 of 22 
 
 
(years), start date of protocol treatment, day of decision on clinical PD, day of decision on 
radiological PD, final day of imaging test, final day on which progression-free survival is confirmed, 
start date of follow-up treatment 
 
7.2.7.13  List of survival survey results 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, survival survey results, last confirmed date of survival, date 
of death, reason of death (other details) 
 
7.2.7.14  List of laboratory test values 
Display items: 
 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, laboratory test items, test date, measured values (SI), Unit 
(SI), site reference values (SI) (lower limit – upper limit) 
Test items: Same as 7.2.6.2. 
 
7.3  Criteria for interim analysis and premature discontinuation 
No interim analyses are scheduled. 
 
7.4  Sensitivity analysis 
Sensitivity analysis of primary endpoint 
For the PFS rate at 6 months (the primary endpoint), results will be calculated for the case in 
which the period is terminated at the point follow-up treatment is initiated, and the difference 
between major analysis results will be confirmed. 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the “full 
analysis set,” and the point estimation value of survival rate and its 95% confidence interval 
(two-sided) will be calculated at the quartile of PFS and specified time points. The Log-Log 
conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence intervals of the 
quartiles for PFS. 
In evaluating PFS, results will be calculated for the case of termination at the point follow-up 
treatment is initiated (start date of follow-up treatment), and the difference between that and the 
results for the case in which the period is cut off on the last confirmed date of progression-free 
status. 
 


Page 22 of 22 
 
 
8.  References 
1) Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials 1996; 17: 343–46. 


Page 1 of 22 
 
 
 
APOLLON study 
(A phase I/II study for the safety and efficacy of Panitumumab in 
combination with TAS-102 for patients with RAS wild-type metastatic 
colorectal cancer refractory to standard chemotherapy) 
(Protocol number: Panitumumab-1501) 
 
Statistics Analysis Plan 
 
Version 2.0 
 
 
 
 
 
PPD
PPD
PPD


Page 2 of 22 
 
 
Table of Contents 
1. History of preparation and revision ......................................................................................... 3 
2. Analysis Plan Objectives ........................................................................................................ 4 
3. Time period for Analysis ........................................................................................................ 4 
4. Analysis data set .................................................................................................................... 5 
4.1 Handling of cases/data ...................................................................................................... 5 
4.2 Number of significant figures in analysis results ................................................................. 6 
5. Software used for analysis ...................................................................................................... 6 
6. Statistical analysis of the phase I part of the study .................................................................... 7 
6.1 Analysis set ..................................................................................................................... 7 
6.2 Analysis of demographic and other baseline characteristics ................................................. 7 
6.3 Safety analysis ................................................................................................................. 8 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy ................ 8 
6.3.2 Listing of DLT events ................................................................................................ 8 
6.3.3 Frequency tabulation of adverse events ....................................................................... 8 
7. Statistical analysis of the phase II part of the study ................................................................. 10 
7.1 Analysis set ................................................................................................................... 10 
7.2 Evaluation of analysis set ............................................................................................... 10 
7.2.1 Eligibility and analysis set ........................................................................................ 10 
7.2.2 Analysis of demographic and other baseline characteristics ......................................... 10 
7.2.3 Medication status ...................................................................................................... 11 
7.2.4 Efficacy analysis ...................................................................................................... 12 
7.2.5 Safety analysis......................................................................................................... 17 
7.2.6 Other safety analysis items ....................................................................................... 18 
7.2.7 Table listing ............................................................................................................ 19 
7.3 Criteria for interim analysis and premature discontinuation ............................................... 22 
7.4 Sensitivity analysis ......................................................................................................... 22 
8. References .......................................................................................................................... 22 
 
 
 
 


Page 3 of 22 
 
 
1. History of preparation and revision 
Version 
Date of approval 
Author 
Reason for revision 
1.0 
June 3, 2016 
 
 
Not applicable, because it is the first 
version 
2.0 
February 28, 2017 
 
 
(1) Addition of definition of protocol 
treatment and acceptable range  
(2) Addition of analysis plan for phase II 
part 
 
 
 
PPD
PPD




Page 5 of 22 
 
 
days of entry. 
4. Analysis data set 
4.1 Handling of cases/data 
(1) Handling of laboratory values/subjective and objective findings of adverse events 
Adverse events recorded on the adverse event form will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred terms 
(PTs). Skin disorders will be regarded as events classified into “Skin and subcutaneous tissue 
disorders” of SOC or “Paronychia” by PT. The PTs classified as skin toxicity (Rash acneform, 
Paronychia, Dry skin, Pruritus) are defined in Table 4.1. 
 
Table 4.1 Events classified as skin toxicity 
Rash acneform 
Acne, Dermatitis acneiform, Folliculitis, Rash, Dermatitis, Drug eruption, 
Rash pruritic, Eczema, Skin disorder, Rash generalized, Seborrhoeic dermatitis  
Paronychia 
Paronychia, Nail avulsion, Onychoclasis, Onychomadesis, Nail disorder, 
Ingrowing nail, Excessive granulation tissue, Pyogenic granuloma  
Dry skin 
Dry skin, Skin fissures, Xeroderma, Skin exfoliation, Skin chapped, Eczema 
asteatotic, Hyperkeratosis 
Pruritus 
Pruritus, General pruritus 
 
(2) Handling of adverse event grade 
If an AE is assessed multiple times in the same subject, the highest grade among all AE 
assessments shall be reported as the worst grade of the AE. 
(3) Handling of missing/ejected data 
Missing data will not be complemented unless the details of individual analysis items are specified. 
When rejecting data, the corresponding data will be indicated and the reason for rejection clarified in 
a table. However, handling of patients with no occurrence of events related to Progression-Free 
Survival (PFS), Overall Survival (OS), or Time to Treatment Failure (TTF) will be described in each 
section. 
(4) Protocol treatment and acceptable range for tests 
Performed items 
Protocol specification 
Allowance range 
Protocol treatment 
From the date of treatment of 
the previous course (Day 1) to 
after 4 weeks (Day 29) 
Scheduled day ± 3 days 
 
 


Page 6 of 22 
 
 
4.2  Number of significant figures in analysis results 
Percentages (%) expressing frequency distribution will be rounded to one decimal place unless the 
details of individual analysis items are specified. 
Among summary statistics (number of cases, the mean, standard deviation, minimum, maximum, 
and inclusive quartiles), the mean, standard deviation, and quartiles will be rounded to one decimal 
place lower than the original data. 
P-values will be indicated to 4 decimal places rounded from the 5th decimal. However, a p-value 
less than 0.0001 will be expressed as “p < 0.0001.” Hazard ratios and their 95% confidence intervals 
will be indicated to 2 decimal places rounded from the 3rd decimal. 
 
5.  Software used for analysis 
The statistical software used for analysis will be 
 
 
 
CCI


Page 7 of 22 
 
 
6.  Statistical analysis of the phase I part of the study 
6.1  Analysis set 
Two analysis sets will be created for the phase I part of the study: “set of enrolled subjects who 
received at least one dose of protocol treatment and satisfied all of the enrollment criteria” and the 
“DLT evaluation set.” The DLT evaluation set will be based on the following definition from the 
protocol, Section 8.9.2:  
Subjects enrolled in the phase I part of the study will be included in the DLT evaluation set. 
Subjects will be excluded from the DLT evaluation if at least the designated dose of protocol 
treatment is not administered by the end of Course 1 (except when the protocol treatment is 
discontinued due to DLT), if there are major protocol deviations such as the use of contraindicated 
drugs, or if the subject is determined to be unsuitable for the DLT evaluation. The designated dose is 
75% (15 doses) of the total number of doses (20 doses) of panitumumab (2 doses of 6 mg/kg) and 
TAS-102 (2 doses daily of 35 mg/m2) on Days 1-5 and Days 8-12. 
 
6.2  Analysis of demographic and other baseline characteristics 
The following analyses will be conducted in the “set of enrolled subjects who received at least one 
dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
(1) Discrete data:  
A frequency distribution for the discrete data will be computed indicating the percentage (%) with 
the analysis set as a denominator. Aggregation items are as follows: 
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
tumor (solitary, multiple), primary tumor location [colon (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon), rectum (rectosigmoid, rectum)], information on metastasis 
(number of organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, peritoneum, 
lymph node, bone, adrenal gland, skin, and others), ECOG Performance status (P.S.) [before 
treatment on Day 1 of Course 1 (0, 1)], resection of primary tumor (yes, no), adjuvant chemotherapy 
(yes, no), number of previous treatments (1, 2, 3), complications (absence, presence) 
(2) Continuous data:  
Summary statistics (number of cases, mean, standard deviation, minimum, maximum, and 
inclusive quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment). 
 


Page 8 of 22 
 
 
6.3  Safety analysis 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy 
In accordance with the protocol, Section 8.9.3., the number of cases determined as DLTs among 
subjects in the DLT evaluation set will be shown and the percentage (%) will be indicated with the 
total number of cases in the DLT evaluation set as a denominator. 
 
6.3.2 Listing of DLT events 
A table listing events determined as DLTs in the DLT evaluation set will be prepared. 
Display items:  
Subject No., sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment initiation date, DLT 
event name (event name recorded by physician, Lowest Level Terms [LLT] code, LLT Japanese, PT 
code, PT Japanese, SOC code, SOC Japanese), date of onset, severity, causal relationship of adverse 
event with protocol treatment, causal relationship with panitumumab, seriousness, discontinuation of 
protocol treatment, outcome, date of resolution 
 
6.3.3  Frequency tabulation of adverse events 
The following analyses regarding treatment-emergent adverse events (TEAEs) and skin toxicity 
will be performed on the “set of enrolled subjects who received at least one dose of protocol 
treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
TEAEs are adverse events that develop after initiation of protocol treatment. 
Skin toxicity are events meeting the definitions of TEAEs in Table 4.1. 
TEAEs will be coded using MedDRA and summarized by SOC and PTs.  
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
6.3.3.1Frequency tabulation of all TEAEs 
6.3.3.2Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
6.3.3.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 
6.3.3.4Frequency tabulation of all TEAEs by severity 
6.3.3.5Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
6.3.3.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
6.3.3.7Frequency tabulation of TEAEs for action taken for protocol treatment was 


Page 9 of 22 
 
 
“discontinuation” 
6.3.3.8Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 
6.3.3.9Frequency tabulation of serious TEAEs 
6.3.3.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
6.3.3.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
6.3.3.12Frequency tabulation of non-serious TEAEs with ≥ 5% incidence 
6.3.3.13 Frequency tabulation of TEAEs of Grade ≥ 3 
6.3.3.14 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
protocol treatment was “related” 
6.3.3.15 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
6.3.3.16 The incidence rate of TEAEs of Grade ≥ 3 
6.3.3.17 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with protocol 
treatment was “related” 
6.3.3.18 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
 
The following analyses will be performed on the “set of enrolled subjects who received at least 
one dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation 
set.” 
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 
confidence intervals will be calculated using the following formula:  
 
95% confidence interval of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
 
 
 
 


Page 10 of 22 
 
 
7.  Statistical analysis of the phase II part of the study 
7.1  Analysis set 
In the phase II part of the study, statistical analysis will be performed on a “full analysis set” and 
“safety analysis set.” The “full analysis set” will be the main efficacy analysis set, and is defined as 
“subjects enrolled in phase I and II who received at least one dose of protocol treatment (RD) and 
satisfied all of the enrollment criteria.” RD is the recommended dose that is confirmed in the phase I 
part. The "safety analysis set" is defined as “subjects enrolled in phase I and II who received at least 
one dose of either panitumumab or TAS102.” Additionally, the set of all subjects who are enrolled in 
this study is defined as "all enrolled subjects." 
The statistics representative and analysis personnel should finalize a statistical analysis plan 
before data fixation based on confirmation of the definition of analysis sets and appropriateness of 
analytical handling rules of the subject data in the analysis sets, and additional handling rules for the 
issues that are not determined at planning before data fixation. 
 
7.2  Evaluation of analysis set 
7.2.1  Eligibility and analysis set 
A flow chart showing the breakdown of “all enrolled subjects,” “full analysis set,” and “safety 
analysis set,” and reasons for patients not being included in the analysis set will be tabulated and 
shown with a flow chart. 
Reason for exclusion of safety analysis set: 
• 
Never received panitumumab or TAS102 
 
Reason for exclusion of the full analysis set 
• 
Not meeting enrollment criteria 
• 
Never received protocol treatment (RD) 
 
7.2.2  Analysis of demographic and other baseline characteristics 
7.2.2.1  Demographic and other baseline characteristics 
The following analyses will be performed on “all enrolled subjects,” the “full analysis set,” and 
the “safety analysis set”:  
 
 


Page 11 of 22 
 
 
(1) Discrete data 
A frequency distribution will be tabulated for discrete data, and the percentage (%) will be 
indicated with the analysis set as a denominator. Tabulation items are as follows:  
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
tumor (solitary, multiple), primary tumor location [colon (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon), rectum (rectosigmoid, rectum)], information on metastasis 
(number of organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, peritoneum, 
lymph node, bone, adrenal gland, skin, and others), ECOG Performance status (P.S.) [before 
treatment on Day 1 of Course 1 (0, 1)], resection of primary tumor (yes, no), adjuvant chemotherapy 
(yes, no), number of previous treatments (1, 2, 3), complications (absence, presence). 
 
(2) Continuous data 
Summary statistics (number of cases, the mean, standard deviation, minimum, maximum, 
quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment). 
 
7.2.2.2  Breakdown of complications 
The frequency distribution of complications in “all enrolled subjects,” “full analysis set,” and 
“safety analysis set” will be tabulated, and the percentage (%) will be indicated with the analysis set 
as the denominator. Complications will be coded using MedDRA and summarized by SOC and PTs. 
 
7.2.3 Medication status 
7.2.3.1  Completion of administration 
The summary statistics (number of cases, mean, median, standard deviation, minimum, maximum, 
quartiles) of the cumulative dose and relative dose intensity (RDI) for each course up to Course 6 
and over the period up to Course 6 will be calculated by drug for the “full analysis set” and “safety 
analysis set.” For the RDI up to Course 6, a time plot with a boxplot will be constructed. The RDI 
will be calculated using the following formulae:  
 
RDI (%) = (actual dose/initial planned dose) × (28/number of days until completion of specific 
actual course) × 100 
 
Total RDI (%) = (all actual dose/all planned dose) x (168/actual number of days of all courses) × 
100 
 


Page 12 of 22 
 
 
7.2.3.2  Reason for discontinuation of protocol treatment 
Reasons for discontinuation of patients who withdraw up to Course 6 and during the entire study 
period in the “full analysis set” and “safety analysis set” will be tabulated, and the percentage (%) 
will be indicated with the respective analysis set as the denominator. 
Reasons for discontinuation of protocol treatment:  
• 
Lack of efficacy (progression) 
• 
Adverse event 
• 
Voluntary discontinuation 
• 
Death during protocol treatment 
• 
Significant deviation from the protocol 
• 
Lost to follow-up 
• 
Discontinuation of the entire study 
• 
Pregnancy 
• 
Others 
 
7.2.3.3  Dose reduction status 
The frequency and percentage (%) of the subjects with dose reduction from the initial dose up to 
Course 6 and over the entire study period will be tabulated for each drug for the “full analysis set” 
and “safety analysis set.” Similarly, the frequency and percentage (%) will be tabulated for each 
specified course (6 courses). 
 
7.2.3.4  Follow-up status 
The quartiles of follow-up period will be calculated in the “full analysis set” and “safety analysis 
set.” The follow-up period is the period from the day of enrollment until the day of completion of 
follow-up. The reverse Kaplan-Meier method will be used to calculate the quartiles of the follow-up 
period.1) The final date of follow-up is the date before the date of death for the case of death, and on 
the final day on which survival is confirmed for surviving subjects 
 
7.2.4  Efficacy analysis 
7.2.4.1  Primary endpoint and analysis method 
[Primary endpoint] 
Progression-free survival (PFS rate) at 6 months after enrollment  
The PFS rate 6 months after enrollment, the primary endpoint, is the gross proportion of surviving 
subjects without documented progression up to 6 months after enrollment (date of enrollment + 24 
weeks ± 2 weeks), counting from the day of enrollment. Subjects with no imaging data on 
progression at 6 months after enrollment and subjects lost to follow-up will be included in the 


Page 13 of 22 
 
 
denominator, but will not be handled as progression-free. 
 
Definition of progression:  
Progression will include both progressive disease (PD) based on diagnostic imaging assessed 
according to RECIST ver. 1.1 and primary disease progression that cannot be confirmed by 
diagnostic imaging (clinical progression). When progression is documented by diagnostic imaging, 
the day on which the diagnostic imaging is performed will be the progression date. For clinical 
progression, the day of the clinical determination will be the progression date. In a case in which, for 
example, tumor diameter has become extremely small, if the status is determined to be “not definite 
progression” clinically, although the assessment is PD according to the response criteria, the 
assessment of PD according to the response criteria will take precedence and the status will be 
considered progression. (In this case, the clinical determination on continuing protocol treatment will 
take precedence.) Even if the assessment is not PD according to the response criteria, if there is 
definite clinically documented progression, the clinical determination will take precedence and the 
status will be considered progression. 
 
[Main analysis] 
The following analysis will be performed on the “full analysis set.” 
PFS rate at 6 months is calculated by counting of subjects with progression, without progression, 
and unconfirmed at 6 months. Based on the observed PFS rate at 6 months from the day of 
enrollment, binomial test will be conducted on the null hypothesis “value will be determined invalid 
at PFS rate ≤ 29%.” Significant level will be 2.5% (one-sided) in the main analysis. For interval 
estimation, accurate 90% confidence interval (two-sided) based on binomial distribution will be 
used. 
 
7.2.4.2  Secondary endpoints and analysis method 
[Secondary endpoints] 
1) Progression-free survival (PFS) 
PFS is the period from the day of enrollment until the day of documented PD (radiological 
decision or clinical decision) or the day of death due to any cause, whichever comes earlier. 
For surviving subjects without documented progression, the period will be cut off on the final 
day on which progression-free status is confirmed (final day of progression-free survival 
confirmation). Events and the cut-off will also be handled the same way in subjects who have 
discontinued protocol treatment for reasons such as toxicity and refusal of treatment, even if 
another (follow-up) therapy is added. Thus, the time of treatment discontinuation or the day of 


Page 14 of 22 
 
 
follow-up treatment initiation will not be the cut-off. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of PFS and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for PFS. 
 
2) Overall survival (OS) 
OS is the period from the day of enrollment until death by any cause. For surviving subjects, 
the period is terminated on the final day of survival confirmation or data cut-off date, whichever 
occurs earlier. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of OS and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for OS. 
 
3) Response rate (RR) 
RR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is either complete response or partial response. Overall response will be 
graded by favorability in the order of complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), and not evaluable (NE). Best overall response is the 
best response recorded throughout all courses. 
[Analysis method] 
RR of target lesion and its 95% confidence interval (two-sided) will be calculated in the “full 
analysis set.” 
 
Further, the maximum tumor reduction rate will be calculated for each subject, and a waterfall 
plot will be created by arranging the maximum tumor reduction rate in ascending order. Lines 
of reference at -30% indicating PR and at + 20% indicating PD will be drawn. 


Page 15 of 22 
 
 
 
Reduction ratio of SoD = SoD at evaluation point −SoD before treatment 
SoD before treatment
 × 100% 
 
4) 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 any cause, whichever occurs earlier. For surviving 
subjects without documented PD, the period will be cut off on the final day when specified 
diagnostic imaging reveals no PD (final day of progression-free survival confirmation). For 
surviving subjects 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 progression-free survival confirmation). 
[Analysis method] 
The Kaplan-Meier survival curve will show the subject status until the onset of event for the 
subjects who showed response among the “full analysis set,” and the point estimation value of 
survival rate and its 95% confidence interval (two-sided) will be calculated at the quartile of 
DOR and specified time points. 
 
5) Disease control rate (DCR) 
DCR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is CR, PR, or SD. 
[Analysis method] 
DCR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set.” 
 
6) Time to treatment failure (TTF) 
TTF is the period from the day of enrollment until the day of the decision to discontinue 
protocol treatment, the day of documented progression during protocol treatment (day of 
decision on clinical PD or radiological PD), or the day of death due to any cause, whichever 
comes earlier. Subjects not included in the above criteria will be censored at the dose starting 
date in the final course. 
[Analysis method] 


Page 16 of 22 
 
 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and the point estimation value of survival rate and its 95% confidence 
interval (two-sided) will be calculated at the quartile of TTF and specified time points. The 
Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence 
intervals of the quartiles for TTF. 
 
 
 


Page 17 of 22 
 
 
7.2.4.3  Level of significance, confidence coefficient 
Significance level: Main analysis only, 5% (one-sided); other analyses, 5% (two-sided) 
Confidence coefficient: Main analysis only, 90% (two-sided); other analyses, 95% (two-sided) 
 
7.2.5  Safety analysis 
The following analyses regarding TEAEs and skin toxicity will be performed on the “full analysis 
set” and “safety analysis set.” 
TEAEs will be coded using MedDRA and summarized by SOC and PTs. 
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
7.2.5.1Frequency tabulation of all TEAEs 
7.2.5.2Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
7.2.5.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 
7.2.5.4Frequency tabulation of all TEAEs by severity 
7.2.5.5Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
7.2.5.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
7.2.5.7Frequency tabulation of TEAEs for action taken for protocol treatment was 
“discontinuation” 
7.2.5.8Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 
7.2.5.9Frequency tabulation of serious TEAEs 
7.2.5.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
7.2.5.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
7.2.5.12Frequency tabulation of non-serious TEAEs with ≥5% incidence 
 
7.2.5.13 Frequency tabulation  of TEAEs of Grade ≥ 3 
 
7.2.5.14 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
protocol treatment was “related” 


Page 18 of 22 
 
 
7.2.5.15 Frequency tabulation of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
7.2.5.16 The incidence rate of TEAEs of Grade ≥ 3 
7.2.5.17 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with protocol 
treatment was “related” 
7.2.5.18 The incidence rate of TEAEs of Grade ≥ 3 for which the causal relationship with 
panitumumab was “related” 
 
Skin toxicity will be analyzed similarly as described above (7.2.5.1 to 7.2.5.30). 
 
The following analyses will be performed on the “full analysis set” and “safety analysis set”:  
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 
confidence intervals will be calculated using the following formula:  
The 95% confidence intervals of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
 
7.2.6  Other safety analysis items 
7.2.6.1  ECOG P.S. 
The frequency distribution of ECOG P.S. in the “full analysis set” and “safety analysis set” will 
be tabulated for each course, and the percentage (%) will be indicated with the analysis set at Day 1 
of that course (excluding withdrawal cases) as the denominator. 
 
7.2.6.2  Laboratory tests 
A shift table will be prepared by performing a cross tabulation (number of cases and the 
percentages) of the results of CTCAE grading based on laboratory values for each test item in the 
“full analysis set” and “safety analysis set,” using the worst grade at the start and after the start of 
treatment. The percentage (%) will be indicated with the respective analysis set as the denominator. 
Test items: 
Neutrophil count, platelet count, hemoglobin level, total bilirubin, ALT (GPT), AST (GOT), 
creatinine, Mg, albumin, Na, Ca 
 


Page 19 of 22 
 
 
7.2.7 Table listing 
The following tables will be created for the “safety analysis set”: 
 
7.2.7.1  List of subjects who discontinued protocol treatment  
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, date of discontinuation, reason for discontinuation, adverse 
event name (event name recorded by physician, LLT code, LLT Japanese, PT code, PT Japanese, 
SOC code, SOC Japanese), date of onset, severity, causal relationship of adverse event with protocol 
treatment, causal relationship with panitumumab, seriousness, discontinuation of protocol treatment, 
outcome, date of resolution  
 
7.2.7.2  List of subjects/data excluded from analysis 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, reason for exclusion 
 
7.2.7.3  List of fatal cases 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, date of death, reason for death, adverse event name (event 
name recorded by physician, LLT code, LLT Japanese, PT code, PT Japanese, SOC code, SOC 
Japanese), date of onset, seriousness, causal relationship of adverse event with protocol treatment, 
causal relationship with panitumumab, seriousness, discontinuation of protocol treatment, outcome, 
date of resolution  
 
7.2.7.4  List of treatments 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, primary lesion (information on primary organ, site, 
with/without resection, date of surgery), metastatic lesion (number of organs with metastases, site, 
with/without resection, date of surgery), performing a palliative colostomy (with/without, date of 
surgery), bypass surgery (with/without, date of surgery), radiation therapy (radical irradiation) 
(with/without, date of surgery, date of final dose), first-line treatment (start date, treatment details), 
second-line treatment (treatment details), third-line treatment (with/without, treatment details), 
preoperative/postoperative adjuvant chemotherapy (with/without, time period, oxaliplatin-containing 


Page 20 of 22 
 
 
regimen, date of final dose) 
 
7.2.7.5  List of protocol treatment status 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, start date of TAS102 by course, dose, number of doses, date 
of panitumumab administration, dose, presence or absence of discontinuation of protocol treatment, 
date of discontinuation, reason for discontinuation 
 
7.2.7.6  List of complications 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, name of complication (name of complication recorded by 
physician, LLT code, LLT Japanese, PT code, PT Japanese, SOC code, SOC Japanese)  
 
7.2.7.7  Table of MedDRA-coded AEs 
Display items: 
Name of AE recorded by physician, LLT code, LLT Japanese, PT code, PT Japanese, SOC code, 
SOC Japanese 
 
7.2.7.8  List of TEAEs 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, adverse event name (event name recorded by physician, LLT 
code, LLT Japanese, PT code, PT Japanese, SOC code, SOC Japanese), date of onset, severity, 
causal relationship with protocol treatment, causal relationship with panitumumab, seriousness, 
discontinuation of protocol treatment, outcome, date of resolution.  
 
7.2.7.9  List of Deaths and other serious adverse events 
Display items: 
Same as “List of TEAEs” 
 
7.2.7.10  List of skin toxicity 
Display items: 
Same as “List of TEAEs” 
 


Page 21 of 22 
 
 
7.2.7.11  List of RECIST response evaluations 
Display items:  
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, evaluation period, sum of target lesion diameter (before 
treatment, at evaluation), reduction rate of sum of target lesion diameter, results of response 
evaluation of target lesion, results of response evaluation of non-target lesion, development of new 
lesion, site of new lesion, results of overall response evaluation 
 
Reduction ratio of SoD = SoD at evaluation point −SoD before treatment 
SoD before treatment
 × 100% 
 
7.2.7.12  List of determinations of PD 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, day of decision on clinical PD, day of decision on 
radiological PD, final day of imaging test, final day on which progression-free survival is confirmed, 
start date of follow-up treatment 
 
7.2.7.13  List of survival survey results 
Display items: 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, survival survey results, last confirmed date of survival, date 
of death, reason of death (other details) 
 
7.2.7.14  List of laboratory test values 
Display items: 
 
 
Subject No., enrollment phase, DLT evaluation set, full analysis set, safety analysis set, sex, age 
(years), start date of protocol treatment, laboratory test items, measured values, site reference values 
(lower limit – upper limit) 
Test items: Same as 7.2.6.2. 
 
 
 


Page 22 of 22 
 
 
7.3  Criteria for interim analysis and premature discontinuation 
No interim analyses are scheduled. 
 
7.4  Sensitivity analysis 
Sensitivity analysis of primary endpoint 
For the PFS rate at 6 months (the primary endpoint), results will be calculated for the case in 
which the period is terminated at the point follow-up treatment is initiated, and the difference 
between major analysis results will be confirmed. 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the “full 
analysis set,” and the point estimation value of survival rate and its 95% confidence interval 
(two-sided) will be calculated at the quartile of PFS and specified time points. The Log-Log 
conversion of Brookmeyer and Crowley will be used to calculate the 95% confidence intervals of the 
quartiles for PFS. 
In evaluating PFS, results will be calculated for the case of termination at the point follow-up 
treatment is initiated (start date of follow-up treatment), and the difference between that and the 
results for the case in which the period is cut off on the last confirmed date of progression-free 
status. 
 
8.  References 
1) Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials 1996; 17: 343–46. 


Page 1 of 16 
 
 
 
APOLLON study 
(A phase I/II study for the safety and efficacy of Panitumumab in 
combination with TAS-102 for patients with RAS wild-type metastatic 
colorectal cancer refractory to standard chemotherapy) 
(Protocol number: Panitumumab-1501) 
 
Statistics Analysis Plan 
 
Version 1.0 
 
 
 
 
 
PPD
PPD
PPD


Page 2 of 16 
 
 
Table of Contents 
1. History of preparation and revision .................................................................................................. 3 
2. Analysis Plan Objectives ................................................................................................................... 4 
3. Time period for Analysis ................................................................................................................... 4 
4. Analysis data set ................................................................................................................................ 4 
4.1 Handling of cases/data ................................................................................................................ 4 
4.2 Number of significant figures in analysis results ........................................................................ 5 
5. Software used for analysis ................................................................................................................ 5 
6. Statistical analysis of the phase I part of the study ........................................................................... 6 
6.1 Analysis set ................................................................................................................................. 6 
6.2 Analysis of demographic and other baseline characteristics ....................................................... 6 
6.3 Safety analysis ............................................................................................................................ 6 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy ................... 6 
6.3.2 Listing of DLT events .......................................................................................................... 7 
6.3.3 Frequency tabulation of adverse events ............................................................................... 7 
6.3.4 Table listing .......................................................................................................................... 8 
7. Statistical analysis of the phase II part of the study .......................................................................... 9 
7.1 Analysis set ................................................................................................................................. 9 
7.2 Evaluation of analysis set .......................................................................................................... 10 
7.2.1 Eligibility and analysis set ................................................................................................. 10 
7.2.2 Analysis of demographic and other baseline characteristics .............................................. 10 
7.2.3 Medication status ............................................................................................................... 10 
7.2.4 Efficacy analysis ................................................................................................................ 11 
7.2.5 Safety analysis ................................................................................................................... 15 
7.2.6 Table listing ........................................................................................................................ 16 
7.3 Criteria for interim analysis and premature discontinuation ..................................................... 16 
7.4 Sensitivity analysis.................................................................................................................... 16 
7.4.1 Sensitivity analysis of primary endpoint ............................................................................ 16 
7.4.2 Sensitivity analysis of secondary endpoints ....................................................................... 16 
8. References ....................................................................................................................................... 16 
 
 
 
 


Page 3 of 16 
 
 
1. History of preparation and revision 
Version 
Date of approval 
Author 
Reason for revision 
1.0 
June 3, 2016 
 
 
Not applicable, because it is the first 
version 
 
 
 
PPD




Page 5 of 16 
 
 
(PTs). Skin disorders will be regarded as events classified into “Skin and subcutaneous tissue 
disorders” of SOC or “Paronychia” by PT. The PTs classified as skin toxicity (Rash acneiform, 
Paronychia, Dry skin, Pruritus) are defined in Table 4.1. 
 
 
Table 4.1 Events classified as skin toxicity 
Rash acneiform 
Acne, Dermatitis acneiform, Folliculitis, Rash, Dermatitis, Drug eruption, 
Rash pruritic, Eczema, Skin disorder, Rash generalized, Seborrhoeic dermatitis  
Paronychia 
Paronychia, Nail avulsion, Onychoclasis, Onychomadesis, Nail disorder, 
Ingrowing nail, Excessive granulation tissue, Pyogenic granuloma  
Dry skin 
Dry skin, Skin fissures, Xeroderma, Skin exfoliation, Skin chapped, Eczema 
asteatotic, Hyperkeratosis 
Pruritus 
Pruritus, General pruritus 
 
(2) Handling of adverse event grade 
If an AE is assessed multiple times in the same subject, the highest grade among all AE 
assessments shall be reported as the worst grade of the AE. 
(3) Handling of missing/ejected data 
Missing data will not be complemented unless the details of individual analysis items are specified. 
When rejecting data, the corresponding data will be indicated and the reason for rejection clarified in 
a table. However, handling of patients with no occurrence of events related to Progression-Free 
Survival (PFS), Overall Survival (OS), or Time to Treatment Failure (TTF) will be described in 
Section 7.2.4.3. 
 
4.2  Number of significant figures in analysis results 
Percentages (%) expressing frequency distribution will be rounded to one decimal place unless the 
details of individual analysis items are specified. 
Among summary statistics, mean and standard deviation will be rounded to one decimal place 
lower than the original data. 
P-values will be indicated to 4 decimal places rounded from the 5th decimal. However, a p-value 
less than 0.0001 will be expressed as “p < 0.0001.” Hazard ratios and their 95% confidence intervals 
will be indicated to 2 decimal places rounded from the 3rd decimal. 
 
5.  Software used for analysis 
The statistical software used for analysis will be 
 
 
 
CCI


Page 6 of 16 
 
 
6.  Statistical analysis of the phase I part of the study 
6.1  Analysis set 
Two analysis sets will be created for the phase I part of the study: “set of enrolled subjects who 
received at least one dose of protocol treatment and satisfied all of the enrollment criteria” and the 
“DLT evaluation set.” The DLT evaluation set will be based on the following definition from the 
protocol, Section 8.9.2:  
Subjects enrolled in the phase I part of the study will be included in the DLT evaluation set. 
Subjects will be excluded from the DLT evaluation if at least the designated dose of protocol 
treatment is not administered by the end of Course 1 (except when the protocol treatment is 
discontinued due to DLT), if there are major protocol deviations such as the use of contraindicated 
drugs, or if the subject is determined to be unsuitable for the DLT evaluation. The designated dose is 
75% (15 doses) of the total number of doses (20 doses) of panitumumab (2 doses of 6 mg/kg) and 
TAS-102 (2 doses daily of 35 mg/m2) on Days 1-5 and Days 8-12. 
 
6.2  Analysis of demographic and other baseline characteristics 
The following analyses will be conducted in the “set of enrolled subjects who received at least one 
dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
(1) Discrete data:  
A frequency distribution for the discrete data will be computed indicating the percentage (%) with 
the analysis set as a denominator. Aggregation items are as follows: 
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
tumor (solitary, multiple), primary tumor location (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon, rectosigmoid, rectum), information on metastasis (number of 
organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, peritoneum, lymph node, 
bone, adrenal gland, skin, and others), ECOG Performance status (P.S.) (at enrollment) (0, 1, 2, 3, 4), 
complications (absence, presence) 
(2) Continuous data:  
Summary statistics (number of cases, mean, standard deviation, minimum, maximum, and 
inclusive quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment). 
 
6.3  Safety analysis 
6.3.1 Incidence of DLT events with panitumumab + TAS-102 combination therapy 
In accordance with the protocol, Section 8.9.3., the number of cases determined as DLTs among 


Page 7 of 16 
 
 
subjects in the DLT evaluation set will be shown and the percentage (%) will be indicated with the 
total number of cases in the DLT evaluation set as a denominator. 
 
6.3.2 Listing of DLT events 
A table listing events determined as DLTs in the DLT evaluation set will be prepared. 
Display items:  
Subject No., sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment initiation date, DLT 
event name (event name recorded by physician, Lowest Level Terms [LLT] code, LLT Japanese, PT 
code, PT Japanese, SOC code, SOC Japanese), date of onset, severity, causal relationship of adverse 
event with protocol treatment, causal relationship with panitumumab, seriousness, discontinuation of 
protocol treatment, outcome, date of resolution 
 
6.3.3  Frequency tabulation of adverse events 
The following analyses regarding treatment-emergent adverse events (TEAEs) and skin toxicity 
will be performed on the “set of enrolled subjects who received at least one dose of protocol 
treatment and satisfied all of the enrollment criteria” and the “DLT evaluation set.” 
TEAEs are adverse events that develop after initiation of protocol treatment. 
Skin toxicity are events meeting the definitions of TEAEs in Table 4.1. 
TEAEs and skin toxicity will be coded using MedDRA and summarized by SOC and PTs.  
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
6.3.3.1 Frequency tabulation of all TEAEs 
6.3.3.2 Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
6.3.3.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 
6.3.3.4 Frequency tabulation of all TEAEs by severity 
6.3.3.5 Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
6.3.3.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
6.3.3.7 Frequency tabulation of TEAEs for action taken for protocol treatment was 
“discontinuation” 
6.3.3.8 Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 


Page 8 of 16 
 
 
6.3.3.9 Frequency tabulation of serious TEAEs 
6.3.3.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
6.3.3.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
6.3.3.12 Frequency tabulation of TEAEs of Grade ≥ 3 
6.3.3.13 The incidence rate of TEAEs of Grade ≥ 3 
The following analyses will be performed on the “set of enrolled subjects who received at least 
one dose of protocol treatment and satisfied all of the enrollment criteria” and the “DLT evaluation 
set.” 
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 
confidence intervals will be calculated using the following formula:  
 
95% confidence interval of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
6.3.4 Table listing 
The following items will be tabulated for the “set of enrolled subjects who received at least one 
dose of protocol treatment and satisfied all of the enrollment criteria”:  
 
6.3.4.1  List of TEAEs 
Display items:  
Subject No., DLT evaluation set, sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment 
initiation date, DLT event name (event name recorded by physician, LLT code, LLT Japanese, PT 
code, PT Japanese, SOC code, SOC Japanese), date of onset, severity, causal relationship of adverse 
event with protocol treatment, causal relationship with panitumumab, seriousness, discontinuation of 
protocol treatment, outcome, date of resolution 
 
6.3.4.2  List of protocol treatment status 
Display items:  
Subject No., DLT evaluation set, sex, age (years), BMI (kg/m2) (at enrollment), start date of 
protocol treatment, start date of TAS102 by course, dose, number of doses, date of panitumumab 
administration, dose, presence or absence of discontinuation of protocol treatment, date of 


Page 9 of 16 
 
 
discontinuation, reason for discontinuation 
 
6.3.4.3  List of treatment history 
Display items:  
Subject No., DLT evaluation set, sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment 
initiation date, primary lesion (information on primary organ, site, with/without resection, date of 
surgery), metastatic lesion (number of organs with metastases, site, with/without resection, date of 
surgery), performing a palliative colostomy (with/without, date of surgery), bypass surgery 
(with/without, date of surgery), radiation therapy (radical irradiation) (with/without, date of surgery, 
date of final dose), first-line treatment (start date, treatment details), second-line treatment (treatment 
details), third-line treatment (with/without, treatment details), preoperative/postoperative adjuvant 
chemotherapy (with/without, time period, oxaliplatin-containing regimen, date of final dose) 
 
6.3.4.4  List of complications 
Display items:  
Subject No., DLT evaluation set, sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment 
initiation date, name of complication (name of complication recorded by physician, LLT code, LLT 
Japanese, PT code, PT Japanese, SOC code, SOC Japanese) 
 
6.3.4.5  List of laboratory values 
Display items:  
Subject No., DLT evaluation set, sex, age (years), BMI (kg/m2) (at enrollment), protocol treatment 
initiation date, test date, test item (category, item name), measured value, unit, baseline 
 
7.  Statistical analysis of the phase II part of the study 
7.1  Analysis set 
In the phase II part of the study, statistical analysis will be performed on a “full analysis set” and 
“safety analysis set.” The “full analysis set” will be the main efficacy analysis set, and is defined as 
“subjects enrolled in phase I and II who received at least one dose of protocol treatment (RD) and 
satisfied all of the enrollment criteria.” The "safety analysis set" is defined as “subjects enrolled in 
phase I and II who received at least one dose of protocol treatment (RD).” Additionally, the set of all 
subjects who are enrolled in this study is defined as "all enrolled subjects." 
The statistics representative and analysis personnel should finalize a statistical analysis plan 
before data fixation based on confirmation of the definition of analysis sets and appropriateness of 
analytical handling rules of the subject data in the analysis sets, and additional handling rules for the 
issues that are not determined at planning before data fixation. 


Page 10 of 16 
 
 
 
7.2  Evaluation of analysis set 
7.2.1  Eligibility and analysis set 
A flow chart showing the breakdown of “all enrolled subjects,” “full analysis set,” and “safety 
analysis set,” and tabulation of reasons for patients not being included in the analysis set will be 
prepared based on the CONsolidated Standards Of Reporting Trials (CONSORT).1) 
 
7.2.2  Analysis of demographic and other baseline characteristics 
7.2.2.1  Demographic and other baseline characteristics 
The following analyses of the main subject demographic factors will be performed on “all 
enrolled subjects,” the “full analysis set,” and the “safety analysis set”:  
(1) Discrete data 
A frequency distribution will be tabulated for discrete data, and the percentage (%) will be 
indicated with the analysis set as a denominator. Tabulation items are as follows:  
- Age (≥ 20 to ˂ 30 years, ≥ 30 to ˂ 40 years, ≥ 40 to ˂ 50 years, ≥ 50 to ˂ 60 years, ≥ 60 to ˂ 70 
years, ≥ 70 to ˂ 75 years; ≥ 20 to ˂ 65 years, ≥ 65 to ˂ 75 years), sex, information on primary organ 
[tumor (solitary, multiple), primary tumor location (cecum, ascending colon, transverse colon, 
descending colon, sigmoid colon, rectosigmoid, rectum)], information on metastasis [(number of 
organs with metastasis) (0, 1, ≥ 2), organs with metastasis (liver, lung, peritoneum, lymph node, 
bone, adrenal gland, skin, and others)], ECOG Performance status (P.S.) (at enrollment) (0, 1, 2, 3, 4), 
complications (absence, presence). 
 
(2) Continuous data 
Summary statistics (number of cases, the mean, standard deviation, minimum, maximum, 
quartiles) will be calculated for continuous data. 
- Age (years), height (cm), body weight (kg) (at enrollment), BMI (kg/m2) (at enrollment). 
 
7.2.2.2  Breakdown of complications 
The frequency distribution of complications in “all enrolled subjects,” “full analysis set,” and 
“safety analysis set” will be tabulated, and the percentage (%) will be indicated with the analysis set 
as the denominator. Complications will be coded using MedDRA and summarized by SOC and PTs. 
 
7.2.3 Medication status 
7.2.3.1  Completion of administration 
The total completion rate of administration in the “full analysis set” and “safety analysis set” will 
be calculated by course for protocol treatment and for each drug, frequency distribution will be 


Page 11 of 16 
 
 
tabulated, and the percentage (%) will be indicated with the respective analysis set as the 
denominator. 
The cumulative dose over the entire period and the period up to Course 6, and relative dose 
intensity (RDI) over the period up to Course 6, and summary statistics (number of cases, mean, 
median, standard deviation, minimum, maximum) will be calculated by drug. The RDI will be 
calculated using the following formulae:  
 
RDI (%) = (actual dose/initial planned dose) × (28/number of days until completion of specific 
actual course) × 100 
 
Total RDI (%) = (all actual dose/all planned dose) x (168/actual number of days of all courses) × 
100 
 
7.2.3.2  Reason for discontinuation of protocol treatment 
Reasons for discontinuation in the “full analysis set” and “safety analysis set” will be tabulated for 
each course specified, and the percentage (%) will be indicated with the respective analysis set as the 
denominator. For subjects in whom the reason for discontinuation is “Other,” a list will be prepared 
summarizing reasons for discontinuation by status of completion of administration. 
 
7.2.3.3  Dose reduction status 
The frequency and percentage (%) of the subjects with dose reduction in the “full analysis set” 
and “safety analysis set” will be tabulated for each drug. Similarly, the frequency and percentage (%) 
will be tabulated for each specified course (6 courses), and the frequency distribution will be 
tabulated for each reason. 
 
7.2.3.4  Follow-up status 
The quartiles of follow-up period will be calculated in the “full analysis set” and “safety analysis 
set.” The follow-up period is the period from the day of enrollment until the day of completion of 
follow-up. The reverse Kaplan-Meier method will be used to calculate the quartiles of the follow-up 
period.2) 
 
7.2.4  Efficacy analysis 
7.2.4.1  Primary endpoint and analysis method 
[Primary endpoint] 
Progression-free survival (PFS rate) at 6 months after enrollment  
The PFS rate 6 months after enrollment, the primary endpoint, is the gross proportion of surviving 


Page 12 of 16 
 
 
subjects without documented progression up to 6 months after enrollment, counting from the day of 
enrollment. Subjects with no imaging data on progression at 6 months after enrollment and subjects 
lost to follow-up will be included in the denominator, but will not be handled as progression-free. 
 
Definition of progression:  
Progression will include both progressive disease (PD) based on diagnostic imaging assessed 
according to RECIST ver. 1.1 and primary disease progression that cannot be confirmed by 
diagnostic imaging (clinical progression). When progression is documented by diagnostic imaging, 
the day on which the diagnostic imaging is performed will be the progression date. For clinical 
progression, the day of the clinical determination will be the progression date. In a case in which, for 
example, tumor diameter has become extremely small, if the status is determined to be “not definite 
progression” clinically, although the assessment is PD according to the response criteria, the 
assessment of PD according to the response criteria will take precedence and the status will be 
considered progression. (In this case, the clinical determination on continuing protocol treatment will 
take precedence.) Even if the assessment is not PD according to the response criteria, if there is 
definite clinically documented progression, the clinical determination will take precedence and the 
status will be considered progression. For surviving subjects without documented progression, the 
period will be cut off on the final day on which progression-free status is confirmed (final day of 
progression-free survival confirmation). 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 by telephone only will not be allowed.). Events and the cut-off will also be 
handled the same way in subjects who have discontinued protocol treatment for reasons such as 
toxicity and refusal of treatment, even if another (follow-up) therapy is added. Thus, the time of 
treatment discontinuation or the day of follow-up treatment initiation will not be the cut-off. 
[Main analysis] 
The following analysis will be performed on the “full analysis set.” 
PFS rate at 6 months is calculated by counting of subjects with progression, without progression, 
and unconfirmed at 6 months. Based on the observed PFS rate at 6 months from the day of 
enrollment, binomial test will be conducted on the null hypothesis “value will be determined invalid 
at PFS rate ≤ 29%.” Significant level will be 2.5% (one-sided) in the main analysis. For interval 
estimation, accurate 90% confidence interval (two-sided) based on binomial distribution will be 
used. 
 
7.2.4.2  Secondary endpoints and analysis method 
[Secondary endpoints] 


Page 13 of 16 
 
 
• 
Progression-free survival (PFS) 
PFS is the period from the day of enrollment until the day of documented PD or the day of 
death due to any cause, whichever comes earlier. 
[Analysis method] 
Kaplan-Meier method will be used to illustrate survival curve until the onset of event in the 
“full analysis set,” and quartile point and its 95% confidence interval (two-sided) of PFS will be 
calculated. The Log-Log conversion of Brookmeyer and Crowley will be used to calculate the 
95% confidence intervals of the quartiles for PFS. 
 
• 
Overall survival (OS) 
OS is the period from the day of enrollment until death by any cause. For surviving subjects, 
the period is terminated on the final day of survival confirmation or data cut-off date, whichever 
occurs earlier. 
[Analysis method] 
The analysis will be performed in the same manner as for PFS in the “full analysis set.” 
 
• 
Response rate (RR) 
RR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is either complete response or partial response. Overall response will be 
graded by favorability in the order of complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), and not evaluable (NE). 
[Analysis method] 
RR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set.” 
 
• 
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 any cause, whichever occurs earlier. For surviving 
subjects without documented PD, the period will be cut off on the final day when specified 
diagnostic imaging reveals no PD (final day of progression-free survival confirmation). For 
surviving subjects without documented PD for whom curative resection is indicated during 


Page 14 of 16 
 
 
protocol treatment, the period will be cut off on the final day when specified preoperative 
diagnostic imaging reveals no PD (final day of progression-free survival confirmation). 
[Analysis method] 
The Kaplan-Meier survival curve will show the subject status until the onset of event for the 
subjects who showed response among the “full analysis set,” and the point estimation value of 
survival rate and its 95% confidence interval (two-sided) will be calculated at the quartile of 
survival period and specified time points. 
 
• 
Disease control rate (DCR) 
DCR is the percentage of subjects whose best overall response after enrollment according to 
RECIST ver. 1.1 is CR, PR, or SD. Overall response will be graded by favorability in the order 
of CR, PR, SD, PD, and NE 
[Analysis method] 
DCR and its 95% confidence interval (two-sided) will be calculated in the “full analysis set.” 
 
• 
Time to treatment failure (TTF) 
TTF is the period from the day of enrollment until the day of the decision to discontinue 
protocol treatment, the day of documented progression during protocol treatment, or the day of 
death due to any cause, whichever comes earlier. 
[Analysis method] 
The analysis of TTF will be performed in the same manner as for PFS in the “full analysis set.” 
 
7.2.4.3  Data conversion method and handling of missing data 
Subjects without occurrence of events listed in Section 7.2.4.2 will be treated as discontinued 
subjects in the analysis in the maintenance period for PFS, OS, and TIF. 
The cut-off date will be the final day on which progression-free survival is confirmed, when the 
clinically progression-free status has been confirmed in the PFS analysis, the final day on which 
survival is confirmed in the OS analysis, and the start date of dosing in the final course in the TTF 
analysis. 
 
7.2.4.4  Level of significance, confidence coefficient 
Significance level: Main analysis only, 5% (one-sided); other analyses, 5% (two-sided) 


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Confidence coefficient: Main analysis only, 90% (two-sided); other analyses, 95% (two-sided) 
 
7.2.5  Safety analysis 
The following analyses regarding TEAEs and skin toxicity will be performed on the “full analysis 
set” and “safety analysis set.” 
TEAEs and skin toxicity will be coded using MedDRA and summarized by SOC and PTs. 
A subject with multiple events in the same SOC will be counted once for that SOC. A subject with 
multiple events with the same PT will be counted once for that PT. 
 
7.2.5.1 Frequency tabulation of all TEAEs 
7.2.5.2 Frequency tabulation of TEAEs for which the causal relationship with protocol treatment 
was “related” 
7.2.5.3 Frequency tabulation of TEAEs for which the causal relationship with panitumumab was 
“related” 
7.2.5.4 Frequency tabulation of all TEAEs by severity 
7.2.5.5 Frequency tabulation of TEAEs by severity for which the causal relationship with protocol 
treatment was “related” 
7.2.5.6 Frequency tabulation of TEAEs by severity for which the causal relationship with 
panitumumab was “related” 
7.2.5.7 Frequency tabulation of TEAEs for action taken for protocol treatment was 
“discontinuation” 
7.2.5.8 Frequency tabulation of TEAEs by severity for action taken for protocol treatment was 
“discontinuation” 
7.2.5.9 Frequency tabulation of serious TEAEs 
7.2.5.10 Frequency tabulation of serious TEAEs for which the causal relationship with protocol 
treatment was “related” 
7.2.5.11 Frequency tabulation of serious TEAEs for which the causal relationship with 
panitumumab treatment was “related” 
7.2.5.12 Frequency tabulation of TEAEs of Grade ≥ 3 
7.2.5.13 The incidence rate of TEAEs of Grade ≥ 3 
 
The following analyses will be performed on the “full analysis set” and “safety analysis set”:  
The worst grade in each subject will be calculated. The incidence rate of TEAEs of Grade ≥ 3 and 
the 95% confidence intervals using Agresti-Coull methods will be calculated. Similarly, incidence 
rate and the 95% confidence interval of TEAEs will be calculated in the number of TEAE incidence 
with ≥ Grade 3 as the numerator, and the TEAE collecting periods as the denominator. The 95% 


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confidence intervals will be calculated using the following formula:  
The 95% confidence intervals of incidence rate = incidence rate ± 1.96ඨ
incidence rate
TEAE collecting period 
 
 
7.2.6  Table listing 
 
 
7.3  Criteria for interim analysis and premature discontinuation 
No interim analyses are scheduled. 
 
7.4  Sensitivity analysis 
7.4.1  Sensitivity analysis of primary endpoint 
For the PFS rate at 6 months (the primary endpoint), results will be calculated for the case in 
which the period is terminated at the point follow-up treatment is initiated, and the difference 
between major analysis results will be confirmed. 
 
7.4.2  Sensitivity analysis of secondary endpoints 
In assessing PFS under the same conditions as in Section 7.4.1, the result will be calculated for 
cases in which there is a change in handling, to identify the differences between the results. 
 
8.  References 
1) Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger 
M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting 
parallel group randomised trials. BMJ 2010;340:c869. 
2) Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials 1996; 17: 343–46.