Post-resection/Ablation Chemotherapy in Patients With Metastatic Colorectal Cancer Prospective, Randomized, Open, Multicenter Phase III Trial to Investigate the Efficacy of Active Post-resection/Ablation Therapy in Patients With Metastatic Colorectal Cancer
Phase: PHASE3
Conditions: Colorectal Cancer
Sponsor: Dominik Paul Modest

Confidential 
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 Post-resection/ablation chemotherapy  
in patients with metastatic colorectal cancer  
(FIRE-9 - PORT / AIO-KRK-0418) 
 
Prospective, randomized, open, multicenter Phase III trial 
to investigate the efficacy of active post-resection/ablation 
therapy in patients with metastatic colorectal cancer 
Investigational medicinal products 
5-FU, leucovorin, irinotecan, oxaliplatin 
EudraCT no. 
2020-006144-18 
Protocol code 
FIRE-9 - PORT 
AIO trial-no. 
AIO-KRK-0418 
Short title 
mFOLFOXIRI/mFOLFOX-6 versus 
follow-up surveillance after definite 
treatment of colorectal cancer 
metastases 
Sponsor 
Charité Universitätsmedizin Berlin 
Charitéplatz 1 
10117 Berlin 
Sponsor representative 
Prof. Dr. med. Dominik Modest 
Version 3.0 
28-Sep-2021 
Amendment No. 
- 
Information and data included in this protocol contain privileged or confidential information 
which is the property of the sponsor. No person is authorized to distribute it or make it public 
without permission of the sponsor. These restrictions on disclosure will apply equally to all 
future information supplied to you which is indicated as privileged or confidential. This material 
may be disclosed to and used by your staff and associates as may be necessary to conduct 
the clinical study. 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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Responsibilities 
Sponsor 
Charité Universitätsmedizin Berlin 
Charitéplatz 1 
10117 Berlin 
Germany 
Coordinating investigator and 
Representative of the Sponsor 
Prof. Dr. med. Dominik Modest 
Charité – Universitätsmedizin Berlin 
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie 
und Tumorimmunologie am Campus Virchow Klinikum (CVK) 
Augustenburger Platz 1 
13353 Berlin, Germany 
Study coordinators 
Prof. Dr. med. Johann Pratschke  
Chirurgische Klinik (CCM/CVK) 
Charité – Universitätsmedizin Berlin 
Augustenburger Platz 1 
13353 Berlin, Germany  
 
Prof. Dr. med. Sebastian Stintzing 
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie 
und Tumorimmunologie am Campus Charité Mitte (CCM) 
Charité – Universitätsmedizin Berlin 
Charitéplatz 1 
10117 Berlin, Germany 
 
Prof. Dr. med. Igor Maximilian Sauer  
Chirurgische Klinik (CCM/CVK) 
Charité - Universitätsmedizin Berlin 
Augustenburger Platz 1 
13353 Berlin, Germany  
 
PD Dr. med. Nathanael Raschzok  
Chirurgische Klinik (CCM/CVK) 
Charité – Universitätsmedizin Berlin 
Augustenburger Platz 1 
13353 Berlin, Germany  
Scientific chair 
Prof. Dr. med. Volker Heinemann 
Medizinische Klinik und Poliklinik III 
Klinikum der Universität München – LMU München 
Marchioninistr. 15 
81377 München  
Germany 
Medical writing 
Project management 
Data management 
Monitoring 
Pharmacovigilance  
 
 
Institut für Klinische Krebsforschung IKF GmbH 
am Krankenhaus Nordwest 
Steinbacher Hohl 2-26 
60488 Frankfurt am Main, Germany 
www.ikf-khnw.de 
Tel: +49 (0) 69 / 76 01 – 44 20 
Fax: +49 (0) 69 / 76 01 – 36 55 
 
 
 
 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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Biostatistics 
Prof. Dr. rer. nat. Geraldine Rauch 
Institut für Biometrie und Klinische Epidemiologie (iBikE), 
Campus Charité Mitte 
Charitéplatz 1 
10117 Berlin; Germany 
Advisory committee 
Erich Grohmann/Maria Hass 
Deutsche ILCO e.V. 
Thomas-Mann-Str. 40 
53111 Bonn, Germany 
 
Prof. Dr. med. Jens Ricke 
Klinik und Poliklinik für Radiologie, LMU München 
Marchioninistr. 15 
81377 München, Germany 
 
Prof. Dr. med. Matthias Guckenberger 
UniversitätsSpital Zürich 
Klinik für Radio-Onkologie 
Rämistr. 100 
8091 Zürich, Switzerland 
Data Safety Monitoring Board 
Prof. Dr. Michael Geissler 
Klinikum Karlsruhe 
Moltkestraße 90 
76133 Karlsruhe, Germany 
 
PD Dr. Tanja Trarbach 
Klinikum Wilhelmshafen 
Friedrich-Paffrath-Straße 1000 
26389 Wilhelmshafen, Germany 
 
PD Dr. Peter Thuss-Patience 
Augustenburger Platz 1 
13353 Berlin, Germany 
Charité – Universitätsmedizin Berlin 
Translational research 
Prof. Dr. med. Dominik Modest 
Charité – Universitätsmedizin Berlin 
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie 
und Tumorimmunologie am Campus Virchow Klinikum (CVK) 
Augustenburger Platz 1 
13353 Berlin, Germany 
 
Prof. Dr. med. Igor Maximilian Sauer  
Chirurgische Klinik (CCM/CVK) 
Charité - Universitätsmedizin Berlin 
Augustenburger Platz 1 
13353 Berlin, Germany  
Institutional Review Board 
(Ethics Committee) 
Ethik-Kommission des Landes Berlin am Landesamt für 
Gesundheit und Soziales (LAGeSo) Berlin 
Turmstr. 21 
10559 Berlin, Germany 
ethik-kommission@lageso.berlin.de 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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Approval of the Protocol 
Trial title: 
Post-resection/ablation chemotherapy in patients with metastatic colorectal 
cancer (FIRE-9 – PORT / AIO-KRK-0418) 
 
Prospective, randomized, open, multicenter Phase III trial to investigate the 
efficacy of active post-resection/ablation therapy in patients with metastatic 
colorectal cancer 
EudraCT no.: 2020-006144-18 
 
I have approved the protocol version 3.0 dated 28-Sep-2021 and confirm that the clinical trial 
will be conducted in accordance with this protocol, the Declaration of Helsinki, the International 
Conference on Harmonization (ICH) for Good Clinical Practice (GCP) guidelines and the 
applicable regulatory requirements. 
I furthermore confirm that the investigators and institutions involved in the clinical trial are to 
permit clinical trial-related monitoring, audits and regulatory inspections, including provision of 
direct access to source data and documents. 
 
Coordinating Investigator and  
Representative of the Sponsor 
 
 
 
Name 
 
 
 
 
Date 
Signature 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
 Page 5 of 79 
Approval of the Protocol 
Trial title: 
Post-resection/ablation chemotherapy in patients with metastatic colorectal 
cancer (FIRE-9 - PORT / AIO-KRK-0418) 
 
Prospective, randomized, open, multicenter Phase III trial to investigate the 
efficacy of active post-resection/ablation therapy in patients with metastatic 
colorectal cancer 
EudraCT no.: 2020-006144-18 
 
I have approved the protocol version 3.0 dated 28-Sep-2021 and confirm that the clinical trial 
will be conducted in accordance with this protocol, the Declaration of Helsinki, the International 
Conference on Harmonization (ICH) for Good Clinical Practice (GCP) guidelines and the 
applicable regulatory requirements. 
 
Biometrician 
 
 
Name of the biometrician 
 
 
 
 
Date 
Signature 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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Statement of Compliance 
Trial title: 
Post-resection/ablation chemotherapy in patients with metastatic colorectal 
cancer (FIRE-9 – PORT / AIO-KRK-0418) 
 
Prospective, randomized, open, multicenter Phase III trial to investigate the 
efficacy of active post-resection/ablation therapy in patients with metastatic 
colorectal cancer 
EudraCT no.: 2020-006144-18 
 
I have read and understood this protocol and agree to conduct the clinical trial in accordance 
with this protocol, the Declaration of Helsinki, the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP) guidelines and the applicable regulatory requirements. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical trial without the prior written 
consent of the sponsor of the clinical trial. 
 
Principal Investigator 
 
 
 
 
Signature 
Date 
 
 
Principal Investigator 
 
 
 
 
 
 
 
Principal Investigator’s Institution 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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Table of Contents 
TABLE OF CONTENTS ......................................................................................................... 7 
ABBREVIATIONS ................................................................................................................ 10 
1 
TRIAL SUMMARY ........................................................................................................ 12 
2 
TRIAL DESIGN ............................................................................................................. 20 
 
Trial Design .............................................................................................................................. 20 
 
Trial Scheme ............................................................................................................................ 21 
 
Schedule of Trial Activities .................................................................................................... 22 
3 
OBJECTIVES(S), HYPOTHESIS(ES), AND ENPOINT(S) ............................................ 26 
 
Primary Objective, Hypothesis, and Endpoint ..................................................................... 26 
 
Secondary Objective(s), Hypothesis(es), and Endpoint(s) ................................................. 26 
 
Exploratory Objective ............................................................................................................. 27 
4 
BACKGROUND AND RATIONALE ............................................................................. 28 
 
Colorectal Cancer Incidence .................................................................................................. 28 
 
Treatment Options for Colorectal Cancer ............................................................................ 28 
4.2.1 
Fluoropyrimidine plus Oxaliplatin Regimes in Metastatic Colorectal Cancer ............... 28 
4.2.2 
Further Treatment Options for Metastatic Colorectal Cancer ....................................... 29 
 
Rationale .................................................................................................................................. 29 
4.3.1 
Rationale for FOLFOX or FOLFOXIRI as post-resection/ablation therapy .................. 29 
4.3.2 
Rationale for Study Design and Endpoints ................................................................... 30 
 
Ethical Considerations and Benefit-Risk Assessment ....................................................... 31 
5 
METHODOLOGY.......................................................................................................... 32 
 
Trial Population ....................................................................................................................... 32 
5.1.1 
Inclusion Criteria ........................................................................................................... 32 
5.1.2 
Exclusion Criteria .......................................................................................................... 33 
5.1.3 
Lifestyle Considerations ................................................................................................ 35 
5.1.4 
Pregnancy ..................................................................................................................... 35 
 
Trial Intervention(s) ................................................................................................................. 35 
5.2.1 
Timing of Dose Administration ...................................................................................... 36 
5.2.2 
Prerequisites for Application of Trial Intervention ......................................................... 36 
5.2.3 
Treatment 
Modification 
and 
Toxicity 
Management 
of 
FOLFOX/FOLFOXIRI 
Chemotherapy .............................................................................................................. 37 
 
Methods against Bias ............................................................................................................. 38 
5.3.1 
Minimizing Selection Bias ............................................................................................. 38 
5.3.2 
Minimizing measurement bias ...................................................................................... 39 
 
Concomitant Medication ........................................................................................................ 39 
5.4.1 
Acceptable Concomitant Medications ........................................................................... 39 
5.4.2 
Prohibited Concomitant Medications ............................................................................ 40 
 
Removal from Study Treatment and Withdrawal from Study ............................................. 40 
 
Study Discontinuation ............................................................................................................ 41 
6 
TRIAL PROCEDURES AND ASSESSMENTS ............................................................. 42 
 
Trial Procedures ...................................................................................................................... 42 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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6.1.1 
Administrative Procedures ............................................................................................ 42 
6.1.2 
Clinical Procedures/Assessments ................................................................................ 44 
6.1.3 
Clinical Safety Laboratory Procedures/Assessments ................................................... 46 
6.1.4 
Other Procedures .......................................................................................................... 47 
6.1.5 
Visit Requirements ........................................................................................................ 48 
 
Assessment of Safety ............................................................................................................. 51 
6.2.1 
Adverse Events and Laboratory Abnormalities Reporting ............................................ 51 
6.2.2 
Handling and Reporting of Safety Parameters ............................................................. 56 
7 
ACCOMPANYING TRANSLATIONAL RESEARCH PROJECT ................................... 58 
 
Sampling Time Points, Materials and Analyses ................................................................... 58 
7.1.1 
Processing and Storage of blood samples ................................................................... 58 
7.1.2 
Tissue Samples ............................................................................................................ 58 
7.1.3 
Blood Samples .............................................................................................................. 59 
7.1.4 
Analyses ....................................................................................................................... 59 
8 
STATISTICAL ANALYSIS ............................................................................................ 60 
 
Justification of Sample Size ................................................................................................... 60 
 
Analysis .................................................................................................................................... 60 
8.2.1 
Study Populations for Analysis ..................................................................................... 61 
 
Further Analysis ...................................................................................................................... 62 
9 
STUDY MEDICATION .................................................................................................. 63 
 
mFOLFOX-6 ............................................................................................................................. 63 
9.1.1 
Oxaliplatin ..................................................................................................................... 63 
9.1.2 
Leucovorin .................................................................................................................... 64 
9.1.3 
5-Fluorouracil ................................................................................................................ 64 
 
mFOLFOXIRI ............................................................................................................................ 64 
9.2.1 
Irinotecan ...................................................................................................................... 64 
10 ADMINISTRATIVE AND REGULATORY DETAILS ..................................................... 65 
 
Regulatory and Ethical Compliance ...................................................................................... 65 
 
Registration and Request for Authorization of the Trial ..................................................... 65 
 
Ethics Committee .................................................................................................................... 65 
 
Informed Consent.................................................................................................................... 66 
 
Insurance ................................................................................................................................. 66 
 
Confidentiality ......................................................................................................................... 66 
 
Confidentiality of Subject Records ....................................................................................... 66 
 
Confidentiality of Investigator Information .......................................................................... 66 
 
Compliance with Financial Disclosure Requirements ........................................................ 67 
 Quality Management System ................................................................................................. 67 
10.10.1 Quality Control and Quality Assurance ......................................................................... 67 
10.10.2 Audits and Inspections .................................................................................................. 67 
10.10.3 Monitoring ..................................................................................................................... 67 
 Data Management.................................................................................................................... 68 
10.11.1 Plausibility Check, Data Cleaning and Coding ............................................................. 68 
 Publication and Registration of the Trial .............................................................................. 68 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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 Data Safety Monitoring Board ................................................................................................ 69 
11 REFERENCES ............................................................................................................. 70 
12 APPENDICES ............................................................................................................... 73 
Appendix 1: ECOG Performance Status ........................................................................................... 73 
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ........................... 74 
Appendix 3: Contraceptive Guidance and Pregnancy Testing ....................................................... 75 
Appendix 4: Evaluation of radiologic images................................................................................... 78 
 
List of Tables 
Table 1: Schedule of Activities .............................................................................................................. 22 
Table 2: Trial Medication (guidance for administration) ........................................................................ 36 
Table 3: Chemotherapy Dose Adjustments in case of chemotherapy associated toxicity .................... 38 
 
List of Figures 
Figure 1: Illustration of Trial Design ....................................................................................................... 20 
Figure 2: Study Flow Chart .................................................................................................................... 21 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
05-Aug-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 2.0 
 
Confidential 
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Abbreviations 
 
5-FU 
 
5-Fluorouracil 
ALC 
 
Absolute lymphocyte count 
AMG 
Arzneimittelgesetz (Medicinal 
Products Act) 
ANC 
 
Absolute neutrophil count 
aPTT 
Activated partial 
thromboplastin time 
AST 
 
Aspartate aminotransferase 
β-HCG 
beta-Human chorionic 
gonadotropin 
BfArM 
Bundesinstitut für Arzneimittel 
und Medizinprodukte (Federal 
Institute for Drugs and Medical 
Devices 
BP 
 
Blood pressure 
CBC 
 
Complete blood count 
CEA 
 
Carcinoembryonic antigen 
CPIC 
Clinical Pharmacogenetics 
Implementation Consortium 
CRC 
 
Colorectal Cancer 
CRP 
 
C-reactive protein 
CT 
 
Computed tomography 
CTCAE  
Common Terminology Criteria 
 
 
for Adverse Events 
ctDNA  
Circulating tumor DNA 
CTFG  
Clinical Trial Facilitation and 
Coordination Group 
DALY  
Disability-adjusted life years 
DPD  
Dihydropyrimidine 
dehydrogenase 
DSUR 
Development Safety Update 
Report 
EC 
 
Ethics Committee 
ECG 
 
Electrocardiogram 
ECOG   
Eastern Cooperative Oncology 
 
 
Group 
eCRF  
electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic 
acid 
e.g. 
 
exempli gratia (for example) 
EOT 
 
End of Treatment 
 
 
FFPE 
Formalin-fixed, paraffin 
embedded 
FPI 
 
First Patient In 
FSH 
 
Follicle-Stimulating Hormone 
fT3 
 
free triiodothyronine 
fT4 
 
free thyroxine 
gamma-GT 
Gamma-glutamyltransferase 
GCP 
 
Good Clinical Practice 
GCP-V 
GCP-Verordnung (GCP 
Ordinance) 
GCSF 
Granulocyte colony-stimulating 
factor 
GFR 
 
Glomerular filtration rate 
GOT 
Glutamic oxaloacetic 
transaminase 
GPT  
 
Glutamic pyruvic transaminase 
HIV 
Human immunodeficiency 
virus 
HRT 
 
Hormonal replacement therapy 
ICF 
 
Informed consent form 
ICH 
International Conference on 
Harmonization 
i.e. 
 
id est (that is) 
IEC 
 
Independent ethics committee 
INR 
 
International normalized ratio 
IRB 
 
Institutional review board 
ITT 
 
Intent-to-treat 
IUD 
 
Intrauterine device 
IUS 
Intrauterine hormone-releasing 
system 
i.v. 
 
Intravenous 
LDH 
 
Lactate dehydrogenase 
LPI 
 
Last Patient In 
mCRC  
Metastatic Colorectal Cancer 
MDRD 
Modification of Diet in Renal 
Disease 
mFOLFOX 
modified FOLFOX 
mFOLFOXIRI modified FOLFOXIRI 
MRI 
 
Magnetic resonance imaging 
NCI 
National Cancer Institute 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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OS 
 
Overall survival 
P 
 
Pulse 
PFS 
 
Progression-free survival 
PP 
 
Per protocol 
PT 
 
Prothrombin time 
PTCA 
Percutaneous transluminal 
coronary angioplasty 
QoL 
 
Quality of Life 
qxd 
 
every x days 
qxw 
 
every x weeks 
R0 
absence of microscopic 
residual tumor 
R1 
presence of microscopic 
residual tumor 
RBC 
 
Red Blood Cell 
(S)AE  
(Serious) Adverse event 
SAP 
 
Statistical Analysis Plan 
SmPC 
Summary of product 
characteristics 
SOC 
 
Standard of care 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected 
Serious Adverse Reaction 
T 
 
Temperature 
ULN 
 
Upper limit of normal 
UICC 
Union for International Cancer 
Control 
WBC   
White Blood Cell 
WHO 
 
World Health Organization 
WOCBP 
Women of childbearing 
potential 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
05-Aug-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 2.0 
 
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1 Trial Summary 
Title 
Post-resection/ablation chemotherapy in patients with metastatic colorectal cancer 
(FIRE-9 – PORT / AIO-KRK-0418). 
Prospective, randomized, open, multicenter Phase III trial to investigate the efficacy 
of active post-resection/ablation therapy in patients with metastatic colorectal 
cancer 
Short title 
mFOLFOXIRI/mFOLFOX-6 versus follow-up surveillance after definite treatment of 
colorectal cancer metastases 
Sponsor 
Charité Universitätsmedizin Berlin 
Charitéplatz 1 
10117 Berlin 
Coordinating 
investigator 
and 
Representative 
of the Sponsor 
Prof. Dr. med. Dominik Modest 
Charité - Universitätsmedizin Berlin 
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und 
Tumorimmunologie am Campus Virchow Klinikum (CVK) 
Augustenburger Platz 1 
13353 Berlin 
Protocol code FIRE-9 – PORT  
AIO trial-no. 
AIO-KRK-0418 
EudraCT no 
2020-006144-18 
Protocol 
version and 
version date 
Protocol version 3.0 dated 28-Sep-2021 
Investigational 
medicinal 
product(s) 
5-FU, leucovorin, irinotecan, oxaliplatin 
Clinical trial 
phase 
Phase III 
Number of 
patients 
To be assessed for eligibility: n ~ 750 
To be assigned to the trial, i.e. recruited: n = 507 (338 Arm A/169 Arm B) 
Number of trial 
sites 
About 80 trial sites 
Indication 
studied 
Post-resection/ablation chemotherapy in patients with metastatic colorectal cancer  
Background 
and  
rationale 
In Germany, colorectal cancer has a prevalence of 65-80/100.000, resulting in a total 
of ~60.000 new cases every year. Up to 50% of patients develop metastases during 
the course of their disease while 15-25% already present with synchronous 
metastases at first diagnosis [Howlader et al., 2011]. The current 5-year mortality is 
approximately 50% [Robert-Koch-Institut, 2019].In Western Europe, the burden of 
colorectal cancer is reported to be 211 (female) and 298 (male) disability-adjusted 
life years (DALYs) on a population of 100.000 [Soerjomataram et al., 2012]. 
Patients with metastases from colorectal cancer (appr. 40-50% of all patients develop 
metastases) can benefit from the resection or ablation of metastases, although 
relapse occurs in the majority (appr. 70-80%) of these patients [Folprecht et al., 2014; 
Kopetz et al., 2009; Nordlinger et al., 2008; Nordlinger et al., 2013; Van Cutsem et 
al., 2016]. Clearly, a further reduction in relapse rates would improve the long-term 
outcome of these patients. 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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Unfortunately, additive/adjuvant therapy after local treatment of metastases is not 
established by phase III trials. Accordingly, no standard of care treatment to improve 
the relapse rates is available and the current S3-guideline for colorectal cancer does 
not recommend additive chemotherapy due to insufficient evidence on its benefit. 
The present clinical trial aims to generate the missing evidence that additive therapy 
after resection or ablation of metastases may improve PFS and OS in patients with 
colorectal cancer. This is of specific importance since both improvements in 
localized, but also systemic therapies have resulted in increasing numbers of mCRC 
patients undergoing resection and/or ablation of metastases [Kopetz et al., 2019; 
Choti et al., 2016; Cremolini et al., 2015; Cremolini et al., 2017; Heinemann et al., 
2014; Luo et al., 2014; Modest et al., 2018]. 
Objectives 
Primary objective 
• To compare the efficacy of active additive chemotherapy after definitive 
treatment of metastases to structured follow-up only 
Secondary objectives 
• To compare efficacy, safety and patient reported quality of life (QoL) of active 
treatment to structured follow-up only 
Further secondary objective 
Further anti-tumor treatment 
Exploratory objectives 
To identify and characterize molecularly-defined patient subgroups and correlate 
their genetic and molecular tumor characteristics with clinical efficacy and toxicity 
using tumor specimen and blood-based biomarker candidates. 
Endpoints 
Primary endpoint 
• Progression-free survival (PFS) time at the 24 months follow-up defined as 
time from randomization to death or evidence of disease (whatever occurs first) 
 
Secondary endpoints 
Efficacy 
• PFS in patients with/without prior systemic therapy 
• PFS in patients with R1 vs R0 resected lesions as well as ablated vs. purely 
resected lesions  
• Overall survival (OS) 
• Treatments (including efficacy) beyond study participation 
• Local control of lesions according to ablative technique (surgery vs. ablation vs. 
radiation) 
 
Safety 
• Type, incidence, severity, and causal relationship to active chemotherapy of 
non-serious adverse events and serious adverse events (severity evaluated 
according to CTCAE version 5.0) 
 
Quality of life 
• Quality of life (QoL) as assessed with the QoL questionnaire EQ-5D-5L 
 
Exploratory endpoints 
Translational analyses including evaluation of tumor specimen of primary and/or 
metastatic tissue as well as blood samples at different time points 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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• PFS and OS according to circulating tumor DNA at baseline (ctDNA positive vs. 
negative) 
• Outcome in molecular subgroups  
Trial design 
This is an open-label, randomized, controlled, multicenter, phase III study with two 
parallel arms. Patients with metastatic colorectal cancer after definite interventional 
therapy of all lesions are randomized in a 2:1 fashion (favoring active therapy) to 
investigate the efficacy, patient reported quality of life and safety of 
mFOLFOXIRI/mFOLFOX-6 as additive treatment (Arm A) versus active follow-
up/surveillance (Arm B).  
 
During the randomization process stratification will be performed according to the 
following parameters: 
o number of treated metastases: 
 i)   > 2 vs. 1-2 
o pretreatment with systemic therapy for metastatic colorectal cancer: 
 ii)   yes vs. no 
o choice of potential therapy in the trial: 
 iii)   fit for mFOLFOXIRI vs. fit for mFOLFOX-6 
o presence of at least one of the following unfavorable prognostic factor: 
 iv)   peritoneal metastases resected/ known BRAF mutation/  
synchronous metastases defined as evidence of metastases < 12 
months vs. ≥ 12 months after first diagnosis vs. no unfavorable 
prognostic factor 
 
Treatment in Arm A is continued for a maximum of 12 cycles of 2 weeks interval (i.e. 
appr. 24 weeks) or until occurrence of progression evaluated by the investigator or 
unacceptable toxicity. 
 
Patients are followed up with regard to survival and if applicable subsequent anti- 
cancer treatments until death or for at least 5 years after randomization, whichever 
date is earlier. 
 
The trial design is displayed in the following figure: 
 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
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Inclusion 
criteria 
1. 
Patient’s signed informed consent. 
2. 
Patient’s age ≥18 years at the time of signing the informed consent. 
3. 
Histologically confirmed adenocarcinoma of the colon or rectum. 
4. 
Resected (R0 or R1) and/or effectively treated metastases (all techniques 
allowed) of colorectal cancer within 3-10 weeks before randomization AND 
resected primary tumor (synchronous or metachronous). 
5. 
Absence of significant active wound healing complications (if applicable) prior to 
randomization. Resolved wound healing complications after resection/ablation 
are acceptable for inclusion into the trial. 
6. 
No radiographic evidence of active metastatic disease at study entry in a CT 
and/or MRI scan not older than 8 weeks. Pre-surgery/ablation images are 
eligible for the study if all lesions have been addressed in the interval. 
7. 
ECOG performance status 0-2. 
8. 
Adequate bone marrow, hepatic and renal organ function, defined by the 
following laboratory test results: 
• Absolute neutrophil count  1.5 x 109/L (1500/µL) 
• Hemoglobin ≥ 80 g/L (8 g/dL) 
• Platelet count ≥ 100 x109/L (100000/µL) without transfusion 
• Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN) 
• Aspartate aminotransferase (AST/GOT) ≤ 3.0 × ULN. 
• Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault 
formula or according to MDRD ≥ 50 mL/min or serum creatinine ≤ 1.5 x ULN 
9. 
Patients without anticoagulation need to present with an INR < 1.5 x ULN and 
PTT < 1.5 x ULN. Patient with prophylactic or therapeutic anticoagulation are 
allowed into the trial. 
10. Proficient fluorouracil metabolism as defined: 
a) Prior treatment with 5-FU or capecitabine without unusal toxicity 
or 
b) If tested, normal DPD deficiency test according to the standard of the study 
site 
or 
c) If tested, in patients with DPD deficiency test with a CPIC activity score of 
1.0-1.5 fluoropyrimidine dosage should be reduced by 50%  
11. For women of childbearing potential (WOCBP): negative pregnancy test within 
14 days before randomization and agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 
< 1% per year during the treatment period and for at least 6 months after the last 
dose of study treatment. 
A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). Examples of 
contraceptive methods with a failure rate of < 1% per year include bilateral tubal 
ligation, male partner’s sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
For men: With female partners of childbearing potential, men must remain 
abstinent or use a condom plus an additional contraceptive method that together 
result in a failure rate of < 1% per year during the treatment period and for 6 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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months after the last dose of study treatment. Men must refrain from donating 
sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the last dose of study 
medication to avoid exposing the embryo.  
Exclusion 
criteria 
1. 
Treatment of metastases greater than 3 cm with radio-frequency/microwave 
ablation within 24 months prior to study entry if applicable. 
2. 
Treatment of metastases greater than 5 cm with radiation (stereotactic/ 
brachytherapy) within 24 months prior to study entry if applicable. 
3. 
Previous chemotherapy for metastatic or localized disease with > 6 cycles of 
FOLFOX (or FOLFOXIRI) or > 4 cycles of CAPOX/XELOX.  
4. 
New York Heart Association Class III or greater heart failure by clinical 
judgement. 
5. 
Myocardial infarction within 6 months prior to randomization; percutaneous 
transluminal coronary angioplasty (PTCA) with or without stenting within 6 
months prior to randomization. 
6. 
Unstable angina pectoris. 
7. 
Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic 
therapy. 
8. 
Ongoing toxicities > grade 2 NCI CTCAE, in particular peripheral neuropathy. 
9. 
Active uncontrolled infection by investigator’s perspective. 
10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone 
fracture. 
11. Known hypersensitivity to 5-FU, leucovorin, irinotecan or oxaliplatin or to any of 
the other excipients listed in section 6.1 of the corresponding SmPC. 
12. Bone marrow depression after radio- or chemotherapy. 
13. Severe kidney dysfunction (creatinine clearance < 30 ml/min) or changes in 
blood count. 
14. Recent or concomitant treatment with brivudine. 
15. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to 
CTCAE version 5.0 (see appendix)). 
16. Inflammatory bowel disease and/or bowel obstruction. 
17. Simultaneous application of Johannis herbs preparations.  
18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency. 
19. If tested, DPD deficiency test with a CPIC activity score <1. 
20. Major surgical procedure, open biopsy, or significant traumatic injury within 21 
days prior to randomization, or abdominal surgery, abdominal interventions or 
significant abdominal traumatic injury within 21 days prior to randomization or 
anticipation of need for major surgical procedure during the course of the study 
or non-recovery from side effects of any such procedure. 
21. Any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that contraindicates the use of an investigational drug, 
may affect the interpretation of the results, or may render the patient at high risk 
from treatment complications. 
22. Medical history of malignant disease other than mCRC with the following 
exceptions: 
- 
patients who have been disease-free for at least three years before 
randomization 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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- 
patients with adequately treated and completely resected basal cell or 
squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage 
I uterine cancer 
- 
patients with any treated or untreated malignant disease that is associated 
with a 5-year survival prognosis of ≥ 90% and does not require active 
therapy 
23. Known alcohol or drug abuse. 
24. Pregnant or breastfeeding females. 
25. Participation in a clinical trial or experimental drug treatment within 28 days prior 
to potential inclusion in the clinical trial or within a period of 5 half-lives of the 
substances administered in a clinical trial or during an experimental drug 
treatment prior to potential inclusion in the clinical trial, depending on which 
period is longest, or simultaneous participation in another clinical trial while 
taking part in this clinical trial. 
26. Patients depended on Sponsor, investigator or study site. 
27. Suspected SARS-CoV-2 infection with or without symptoms (evaluation 
according to local policy in respective center with respect to actual status of 
pandemic and with reference to the policy that would apply to patients with 
similar therapy outside the trial). This may include assessment of vaccination 
status, anamnesis, physical examination and potentially antigen and/or PCR 
testing. 
28. Patient committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities. 
29. Limited legal capacity. 
Treatment, 
dosage and 
administration 
Arm A: 
14-day cycle (q14d), choice of (by stratification) intravenous therapy for up to 
12 cycles*: 
mFOLFOXIRI: Oxaliplatin 85 mg/m2 2h day 1, Irinotecan 150 mg/m2 90min day 1, 
Leucovorin 400 mg/m2 1-2h day 1, followed by 5-FU 2400 mg/m2 46h. 
or 
mFOLFOX-6: Oxaliplatin 85 mg/m2 2h day 1, Leucovorin 400 mg/m2 1-2h day 1, 
5‑FU 400 mg/m2 bolus**, followed by 5-FU 2400 mg/m2 46h. 
*NOTE: Both regimens should be adjusted individually for the total dose of oxaliplatin, i.e. a 
maximum of 12 cycles taking neoadjuvant therapy any other treatment prior to the planed 
trial intervention into account. Thus, for patients pre-treated with q14d FOLFOX(IRI) or q21d 
CAPOX/XELOX, the trial intervention should be adjusted by a de-escalation to FOLFIRI or 
further to fluoropyrimidine monotherapy (following FOLFOXIRI) or to single-agent 
fluoropyrimidine (following FOLFOX) to allow for a total trial intervention duration of 6 months 
(see Section 5.2.3.1 for details). 
**5-FU 400 mg/m2 bolus can be used according to site specific routine. 
 
Further de-escalations and dose modifications are allowed per institutional 
standard as investigators decision. 
 
The treatment is continued in Arm A for a maximum of 12 cycles or until 
relapse/progression according to the local investigator or unacceptable toxicity 
whatever comes first. 
 
 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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Arm A and B: 
Within the structured follow-up for up to 60 months after randomization CT scans of 
thorax/abdomen and/or MRI scans should be scheduled every 3 months within the 
24 months after randomization. After the first two relapse-free years, intervals are 
extended to 6 months in the third and following years after randomization. 
Translational 
research 
The translational research program consists of the following steps but might be 
modified or expanded taking latest scientific data into account: 
1. 
Characterization of the initial resected/ablated tumor (primary and/or 
metastases) for DNA mutations and RNA expressions (for example panel NGS 
and mRNA expression analysis) 
2. 
Longitudinal assessments of tumor markers and circulating tumor DNA 
(according to initial tumor characteristics), assessments should include the 
baseline, 3 months and 6 months timepoints (and further timepoints as long as 
no relapse occurred). 
3. 
Characterization of tumor specimen obtained after relapse of disease during or 
after study (if occurring and available) for DNA mutations and RNA expressions. 
4. 
Correlation of 1) with 3) and eventually also correlation of relapse tumor tissue 
with acquired changes in samples of 2)  
This paired sample collection including relapse specimen plus the longitudinal 
assessment of circulating tumor DNA will be performed in order to inform about early 
detection of relapse (potentially prior to radiographic correlate), relapse patterns 
(based on initial spread and the ablative technique) and molecular background of 
relapse (tumor evolution, secondary mutations, expressions).  
Statistical 
considerations  
The primary endpoint will be PFS (progression-free survival, defined as 
progression/relapse or death from any cause) at 24 months after randomization. 
Our assumptions are based on the only available analysis of two pooled, early-
stopped trials in the adjuvant/additive setting using fluoropyrimidine monotherapies 
[Mitry et al., 2008] that reported a hazard ratio for PFS in favor of active treatment of 
0.76 (the originally reported hazard ratio was reported reversed as 1.32) that 
translated into a similar effect for the endpoint overall survival. This again support the 
validity of the primary endpoint PFS in this trial. We hypothesize a slightly larger 
effect for PFS in favor of active therapy due to the 2-3 drug regimens resulting in an 
estimated hazard ration of 0.70.  
For 
the 
control 
arm 
(surgery 
alone) 
with 
structured 
follow-up, 
a 
progression/relapse/death-free rate of 40% at time point 24 months was observed 
translating into a 60% progression/relapse/death-rate at this time (according to the 
reported control arm [Mitry et al., 2008]). With a hazard ratio 0.70 (=IC 
C=0.0267/0.0382) favoring active treatment, the hypothesized relapse rate at 24 
months in the intervention arm is assumed to be: 47%. With a power of 80%, a 2-
sided alpha of 0,05, a total of 276 events need to be observed in order to detect a 
difference in progression-free survival of a hazard ratio of 0.70 – favoring active 
treatment vs. observation (Schoenfeld formula). Assuming an accrual time of 48 
months and a follow-up time of 24 months, a drop-out/censoring rate of 40% after 24 
months after randomization, a total of 480 patients (320/160 in the respective arms, 
rounded to receive integers and maintain the allocation ratio) is expected to yield the 
required number of events if the accrual rate is constant. The computation was done 
using the software R Version 3.5.1 and the package Rpact. We account for additional 
5% of patients that directly leave the study after randomization and never received 
the study medication. Thus, a total of 507 patients (480/507≈0,95) are planned to be 
recruited. 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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Duration and 
end of trial 
Recruitment 
First patient in (FPI) to Last patient in (LPI):  48 months 
Analysis 
Primary endpoint (PFS) at 24 months 
 
 
 
after randomization:  
LPI + 24 months (72 months total) 
Secondary endpoints: 
LPI + 60 months (108 months total) 
End of Study (EOS) 
Last visit of last patient (LVLP)  
Last patient in (LPI) + 60 months  
 
(FPI + 108 months in total) 
GCP statement This clinical trial will be conducted in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki and that are consistent with the 
International Conference on Harmonization (ICH) for Good Clinical Practice (GCP) 
and the applicable regulatory requirements. 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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2 Trial Design 
 Trial Design 
This is an open-label, randomized, controlled, multicenter, phase III study with two parallel 
arms. Patients with metastatic colorectal cancer after definite interventional therapy of all 
lesions are randomized in a 2:1 fashion (favoring active therapy) to investigate the efficacy, 
patient reported quality of life and safety of mFOLFOXIRI/mFOLFOX-6 as additive treatment 
(Arm A) versus active follow-up/surveillance (Arm B). 
 
Figure 1: Illustration of Trial Design 
 
 
 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
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 Trial Scheme 
The trial will consist of both a clinical and translational part. During the study, re-assessments 
(radiologic assessment, blood and QoL) will be conducted for all trial subject of the trial every 
3 months. Tumor biopsies will be collected at screening (baseline sample) and in case of 
relapse of disease if a new tumor sample is obtained. 
The objective of the re-assessments is detection of relapse either radiologically or within the 
translational material (blood samples with ctDNA dynamics and tumor – if available from 
relapses). CT scans of thorax/abdomen and/or MRI scans will be performed every 3 months 
within the 2 years after randomization. After the first two relapse-free years, intervals should 
be stretched to 6 months in the third and following years after study start. Structured follow-up 
for up to 60 months after randomization should be maintained for both arms. 
Patients in Arm A receive additive study drug intervention (mFOLFOXIRI or mFOLFOX-6) for 
up to six months (12 cycles) after randomization with additional clinical and safety 
assessments as specified in Section 2.3.  
Allocation to study treatment FOLFOX/FOLFOXIRI for patients in Arm A is stratified and done 
by investigator’s choice. The decision considers but is not limited to factors as age, 
performance status, previous therapy, and side effects of previous therapy. Since obligatory 
criteria cannot be made treatment allocation will not be regulated by the protocol but 
stratification will avoid that treatment allocation promotes any bias.  
Figure 2: Study Flow Chart 
 

Charité Universitätsmedizin Berlin  
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
Protocol Version 3.0 
 
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 Schedule of Trial Activities 
Table 1: Schedule of Activities 
Trial Period: 
Pre-study 
SOC 
intervention# 
Screening and 
Randomization 
Phase 
Structured Follow-up (Arm A and B) 
+ Trial Intervention (Arm A only) 
 
Timing and assessment window: 
up to 10 
weeks 
prior to 
random. 
 
Inclusion is 
possible 3-10 
weeks after the 
SOC intervention 
after successful 
screening 
3mo. 
(± 2w) 
6mo. 
(± 2w) 
9mo. - 24mo. 
(q3mo. ± 2w)§ 
at least 60mo. 
after random. or 
until death 
(q6mo. ± 1mo.) 
Administrative Procedures 
Definite treatment of colorectal cancer metastases 
A/B 
 
 
 
 
 
Informed Consent 
 
A/B 
 
 
 
 
Inclusion/Exclusion Criteria 
 
A/B 
 
 
 
 
Demographics and Medical History 
 
A/B 
 
 
 
 
Prior and Concomitant Medication Reviewa) 
 
A/B 
A 
 
 
Prior FOLFOX(IRI) or CAPOX/XELOX therapy 
 
A/B 
 
 
 
 
Randomization 
 
A/B 
 
 
 
 
Clinical Procedures/Assessments 
ECOG Performance Status 
 
A/B 
A/B 
A/B 
A/B 
 
Full Physical Examinationb) 
 
A/B 
 
 
 
 
 
 
 
 
 
 
 
A‡ 
 
 
Directed Physical Examination 
 
 
A 
(A) 
 
 
 
Review Adverse Eventsc) 
 
A/B 
A/B 
A/B 
 
Heightd), Weight and Vital Signs (T, P, BP) 
 
A/B 
A 
(A) 
A‡ 
 
 
12-Lead Electrocardiograme) 
 
A/B 
A 
 
 
 
 
 
A 
 
 
 
 
A‡ 
 
 
Covid-19 assessmentr) 
 
A/B 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 

Charité Universitätsmedizin Berlin  
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
Protocol Version 3.0 
 
Confidential 
 Page 23 of 79 
Trial Period: 
Pre-study 
SOC 
intervention# 
Screening and 
Randomization 
Phase 
Structured Follow-up (Arm A and B) 
+ Trial Intervention (Arm A only) 
 
Timing and assessment window: 
up to 10 
weeks 
prior to 
random. 
 
Inclusion is 
possible 3-10 
weeks after the 
SOC intervention 
after successful 
screening 
3mo. 
(± 2w) 
6mo. 
(± 2w) 
9mo. - 24mo. 
(q3mo. ± 2w)§ 
at least 60mo. 
after random. or 
until death 
(q6mo. ± 1mo.) 
mFOLFOXIRI or mFOLFOX-6 or de-escalated 
treatment regimens, if applicable (q14d + 5d)f) 
 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 
Further anticancer therapy status 
 
 
A/B 
Survival Status 
 
 
A/B 
A/B 
A/B 
A/B 
Laboratory Procedures/Assessments 
Pregnancy Test – Urine or Serum -HCGg) 
 
A/B 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
A‡ 
 
 
PT/INR and aPTTh) 
 
A/B 
(A) 
 
 
CBC with Differentiali),j) 
 
A/B 
A 
(A) 
A‡ 
 
 
Comprehensive Serum Chemistry Paneli),k) 
 
A/B 
A 
(A) 
A‡ 
 
 
Quality of Life 
EQ5D5L Questionnaire 
 
A/B 
A/B 
A/B 
A/B 
A/B 
Efficacy Measurements 
Tumor Imaging and CEA 
A/B 
A/Bl) 
A/Bm) 
A/Bm) 
A/Bm) 
A/Bn) 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue Collection / 
Biopsy 
 
A/Bo) 
A/Bp) 
Correlative Biomarker Studies / Blood Collectionq) 
 
A/B 
A/B 
A/B 
A/B 
 
 # 
Pre-study treatment of colorectal cancer metastases by ablation/radiation should be performed to study site specific routine and is considered SOC. 

Charité Universitätsmedizin Berlin  
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
Protocol Version 3.0 
 
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 § 
If the patient progresses within 24 months after randomization an additional visit (=EOT visit) should be scheduled as timely as possible and the corresponding 
assessment should be performed. 
 ‡  
The regular assessments should be performed during the last chemotherapy cycle. If the patient progresses earlier an additional visit (=EOT visit) should be scheduled 
as timely as possible and the corresponding clinical and laboratory assessments should be performed. 
 
A/B 
To be conducted/assessed/measured for both Arms. 
 A 
To be conducted/assessed/measured for Arm A. 
 (A)  
To be conducted/assessed/measured for Arm A according to study site standards or if clinically indicated; only to be documented if abnormal. 
 
 a)  
Prior and concomitant medication should be reviewed for both Arms to assess eligibility. For Arm A, concomitant medication should also be reviewed during 
chemotherapy. 
 b)  
Full physical examination at Screening and after last dose of trial intervention. Directed physical examination during treatment cycles as per study site standards or 
if clinically indicated. It is recommended to interview patients during the COVID-19 pandemic for respective symptoms including fever, cough and headaches and to 
initiate comprehensive diagnostic in cases of suspected infections. It is also recommended to assess patients during the COVID-19 pandemic according to the 
individual policy as regulated by the site, county or state. 
 c)  
Adverse events should be reviewed for both Arms to assess eligibility. For Arm A, adverse events should be documented during trial intervention at every visit and 
up to 4 weeks after the last chemotherapy administration. For Arm B, adverse events should be queried at every visit (planned and unplanned) during the first 7 
months from randomization – but at least twice – by an unbiased open question. Thereafter, adverse events should be queried every three months for both groups 
by an unbiased open question for up to two years after randomization. 
 d) 
Height will be measured at Screening only. Vital signs should include temperature, pulse and blood pressure. 
 e)  
To be repeated prior to the first administration if ECG from screening is older than 8 weeks. To be performed at least once during treatment, i.e. at cycle 7. 
 f) 
mFOLFOXIRI regimen: Oxaliplatin 85 mg/m² 2h day 1, Irinotecan 150 mg/m² 90min day 1, Leucovorin 400 mg/m² 1-2h day 1, followed by 5-FU 2400 mg/m² 46h. 
 
 
mFOLFOX-6 regimen: Oxaliplatin 85 mg/m² 2h day 1, Leucovorin 400 mg/m² 1-2h day 1, followed by 5-FU 2400 mg/m² 46h. A 5-FU bolus of 400mg/m² prior to the 
5-FU continuous infusion might be administered at the discretion of the investigator.  
 
 
See protocol section 5.2 for dose adjustments in patients with a reduced DPD activity.  
 
 
See protocol section 5.2.3.1 for de-escalated treatment regimens in case of previous oxaliplatin application.  
 g)  
To be performed in women of childbearing potential only. WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test. This test 
should be repeated a maximum of 24 hours before study drug administration. Following initiation of treatment, pregnancy testing will be performed every second 
cycle (at least monthly) during treatment and until the end of relevant systemic exposure to the study medication in accordance with the CTFG guidance on 
contraception. 
 h) 
Quick’s time [PT/INR], aPTT. Quick’s time [PT/INR] during treatment is clinically indicated – and therefore needs to be monitored – in case of concomitant use of 5-
FU and oral anticoagulants. 
 i) 
These assessments may be performed up to 3 days prior to the treatment administration in order to have the results available on the visit day. 

Charité Universitätsmedizin Berlin  
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
Protocol Version 3.0 
 
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 j) 
White Blood Cell (WBC) count with differential & Absolute Neutrophil Count (ANC); Absolute Lymphocyte Count (ALC); Red Blood Cells (RBCs); Platelet count; 
Hemoglobin; Hematocrit. 
 k) 
Alkaline phosphatase; Aspartate aminotransferase (AST); Potassium; Sodium; Total Bilirubin; Direct Bilirubin (If total bilirubin is elevated above the upper limit of 
normal); Creatinine. 
 l)  
Separate tumor imaging at Screening will only be performed if last available tumor imaging is older than 10 weeks. Carcinoembryonic antigen (CEA) should be 
determined in addition. 
 m)  
Tumor imaging during the first 24 months after randomization will be performed every 3 months (q3mo. ± 2 weeks) calculated from the date of the last imaging. 
Earlier imaging can be performed if clinically indicated. CEA should be determined in addition to monitor the efficacy of therapy.  
 n)  
Tumor imaging thereafter will be performed every 6 months (q6mo. ± 1 mo.) calculated from the date of the last imaging. Earlier imaging can be performed if 
clinically indicated. CEA should be determined in addition to monitor the efficacy of therapy. 
 o) 
If patients consent to accompanying translational research project: Archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not 
previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue 
(archived specimen ≤ 6 months may be acceptable). 
 p)  
If patients consent to accompanying translational research project: If the patient progresses and a new biopsy is obtained within the clinical routine. 
 q) 
If patients consent to accompanying translational research project: EDTA blood (10 ml), serum (10 ml) and Streck tubes (10 ml) samples should be taken at 
Screening and every three months during the first 24 months after randomization and every 6 months thereafter. For patients in Arm A, the blood samples for the 3 
months and 6 months timepoint should be drawn prior to the study medication administration (pre-dose). 
 r) 
Assessment of Covid-19 should be conducted according to the actual pandemic situation AND institutional policy that is applied to any patients that receives 
FOLFOX/FOLFOXIRI for colorectal cancer outside the trial. This may require assessment of vaccination status, physical examination, anamnesis and Covid-19 
tests (e.g. antigen test and/or PCR testing). SARS-CoV-2-positive patients should not participate in the trial or chemotherapy application should be delayed as long 
as the patient is positive for SARS-CoV-2. 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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3 Objectives(s), Hypothesis(es), and Enpoint(s) 
 Primary Objective, Hypothesis, and Endpoint 
(1) Objective: 
To compare the efficacy of active additive chemotherapy after definitive treatment 
of metastases to structured follow-up. 
Hypothesis: 
Active additive chemotherapy after definitive treatment of metastases improves 
progression-free survival. 
Corresponding Endpoint: 
PFS – Progression-free survival time defined as time from randomization to death 
or evidence of disease relapse/progression (whatever occurs first) 
 
 Secondary Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective: 
To compare efficacy of active treatment to structured follow-up by further efficacy 
parameters and in different subgroups. 
Hypothesis: 
Subgroups, defined by various clinical parameters, display differences in efficacy 
after active additive chemotherapy after definitive treatment of metastases.  
Corresponding Endpoint(s): 
PFS in  
• 
patients with/without prior systemic therapy; 
• 
in patients with R1 vs. R0 resected lesions; 
• 
patients with ablated vs. purely resected lesions. 
OS – Overall survival (OS) as time from randomization to the date of death of any 
cause. 
Number and type of treatments (including efficacy) beyond study participation. 
Local or distant control of lesions according to ablative technique (surgery vs. 
ablation vs. radiation) 
(2) Objective: 
To compare safety of active treatment to structured follow-up only 
Hypothesis: 
Number of patients with SAEs is higher in the active treatment arm compared to the 
structured follow-up, but comparable to fluoropyrimidine regimes in similar settings. 
Corresponding Endpoint: 
(Serious) Adverse Events – Type, incidence, severity, and causal relationship to 
active chemotherapy of non-serious adverse events and serious adverse events 
(severity evaluated according to CTCAE version 5.0) 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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(3) Objective: 
To compare patient reported quality of life (QoL) of active treatment to structured 
follow-up only. 
Hypothesis: 
QoL is moderately impacted by the active treatment for patients in Arm A, but 
comparable to fluoropyrimidine regimes in similar adjuvant settings. 
Corresponding Endpoint: 
QoL – Quality of life (QoL) as assessed with the QoL questionnaire EQ-5D-5L. 
 
 Exploratory Objective 
(1) Objective: 
To identify and characterize patient subgroups with greatest benefit from treatment 
including efficacy and toxicity using tumor specimen of primary and/or metastatic 
tissue as well as blood samples at different time points for the identification of 
biomarker candidates 
Hypothesis: 
Molecularly-defined subgroups display differences in efficacy and safety after active 
additive chemotherapy after definitive treatment of metastases.  
Corresponding Endpoint: 
PFS, OS and Safety according to circulating tumor DNA at baseline (ctDNA positive 
vs. negative). 
PFS, OS and Safety according to molecular subgroups. 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
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4 Background and Rationale 
 Colorectal Cancer Incidence 
Colorectal cancer (CRC) is one of the most frequent malignancies in developed countries and 
one of the leading causes of cancer-related deaths [Ferlay et al., 2007; Garcia et al., 2007; 
Siegel et al., 2012]. Worldwide there are more than 1 million new cases diagnosed every year. 
In Germany, colorectal cancer has a prevalence of 65-80/100.000, resulting in a total of 
~60.000 new cases every year. Up to 50% of patients develop metastases during the course 
of their disease while 15-25% already present with synchronous metastases at first diagnosis 
[Howlader et al., 2011]. The current 5-year mortality is approximately 50% [Robert-Koch-
Institut, 2019]. 
In Western Europe, the burden of colorectal cancer is reported to be 211 (female) and 298 
(male) disability-adjusted life years (DALYs) on a population of 100.000 [Soerjomataram et al., 
2012]. Given the available screening-programs in developed countries, no severe 
socioeconomic impact within the incidence appears present. Life-style attitudes however may 
affect individual risk.  
 
 Treatment Options for Colorectal Cancer 
When diagnosed before nodal involvement, treatment is usually limited to surgical resection. 
Patients with nodal involvement are candidates for adjuvant chemotherapy with 
fluoropyrimidines with or without oxaliplatin following initial surgery in the attempt to prevent 
metastatic recurrence of the disease [Schmoll et al., 2012]. Once spread to distant sites, 
treatment essentially consists of palliative chemotherapy. 
 
4.2.1 Fluoropyrimidine plus Oxaliplatin Regimes in Metastatic Colorectal Cancer 
For most patients with metastatic colorectal cancer (mCRC) palliative chemotherapy regimens 
with fluoropyrimidines and oxaliplatin and/or irinotecan remain the standard of care in first- and 
second-line therapy [Van Cutsem et al., 2016]. 
A randomized phase III trial conducted by the Groupe Cooperateur Multidisciplinaire en 
Oncologie (GERCOR) demonstrated a comparable efficacy in case of overall response rate 
(ORR), progression free survival (PFS) or overall survival (OS) between an irinotecan-based 
(FOLFIRI; irinotecan, leucovorin and 5-fluorouracil (5-FU)) or an oxaliplatin-based first line 
chemotherapy (mFOLFOX-6; oxaliplatin, FA and 5-FU [Tournigand et al., 2004]).  
However, differences were observed in case of side effects and toxicity with higher numbers 
of patients suffering from grade 3 or 4 mucositis and nausea/vomiting treated with FOLFIRI 
and higher numbers of patients developing grade 3 and 4 neutropenia and neurosensory 
toxicity treated with mFOLFOX-6.  
After failure of first line therapy, irinotecan- or oxaliplatin-based 5-FU-containing 
chemotherapeutic regimes have also been shown to improve OS in second line therapy of 
patients with mCRC [Andre et al., 1999a; Andre et al., 1999b; de Gramont et al., 1997; 

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Maindrault-Goebel et al., 1999; Maindrault-Goebel et al., 2000; Maindrault-Goebel et al., 
2001].  
 
4.2.2 Further Treatment Options for Metastatic Colorectal Cancer 
Patients with metastases from colorectal cancer (appr. 40-50% of all patients develop 
metastases) can benefit from the resection or ablation of metastases, although relapse still 
occurs in the majority (appr. 70-80%) of these patients [Folprecht et al., 2014; Kopetz et al., 
2009; Nordlinger et al., 2008; Nordlinger et al., 2013]. 
Consequently, interventional treatment (surgery, ablation, radiation) with intent to definitely 
treat one or several metastases has been integrated into the treatment algorithm of metastatic 
colorectal cancer and is therefore recommended in current guidelines [Van Cutsem et al., 
2016].  
The evolution of these strategies and consecutive recommendations mostly focus on therapy 
of liver metastases due to the high frequency of this localization (75-80% of all patients) [Van 
Cutsem et al., 2016]. Nevertheless, other metastatic lesions are also treated accordingly if the 
course of disease allows for it (i.e. lung, peritoneum, bone, etc.) [Van Cutsem et al., 2016; 
Carpizo et al., 2009; Gonzalez et al., 2013; Patel et al., 2016].  
 
 Rationale 
The treatment of metastases has become an increasingly frequent situation due to the 
advancements made in surgical and other interventional techniques (such as ablation, 
brachytherapy, stereotactic radiation and others). However, whether patients benefit from 
further additive/adjuvant therapy remains elusive, since the benefit of additive/adjuvant therapy 
after local treatment of metastases is not established by phase III trials. 
Accordingly, no standard of care treatment to improve the relapse rates is available, and unlike 
the previous editions, the current S3-guideline for colorectal cancer does not recommend 
additive chemotherapy since 2017 due to insufficient evidence on its benefit 
(http://www.awmf.org/leitlinien/detail/ll/021-007OL.html). This recommendation however is not 
reflected by other guidelines like the ESMO guideline [Van Cutsem et al., 2016] 
The present clinical trial aims to generate the missing evidence that additive therapy after 
resection or ablation of metastases may improve PFS and OS in patients with colorectal 
cancer. This is of specific importance since both improvements in localized, but also systemic 
therapies have resulted in increasing numbers of mCRC patients undergoing resection and/or 
ablation of metastases [Kopetz et al., 2009; Choti et al., 2016; Cremolini et al., 2015; Cremolini 
et al., 2017; Heinemann et al., 2014; Luo et al., 2014; Modest et al., 2018]. 
 
4.3.1 Rationale for FOLFOX or FOLFOXIRI as post-resection/ablation therapy 
Studies investigating peri- or postoperative therapy in the context of surgery of metastases 
have addressed more or less homogeneous cohorts of liver-limited disease with low risk profile 
for relapse from an actual perspective [Nordlinger et al., 2008; Nordlinger et al., 2013; Mitry et 

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al., 2008; Primrose et al., 2014]. Unfortunately, these studies have failed to define a standard 
for systemic therapy in the context of intervention (i.e. surgery) in metastatic disease.  
Several aspects have limited the implementation: one study represents a pooled analysis of 
two trials with a fluoropyrimidine application (bolus 5-FU) that is no longer used and has been 
replaced by more effective and less toxic regimens (oral capecitabine or infusional 5-FU) [Mitry 
et al., 2008]. Moreover, the effect on outcome was of borderline-significance due to the 
reduced size of the respective trials. 
The second major trial in metastatic colorectal cancer investigated pre- and postoperative 
therapy with a combination regimen (FOLFOX) vs. operation of liver metastases alone. 
Importantly, the median number of metastases resected in this trial was “1”- clearly comprising 
a cohort with favourable risk which due to evolution of therapy is not directly comparable to 
patients with resected metastases in the context of current treatment algorithms. The study 
described a trend towards improvement in outcome that did not translate into a clear benefit in 
survival [Nordlinger et al., 2008; Nordlinger et al., 2013]. 
The rationale for using FOLFOX or FOLFOXIRI as post-resection/ablation treatment is based 
on the fact that these regimens are standard of care in many first- and second-line therapies 
and have proved to be efficacious in various settings, i.e. neoadjuvant, adjuvant and palliative. 
Dosage of the here applied mFOLFOXIRI is mainly based on the adjuvant pancreas study from 
Conroy et al., 2018, which also applied 2400mg/m² of 5-FU and 150mg/m² of Irinotecan. 
Although it is not the same entity, the extrapolation of the therapeutic situation (preceded, often 
complex surgery of the upper gastrointestinal tract) seems to be an important factor for the 
safety and tolerability of this regimen. 
mFOLFOX-6 is a standard regimen for adjuvant therapy of colorectal cancer. The use of a 5-
FU bolus is optional to address eventual pre-existing toxicities.  
 
4.3.2 Rationale for Study Design and Endpoints 
Since there is no established standard and no evidence of clinical improvement by systemic 
treatment after treatment of metastases from colorectal cancer, the control arm will offer 
structured oncological observation every 3 months to patients, which is also recommended as 
standard of care in the actual German treatment guidelines [Schmiegel et al., 2017]. As 
intervention – knowing that many patients will present with subclinical metastases, a highly 
active triplet-regimen (mFOLFOXIRI) or a standard adjuvant regimen (mFOLFOX-6), 
developed both in palliative and adjuvant treatment settings of gastrointestinal cancer will be 
offered to patients [Andre et al., 2004; Conroy et al., 2011; Conroy et al., 2018; Grothey et al., 
2018; Loupakis et al., 2014] 
Progression-free survival (PFS) is the primary endpoint of this trial defined as time from 
randomization to progression (new metastases) or death from any cause. PFS is an 
established surrogate endpoint in trials promoting adjuvant or additive therapy and correlates 
with overall survival (i.e. time form randomization to death from any cause) [Saad et al., 2010 
and references therein]. 
Secondary endpoints include PFS in patients with/without prior systemic therapy, in patients 
with R1 vs. R0 resected lesions as well as ablated vs. purely resected lesions. Further 

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secondary endpoints are overall survival, safety, quality of life, number and type of treatments 
(including efficacy) beyond study participation, PFS and OS according to circulating tumor 
DNA at baseline (ctDNA positive vs. negative), outcome in molecular subgroups, local control 
of lesions according to ablative technique (surgery vs. ablation vs. radiation). These endpoints 
and subgroup analyses are foreseen to identify those patient populations who benefit 
most/least from a post-resection/ablation therapy to allow for a potential fine-tuning of 
treatment in the future. 
As part of the translational research project, blood samples are collected as part of the 
structured follow-up to create a collection of patient material with and without relapse. 
Moreover, the relapses will be recorded as part of the study protocol, including the collection 
of additional tumor tissue and blood samples, if possible, at the time of relapse. Understanding 
the genetic and molecular tumor characteristics, their longitudinal changes and correlating this 
with the baseline characteristics (prior systemic therapy, ablative technique used, resection 
status) and clinical outcome will provided the most complete set of data to answer whether 
patients – and if so, which patients – benefit from an additive/adjuvant therapy after local 
treatment of metastases. 
In summary, the optimal oncological management after removal of metastases is still unclear 
and results of this trial may therefore be practice-changing. 
 
 Ethical Considerations and Benefit-Risk Assessment 
Patients with treated metastases from colorectal cancer represent a high-risk cohort for 
development of new metastases and consecutively death. Therefore, intervention with 
systemic therapy appears clearly justified, also taking into account that intervention with a 
combination regimen (fluoropyrimidine plus oxaliplatin) is accepted in patients with lower stage 
(UICC III) of disease and less risk of relapse. The intervention – although not recommended 
by the actual German guidelines and supported by data – is often discussed in tumor boards, 
regularly leading to “individual” solutions without data that justify chemotherapy in these 
patients – which is also in accordance with European perspectives (ESMO). Participating 
patients will therefore receive either standard of care on the basis of available evidence (watch 
and wait-observation including structured follow-up), or as intervention, up to 6 months of 
therapy that was so far not evaluated in this clinical setting that invokes subclinical metastases 
in the majority of patients at the time of study start. Therefore, a potential disadvantage, 
although possible, seems unlikely. The study will therefore either provide a basis for routine 
treatment of patients or alternatively confirm that additive treatment does not provide a relevant 
benefit and should not be promoted. These observations will be made in the context of a quality 
of life assessment. The trial will be conducted according to the declaration of Helsinki, German 
laws and with respect to protection of data privacy. 

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5 
Methodology 
 Trial Population 
Investigators will recruit patients directly during regular clinical consultation visits in the 
respective center, e.g. after being discussed in a multidisciplinary tumor board. All study 
related investigations and enrolment of patients will only be performed after a written consent 
was collected using the ethics committee approved patient information and consent forms 
(refer to protocol section 10.4). 
Patients fulfilling the inclusion-/exclusion criteria (see below) will be captured online in the 
eCRF as screening patients to obtain a patient number which is used for pseudonymized 
identification throughout the study. 
 
5.1.1 Inclusion Criteria 
Participants are eligible to be included in the trial only if all of the following criteria apply: 
1. Patient’s signed informed consent.  
2. Patient’s age ≥18 years at the time of signing the informed consent. 
3. Histologically confirmed adenocarcinoma of the colon or rectum. 
4. Resected (R0 or R1) and/or effectively treated metastases (all techniques allowed) of 
colorectal cancer within 3-10 weeks before randomization AND resected primary tumor 
(synchronous or metachronous). 
5. Absence of significant active wound healing complications (if applicable) prior to 
randomization. Resolved wound healing complications after resection/ablation are 
acceptable for inclusion into the trial. 
6. No radiographic evidence of active metastatic disease at study entry in a CT and/or MRI 
scan not older than 8 weeks. Pre-surgery/ablation images are eligible for the study if all 
lesions have been addressed in the interval. 
7. ECOG performance status 0-2. 
8. Adequate bone marrow, hepatic and renal organ function, defined by the following 
laboratory test results: 
• Absolute neutrophil count  1.5 x 109/L (1500/µL) 
• Hemoglobin ≥ 80 g/L (8 g/dL) 
• Platelet count ≥ 100 x109/L (100000/µL) without transfusion 
• Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN) 
• Aspartate aminotransferase (AST/GOT) ≤ 3.0 × ULN. 
• Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or 
according to MDRD ≥ 50 mL/min or serum creatinine ≤ 1.5 x ULN 
9. Patients without anticoagulation need to present with an INR < 1.5 x ULN and PTT < 1.5 
x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial. 

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10. Proficient fluorouracil metabolism as defined: 
a) Prior treatment with 5-FU or capecitabine without unusal toxicity 
  or 
b) If tested, normal DPD deficiency test according to the standard of the study site 
  or 
c) If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 
 fluoropyrimidine dosage should be reduced by 50%  
11. For women of childbearing potential (WOCBP): negative pregnancy test within 14 days 
before randomization and agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive methods with a failure rate of < 1% per year during the 
treatment period and for at least 6 months after the last dose of study treatment. 
A woman is considered to be of childbearing potential if she is post-menarcheal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per 
year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
For men: With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure rate of 
< 1% per year during the treatment period and for 6 months after the last dose of study 
treatment. Men must refrain from donating sperm during this same period. 
 
5.1.2 Exclusion Criteria 
Participants are excluded from this trial if any of the following criteria apply: 
1. Treatment of metastases greater than 3 cm with radio-frequency/microwave ablation 
within 24 months prior to study entry if applicable. 
2. Treatment of metastases greater than 5 cm with radiation (stereotactic/ brachytherapy) 
within 24 months prior to study entry if applicable. 
3. Previous chemotherapy for metastatic or localized disease with > 6 cycles of FOLFOX (or 
FOLFOXIRI) or > 4 cycles of CAPOX/XELOX.  
4. New York Heart Association Class III or greater heart failure by clinical judgement. 
5. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal 
coronary angioplasty (PTCA) with or without stenting within 6 months prior to 
randomization. 
6. Unstable angina pectoris. 
7. Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy. 
8. Ongoing toxicities > grade 2 NCI CTCAE, in particular peripheral neuropathy. 

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9. Active uncontrolled infection by investigator’s perspective. 
10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture. 
11. Known hypersensitivity to 5-FU, leucovorin, irinotecan or oxaliplatin or to any of the other 
excipients listed in section 6.1 of the corresponding SmPC. 
12. Bone marrow depression after radio- or chemotherapy. 
13. Severe kidney dysfunction (creatinine clearance < 30 ml/min) or changes in blood count. 
14. Recent or concomitant treatment with brivudine. 
15. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE 
version 5.0 (see appendix)). 
16. Inflammatory bowel disease and/or bowel obstruction. 
17. Simultaneous application of Johannis herbs preparations.  
18. Pernicious or other megaloblastic anemia caused by vitamin B12 deficiency. 
19. If tested, DPD deficiency test with a CPIC activity score <1. 
20. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior 
to randomization, or abdominal surgery, abdominal interventions or significant abdominal 
traumatic injury within 21 days prior to randomization or anticipation of need for major 
surgical procedure during the course of the study or non-recovery from side effects of any 
such procedure. 
21. Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications. 
22. Medical history of malignant disease other than mCRC with the following exceptions: 
• patients who have been disease-free for at least three years before randomization 
• patients with adequately treated and completely resected basal cell or squamous cell 
skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer 
• patients with any treated or untreated malignant disease that is associated with a 5-
year survival prognosis of ≥ 90% and does not require active therapy 
23. Known alcohol or drug abuse. 
24. Pregnant or breastfeeding females. 
25. Participation in a clinical trial or experimental drug treatment within 28 days prior to 
potential inclusion in the clinical trial or within a period of 5 half-lives of the substances 
administered in a clinical trial or during an experimental drug treatment prior to potential 
inclusion in the clinical trial, depending on which period is longest, or simultaneous 
participation in another clinical trial while taking part in this clinical trial. 
26. Patients depending on Sponsor, investigator or study site. 
27. Suspected SARS-CoV-2 infection with or without symptoms (evaluation according to local 
policy in respective center with respect to actual status of pandemic and with reference to 

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the policy that would apply to patients with similar therapy outside the trial). This may 
include assessment of vaccination status, anamnesis, physical examination and 
potentially antigen and/or PCR testing. 
28. Patient committed to an institution by virtue of an order issued either by the judicial or the 
administrative authorities. 
29. Limited legal capacity. 
 
5.1.3 Lifestyle Considerations 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
5.1.3.2 Contraception 
FOLFOX and FOLFOXIRI-based chemotherapy may have adverse effects on a fetus in utero. 
Refer to Appendix 3 for approved methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
 
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant during trial intervention, the participant will be 
immediately discontinued from trial intervention(s). The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor or designee if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or new-born). The study Investigator 
will make every effort to obtain permission to follow the outcome of the pregnancy and report 
the condition of the foetus or new-born to the Sponsor or designee. If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately 
and the pregnancy must be reported to the Sponsor or designee and followed as described in 
Section 6.2.2.5. 
 
 Trial Intervention(s) 
The study drug intervention(s) to be used in Arm A of this trial are mFOLFOX-6 or 
mFOLFOXIRI. A guidance is outlined in Table 2, however, at the discretion of the investigator, 
site specific modifications are permitted, e.g. additional 5-FU bolus, parallel leucovorin and 
oxaliplatin administration or variation of the infusion rates. 

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Table 2: Trial Medication (guidance for administration) 
Drug 
Dose/Potency 
Duration of 
administration*** 
Route of 
Administration 
Day(s) of 
application 
mFOLFOX-6 
regimen: 
Oxaliplatin 
Leucovorin  
5-FU* 
 
 
85 mg/m² 
400 mg/m² 
400 mg/m2 bolus** 
2400 mg/m²  
 
 
2h 
1-2h 
2-5 min 
46h 
 
 
IV Infusion 
IV Infusion 
IV Infusion 
IV Infusion 
 
 
d1 of each 
chemotherapy 
cycle 
mFOLFOXIRI 
regimen: 
Oxaliplatin 
Irinotecan 
Leucovorin  
5-FU* 
 
 
85 mg/m² 
150 mg/m2 
400 mg/m² 
2400 mg/m² 
 
 
2h 
90min 
1-2h 
46h 
 
 
IV Infusion 
IV Infusion 
IV Infusion 
IV Infusion 
 
 
d1 of each 
chemotherapy 
cycle 
* in DPD mutation carriers with a CPIC activity score of 1.0-1.5, 5-FU Dosage should be reduced by 50%.  
** additional 400mg/m2 bolus is permitted but not mandatory.  
*** infusion rates of chemotherapeutical components represent recommendations but might be modified according 
to local standards 
 
The guidance given in this protocol section does not replace the careful reading of the 
summary of product characteristics (SmPC) for each component! 
 
5.2.1 Timing of Dose Administration 
Trial interventions should be administered on day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Schedule of Trial Activities 
(Section 2.3). From the second cycle onwards, the chemotherapy may be administered up to 
5 days after the scheduled day 1 of the respective cycles, due to administrative reasons with 
a minimum time span of 14 days between the cycles.  
All trial interventions will be administered on an outpatient basis. 
 
5.2.2 Prerequisites for Application of Trial Intervention 
The following rule must be followed, as it describes an exclusion criterion: 
• The patient is not eligible to participate in this study if  
o > 12 weeks (> 6 cycles) of FOLFOXIRI or FOLFOX (q14d cycles) 
or 
o > 12 weeks (> 4 cycles) of CAPOX or XELOX (q21d cycles) 
or 
o a combination of the above therapies accumulating in > 12 weeks of therapy 
was received as pre-treatment. 

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5.2.3 Treatment Modification and Toxicity Management of FOLFOX/FOLFOXIRI 
Chemotherapy 
5.2.3.1 De-escalation 
It is strongly recommended that both regimens are adjusted individually for the total dose of 
oxaliplatin taking neoadjuvant/adjuvant therapy any other pre-treatment prior to the planed trial 
intervention into account in order to achieve up to 12 cycles of trial intervention.  
NOTE: In the below guidance, early terminated cycles will be counted as full cycle. 
• It is recommended to de-escalate the patient’s trial intervention from mFOLFOXIRI to 
FOLFOX or FOLFIRI or further to fluoropyrimidine monotherapy or from mFOLFOX-
6 to a single-agent fluoropyrimidine regimen, respectively according to the following 
rules: 
o For each q14d cycle of FOLFOXIRI or FOLFOX pre-treatment the oxaliplatin is 
omitted for the same number of cycles during trial intervention; e.g. 3 cycles of 
FOLFOX pre-treatment results in the omission of oxaliplatin in cycle 10-12 of 
trial intervention. 
o Each q21d CAPOX or XELOX cycle in pre-treatment counts 1.5-fold. Thus, the 
number of CAPOX or XELOX cycles is to be multiplied by 1.5 and rounded up. 
The oxaliplatin is omitted for the same number of cycles during trial intervention; 
e.g. 3 cycles of CAPOX count as 4.5 pre-treatment cycles to be rounded up to 
5. Thus, oxaliplatin is omitted in cycles 8-12 of trial intervention. 
o For a combination of the above therapies, each cycle of FOLFOXIRI or FOLFOX 
pre-treatment counts as 1 cycle and each cycle of CAPOX or XELOX pre-
treatment counts as 1.5 cycles. The cycle numbers are added and rounded up. 
Oxaliplatin is omitted from the same number of cycles of trial intervention. 
o In case of irinotecan-related toxicity in FOLFOXIRI treated patients de-
escalation to FOLFOX and further to fluoropyrimidine monotherapy is possible. 
 
5.2.3.2 Dose Modification 
Hematologic Toxicity: 
In case of neutrophil granulocytes < 500/μl and/or thrombocytes < 50000/μl at any time during 
the treatment cycle, therapy should be stopped until the prerequisites for starting a new cycle 
are met. The anticancer components considered related to the adverse event should be 
reduced by 25% of the starting dose in the following cycle, the 5-FU bolus should be omitted 
if applicable. Alternatively, GCSF application can be considered in case of neutropenia at the 
discretion of the Investigator and is recommended in patients receiving mFOLFOXIRI. A 
maximum of two dose reductions (total reduction of 50% in comparison to the initial dose) is 
allowed in every chemotherapeutical agent. 
However, at the discretion of the Investigator, a chemotherapeutical agent can be interrupted 
or omitted without having previously used the dose reductions suggested below. 
Chemotherapy can be continued with drugs not being related to the observed toxicity.  

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Febrile neutropenia: Chemotherapy should be held. GCSF administration should be 
considered. The dosage of all components should be reduced by 25%, the 5-FU bolus should 
be omitted if applicable. 
 
Non-hematologic toxicity: 
The following table (Table 3) gives an overview on dose adjustments of the chemotherapeutic 
agent most likely responsible for the observed toxicity.  
 
 
Table 3: Chemotherapy Dose Adjustments in case of chemotherapy associated toxicity 
 
Grade 2 
Grade 3 
Grade 4 
1st appearance 
Interrupt treatment until 
resolved to Grade 0-1 
then continue at same 
dose with prophylaxis 
where 
possible 
(alternatively continue 
at 75% of the original 
dose).  
Interrupt treatment until 
resolved to Grade 0-1, 
then continue at 75% of 
original 
dose 
with 
prophylaxis 
where 
possible. 
Discontinue treatment 
unless 
investigator 
considers it to be in the 
best interest of the 
patient to continue at 
50% of original dose, 
once 
toxicity 
has 
resolved to Grade 0-1. 
(after approval by the 
Sponsor) 
2nd appearance of the 
same toxicity 
Interrupt treatment until 
resolved to Grade 0-1, 
then continue at 75% of 
original dose. 
Interrupt treatment until 
resolved to Grade 0-1, 
then continue at 50% of 
original dose. 
 
3rd appearance of the 
same toxicity 
Interrupt treatment until 
resolved to Grade 0-1, 
then continue at 50% of 
original dose. 
Discontinue treatment 
permanently 
 
4th appearance of the 
same toxicity 
Discontinue treatment 
permanently 
 
 
 
 Methods against Bias 
Given that the control (Arm B) is “watch and wait-observation”, no placebo should be applied, 
also to prevent from the potential benefit of the observational group for not being at the hospital, 
not needing an intravenous port system etc. 
 
5.3.1 Minimizing Selection Bias 
5.3.1.1 Treatment Allocation 
Screened and eligible patients will be included in the trial after initiation of the study. Patients 
will be allocated in a strictly concealed way by 2:1 randomization (Intervention vs. Control) 
block with variable block lengths randomization. 

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5.3.1.2 Stratification 
During the randomization process stratification will be performed according to the following 
binary stratification variables: 
o number of treated metastases: 
i) > 2 vs. 1-2 
o pretreatment with systemic therapy for metastatic colorectal cancer: 
ii) 
yes vs. no 
o choice of potential therapy in the trial: 
iii) fit for mFOLFOXIRI vs. fit for mFOLFOX-6 
o presence of at least one of the following unfavorable prognostic factor: 
iv) peritoneal metastases resected/ known BRAF mutation/ synchronous metastases 
defined as evidence of metastases < 12 months vs. ≥ 12 months after first 
diagnosis vs. no unfavorable prognostic factor 
 
5.3.2 Minimizing measurement bias 
Due to the nature of the intervention, blinding is not possible. However, given that the 
intervention in this trial is well established chemotherapy regimen, a center-driven bias caused 
by differing expertise appears highly unlikely and will not be compensated for. 
 
 Concomitant Medication 
5.4.1 Acceptable Concomitant Medications 
All treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All relevant concomitant medication will be recorded on the electronic case 
report form (eCRF). 
All relevant concomitant medications received within 28 days before the first dose of study 
treatment until the last administration of study drug should be recorded. If participants 
experience an SAE, concomitant medication administered 4 weeks after the last administration 
of study drug are to be recorded as defined in Section 6.2. 
Covid-19 vaccination is explicitly permitted and recommended if necessary, at any time during 
the course of the study, all available vaccines are allowed. It is at the investigator’s discretion 
to delay chemotherapy after vaccination. 
 
5.4.1.1 Supportive Care 
Supportive care for treatment-related symptoms will be offered as needed to all patients in this 
study 
 

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5.4.2 Prohibited Concomitant Medications 
Patients in Arm A should not receive any of the following medications during the active 
treatment phase:  
Any concurrent (investigational or non-investigational) other anti-tumor therapy such as 
cytotoxic chemotherapy, hormonal therapy, biological therapy (including monoclonal 
antibodies) or immunotherapy. Any other medication that should not be combined with any of 
the used drugs within the trial as listed in the corresponding SmPCs. 
 
 Removal from Study Treatment and Withdrawal from Study 
Patients will be free to discontinue treatment or withdraw from the study at any time, for any 
reason, or they may be withdrawn/removed if necessary, to protect their health (see reasons 
for withdrawal below). It is understood that an excessive rate of withdrawals can render the 
study uninterpretable; therefore, unnecessary withdrawal of patients should be avoided. 
Patients that will be withdrawn from the study will not be replaced.  
Patients must be removed from study treatment for the following reasons:  
• 
Toxicities requiring discontinuation in the meaning of persistent study drug related 
grade IV SAEs according to the current SmPCs not treatable by de-escalation or 
discontinuation of the causing agent e.g. thrombocytopenia (< 100.000/mm³), 
leukocytopenia (< 3.500/mm³), mouth ulcer, stomatitis, diarrhea, bleeding, hemorrhage 
after 5-FU application or anaphylactic reaction, intestinal ischemia, sepsis, neutropenic 
sepsis, septic shock, macroangiopathic hemolytic anemia, disseminated intravascular 
coagulation, QT prolongation, rhabdomyolysis, gastrointestinal ulcer after Oxaliplatin 
application.  
• 
Withdrawal of consent  
• 
Relapse/progression of disease 
• 
Death 
• 
Investigator decision (in the best interest of the patient) 
• 
Lost to follow up 
• 
Non-compliance 
• 
Pregnancy or insufficient contraception 
• 
Termination of the study by the Sponsor 
If a SARS-CoV-2 infection occurs during treatment phase, antineoplastic treatment must be 
suspended for the time of active infection. 
If there is a medical reason for withdrawal of treatment, the patient will remain under the 
supervision of the investigator until the AEs have been resolved or declined to baseline values. 
If the reason for removal of a patient from the study is an adverse event or an abnormal 
laboratory test result, the principal specific event or test will be recorded on the eCRF. In case 

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of discontinuation of the study treatment, the investigations scheduled for the EOT visit should 
be performed.  
If a patient withdraws consent for further study treatment during the treatment phase, the 
patient should still be followed for structured follow-up (i.e. documentation of the 3-monthly 
visits). If a patient withdraws consent for further participation in the study, follow-up 
assessments will be discontinued.  
Should a patient decide to withdraw, all efforts will be made to complete and report the 
observations as thoroughly as possible.  
In any case, the eCRF section entitled "End of Study" must be completed. 
 
 Study Discontinuation  
The whole study may be discontinued at the discretion of the Sponsor in the event of any of 
the following:  
• 
Medical or ethical reasons affecting the continued performance of the study  
• 
Difficulties in the recruitment of patients  
• 
Occurrence of AEs unknown to date in respect of their nature, severity and duration or 
the unexpected incidence of known AE 
Further the study will be discontinued if: 
• Favorable opinion and/or approval is revoked 
• A necessary adaption of the maximum insurance sum in not possible 

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6 Trial Procedures and Assessments 
 Trial Procedures 
• 
Study procedures and their timing are summarized in the Schedule of Trial Activities in 
Section 2.3. Individual trial procedures are described in detail below. 
• 
Adherence to the trial design requirements, including those specified in the Schedule 
of Trial Activities in Section 2.3 is essential and required for trial conduct. Nevertheless, 
it may be necessary to perform these procedures at unscheduled time points if deemed 
clinically necessary by the investigator. 
• 
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training and experience) staff. 
• 
All screening evaluations must be completed and reviewed to confirm that potential trial 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Additional evaluations/testing may be deemed necessary by the Investigator or the 
Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g. HIV, Hepatitis C), and 
thus local regulations may require that additional informed consent be obtained from 
the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations. 
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the Schedule of Trial Activities (Section 2.3). 
 
6.1.1 Administrative Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in the clinical trial and before any study related procedures are performed. If there 
are changes to a participant’s status during the study (e.g. health requirements) the 
investigator must ensure appropriate consent is in place. 
 
6.1.1.2 General Informed Consent 
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/IEC’s 

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approval/favourable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent form 
or addendum to the original consent form that captures the participant’s dated signature or by 
the participant’s legally acceptable representative’s dated signature. 
Specifics about the trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
6.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria (Section 5.1.1 and Section 5.1.2) will be reviewed by the 
investigator or qualified designee to ensure that the participant qualifies for this trial. 
 
6.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator. Details regarding the patient’s 
colorectal cancer for which the participant has enrolled in this study will be recorded separately 
and not listed as medical history. 
 
6.1.1.5 Prior and Concomitant Medications Review 
6.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the participant within 28 
days before starting the trial. Prior anti-cancer treatment, if allowed by the inclusion/exclusion 
criteria, for the patient’s colorectal cancer will be recorded separately and not listed as a prior 
medication.  
 
6.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record relevant medication, if any, taken by the 
participant during the trial. All medications related to reportable SAEs should be recorded as 
defined in Section 6.2. 
 

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6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new 
or worsening AEs as specified in the Schedule of Activities (Section 2.3) and more frequently 
if clinically indicated. Adverse experiences will be graded and recorded throughout the study 
and during the follow-up period according to NCI CTCAE Version 5.0 (see Appendix 2: 
Common Terminology Criteria for Adverse Events V5.0 (CTCAE). Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading and action taken with 
regard to study intervention.  
Please refer to Section 6.2 for detailed information regarding the assessment and recording of 
AEs.  
 
6.1.2.2 Full Physical Exam 
The Investigator or qualified designee will perform a complete physical exam during the 
screening period (both arms). Clinically significant abnormal findings should be recorded as 
medical history. An additional full physical exam should be performed at the end of trial 
intervention (Arm A). After the first dose of study treatment new clinically significant abnormal 
findings should be recorded as AEs. 
Investigators should pay attention to clinical signs related to previous serious illnesses. 
 
6.1.2.3 Directed Physical Exam 
A directed physical exam should be performed at Day 1 Cycle 1 (Arm A). During the course of 
active treatment, the Investigator or qualified designee will perform a directed physical exam 
as clinically indicated and according to site specific routine. After the first dose of study 
intervention, new clinically significant abnormal findings should be recorded as AEs.  
Investigators should pay attention to clinical signs related to previous serious illnesses. 
 
6.1.2.4 Vital Signs 
The Investigator or qualified designee will take vital signs at screening for patients of both 
arms. In addition, for patients in Arm A prior to the administration of study treatment (Day 1 
Cycle 1) and at the end of trial intervention. During the course of active treatment, the 
Investigator or qualified designee will take vital signs as clinically indicated and according to 
site specific routine and will record abnormal findings only if clinically significant. Vital signs 
should include temperature, pulse, weight and blood pressure. Height will be measured at 
screening only. 
 
6.1.2.5 12-Lead Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed at screening (both Arms). For 
Arm A, ECG should be repeated prior to the first administration if screening ECG is older than 

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8 weeks, at least once during treatment at cycle 7 and at discontinuation of trial intervention 
and whenever clinically indicated using local standard procedures. Clinically significant 
abnormal findings from screening visit should be recorded as medical history, clinically 
significant abnormal findings during treatment should be recorded as adverse event. 
 
6.1.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The Investigator or qualified designee will assess the ECOG status (see Appendix 1) at 
screening and every three months thereafter for the first 2 years after randomization.  
 
6.1.2.7 Tumor Imaging and Assessment of Disease 
Tumor imaging is recommended to be acquired by computed tomography (CT). Magnetic 
resonance imaging (MRI) may be alternatively used when CT with iodinated contrast is 
contraindicated, when local practice mandates it or if clinically appropriate. It is recommended 
to use the same imaging technique regarding modality, and the use of contrast should be used 
in a participant throughout the study to optimize the reproducibility of the assessment of 
existing and new tumor burden and improve the accuracy of the assessment. Imaging should 
include the chest, abdomen, and pelvis at baseline to ensure absence of disease and it is 
recommended to continue with this assessment for all subsequent imaging time points. 
Participant baseline and follow-up imaging will be determined using local assessment 
(Investigator assessment), which in case of this trial is equal to evidence of new (previously 
untreated) lesions during study conduct. In addition, images (including via other modalities) 
that are obtained at an unscheduled time point to determine disease progression, as well as 
imaging obtained for other reasons, but which demonstrate radiologic progression, should also 
be used to determine progression. 
 
6.1.2.7.1 Initial Tumor Imaging 
Initial tumor imaging at Screening will only be performed if last available tumor imaging is older 
than 10 weeks. The study team must review screening images to confirm the participant has 
no clinical or radiological evidence of disease (if images were obtained after treatment of 
metastatic disease) or all known lesions have been treated in the meantime.  
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they cover thorax and abdomen and not older than 10 weeks prior 
to the start of study intervention.  
Tumor imaging prior to the definite treatment of colorectal cancer metastases as well as follow-
up images should be (additionally if applicable) provided for centrally assessing the local 
control of lesions according to ablative technique (surgery vs. ablation vs. radiation). 
 

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6.1.2.7.2 Tumor Imaging During the Study 
On-study imaging will be performed every 3 months (q3mo. ± 2 weeks) starting from the day 
of randomization and regardless of treatment cycle time points (Arm A) for the first two years 
after randomization and every 6 months (q6mo. ± 1 months) thereafter calculated from the 
date of the last imaging, respectively. Imaging can be performed more frequently if clinically 
indicated and complemented with ultrasound assessments in the intervals if indicated by the 
judgement of the investigator. Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts (Arm A). Imaging should continue to be performed until 
relapse is identified by the Investigator or the patients has been observed for at least 5 years 
after randomization. 
 
6.1.2.7.3 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging every 
3 months (q3mo. ± 2 weeks) within the first two years after randomization and every 6 months 
(q6mo. ± 1 months) thereafter to monitor disease status until disease progression, death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
 
6.1.2.7.4 Radiologic Assessment of Disease 
Tumor images will be assessed by the local investigator for tumor relapse. The individual 
judgement of the investigator will serve as the basis for all protocol guidelines related to 
disease status (e.g. continuation or discontinuation of study intervention).  
 
6.1.2.8 Covid-19 policy 
Assessment of Covid-19 should be conducted according to the actual pandemic situation AND 
institutional policy that is applied to any patient that receives FOLFOX/FOLFOXIRI for 
colorectal cancer outside the trial. This may require assessment of vaccination status, physical 
examination, anamnesis and Covid-19 tests (e.g. antigen test and/or PCR testing). SARS-
CoV-2-positive (without exceptions no matter if symptomatic or without symptoms) patients 
should not participate in the trial or chemotherapy application should be delayed as long as 
the patient is positive for SARS-CoV-2. Respective assessments should be repeated at any 
time if the investigator judgement, particularly in cases that present with new or changed risk 
factors (efficacy of vaccines, contact with infected patients etc). 
 
6.1.3 Clinical Safety Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below and timing and frequency is specified in the Schedule of Trial Activities (Section 
2.3).  

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• The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the eCRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition. 
• If laboratory values from non protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (e.g. SAE or AE or dose modification), 
then the results must be recorded on the appropriate eCRF page. 
• For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 after the last dose of study intervention, every attempt 
should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator. 
Laboratory tests for hematology, chemistry, and others are specified within the Visit 
Requirements in Section 6.1.5. 
Laboratory tests for screening should be performed within 7 days prior to the first dose of 
treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 24 hours 
prior to dosing. Results must be reviewed by the Investigator or qualified designee and found 
to be acceptable prior to each dose of study treatment.  
 
6.1.4 Other Procedures 
6.1.4.1 Withdrawal/Discontinuation 
Participants who withdraw prior to completion of the trial should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal. Any AEs that 
are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 6.2. 
 
6.1.4.2 Withdrawal from Translational Research / Future Biomedical Research  
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator. The investigator will inform the 
Sponsor. It is the responsibility of the investigator to subsequently inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed prior to the request for withdrawal being received will continue to be used 
as part of the overall research study data and results. No new analyses should be generated 
after the request is received. 
In the event that the specimens have been completely anonymized, there will be no link 
between the participant’s personal information and their specimens. In this situation, the 
request for specimen withdrawal cannot be processed. 
 

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6.1.5 Visit Requirements 
Visit requirements are outlined in the Schedule of Trial Activities in Section 2.3. Specific 
procedure-related details are provided above in the Section 6.1.1 – Section 6.1.4. 
 
6.1.5.1 Screening and Randomization  
Inclusion is possible 3-10 weeks after the SOC intervention after successful screening: 
• 
Obtain informed consent. 
• 
Check of Inclusion/Exclusion criteria. 
• 
Review / documentation of demographics and medical history. 
• 
Review / documentation of prior and concomitant medication. 
• 
Review of prior FOLFOX(IRI) or CAPOX/XELOX therapy 
• 
Baseline tumor imaging (separate tumor imaging at Screening will only be performed if 
last available tumor imaging is older than 10 weeks.) 
• 
Carcinoembryonic antigen 
• 
12-Lead Electrocardiogram. 
 
At maximum 14 days before first administration of study medication: 
• 
ECOG performance status. 
• 
Full physical examination. 
• 
Review of adverse events 
• 
Height, weight and vital signs (should include temperature, pulse and blood pressure). 
 
At maximum 7 days before first administration of study medication: 
• 
WOCBP only: Pregnancy Test – urine or serum β-HCG 
• 
Coagulation (Quick’s time [PT/INR], aPTT). 
• 
CBC with differential:  
White Blood Cell (WBC) count with differential and Absolute Neutrophil Count (ANC); 
Absolute Lymphocyte Count (ALC); Red Blood Cells (RBCs); Platelet count; 
Hemoglobin; Hematocrit. 
• 
Comprehensive serum chemistry panel:  
Alkaline phosphatase; Aspartate aminotransferase (AST); Potassium; Sodium; Total 
Bilirubin; Direct Bilirubin (if total bilirubin is elevated above the upper limit of normal); 
Creatinine.  
• 
Assessment of Covid-19 should be conducted according to the actual pandemic 
situation AND institutional policy that is applied to any patient that receives 

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FOLFOX/FOLFOXIRI for colorectal cancer outside the trial. This may require 
assessment of vaccination status, physical examination, anamnesis and Covid-19 tests 
(e.g. antigen test and/or PCR testing). SARS-CoV-2-positive patients should not 
participate in the trial or chemotherapy application should be delayed as long as the 
patient is positive for SARS-CoV-2. 
 
After all screening assessments have been performed and results are available to confirm 
inclusion/exclusion criteria: 
• 
Randomization 
 
6.1.5.2 Trial Intervention (Arm A only) 
Trial intervention should start as close to the randomization as possible. The following is 
performed as part of the trial intervention for subjects in Arm A only. 
 
At maximum 72 hours before Day 1 of Cycle 1: 
• 
WOCBP only: Pregnancy Test – urine or serum β-HCG 
• 
Quick’s time [PT/INR] (only in case of concomitant use of 5-FU and oral anticoagulants) 
• 
CBC with differential:  
White Blood Cell (WBC) count with differential and Absolute Neutrophil Count (ANC); 
Absolute Lymphocyte Count (ALC); Red Blood Cells (RBCs); Platelet count; 
Haemoglobin; Haematocrit. 
• 
Comprehensive serum chemistry panel:  
Alkaline phosphatase; Aspartate aminotransferase (AST); Potassium; Sodium; Total 
Bilirubin; Direct Bilirubin (if total bilirubin is elevated above the upper limit of normal); 
Creatinine. 
 
Day 1 of Cycle 1(assessments can be performed up to 2 days before application of drugs): 
• 
Assessment of Covid-19 should be conducted according to the actual pandemic 
situation AND institutional policy that is applied to any patient that receives 
FOLFOX/FOLFOXIRI for colorectal cancer outside the trial. This may require 
assessment of vaccination status, physical examination, anamnesis and Covid-19 tests 
(e.g. antigen test and/or PCR testing). SARS-CoV-2-positive patients should not 
participate in the trial or chemotherapy application should be delayed as long as the 
patient is positive for SARS-CoV-2.  
• 
Directed Physical Examination. 
• 
Weight and Vital Signs (temperature, pulse and blood pressure). 
• 
12-Lead Electrocardiogram, only if ECG from screening is older than 8 weeks. 

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• 
Review / documentation of prior and concomitant medication 
• 
Administration of mFOLFOXIRI or mFOLFOX-6 or de-escalated treatment regimens, if 
applicable. 
 
Day 1 of Cycle 2-12 (assessments can be performed up to 2 days before application of drugs): 
• 
Assessment of Covid-19 should be conducted according to the actual pandemic 
situation AND institutional policy that is applied to any patient that receives 
FOLFOX/FOLFOXIRI for colorectal cancer outside the trial. This may require 
assessment of vaccination status, physical examination, anamnesis and Covid-19 tests 
(e.g. antigen test and/or PCR testing). SARS-CoV-2-positive patients should not 
participate in the trial or chemotherapy application should be delayed as long as the 
patient is positive for SARS-CoV-2. 
• 
Review / documentation of prior and concomitant medication 
• 
Administration of mFOLFOXIRI or mFOLFOX-6 or de-escalated treatment regimens, if 
applicable. 
 
During Cycle 2-12: 
• 
WOCBP only: Pregnancy Test – urine or serum β-HCG – to be performed at every 
second cycle (at least monthly) during treatment and until the end of relevant systemic 
exposure to the study drug (i.e. ~30 days after the last dose), in accordance with the 
CTFG guidance on contraception. 
• 
Quick’s time [PT/INR] (only in case of concomitant use of 5-FU and oral anticoagulants) 
• 
Directed Physical Examination. 
• 
Weight and Vital Signs (temperature, pulse and blood pressure). 
• 
12-Lead Electrocardiogram at Cycle 7  
• 
CBC with differential.*  
• 
Comprehensive serum chemistry panel.* 
*besides the frequency of the laboratory assessments, which should be scheduled according to study site standards 
or as clinically indicated, also the type of lab parameters to be tested should follow study site standards. 
 
End of trial intervention: 
• 
Full Physical Examination 
• 
Weight and Vital Signs (temperature, pulse and blood pressure) 
• 
12-Lead Electrocardiogram 
• 
Quick’s time [PT/INR] (only in case of concomitant use of 5-FU and oral anticoagulants) 
• 
CBC with differential:  

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White Blood Cell (WBC) count with differential and Absolute Neutrophil Count (ANC); 
Absolute Lymphocyte Count (ALC); Red Blood Cells (RBCs); Platelet count; 
Haemoglobin; Haematocrit. 
• 
Comprehensive serum chemistry panel:  
Alkaline phosphatase; Aspartate aminotransferase (AST); Potassium; Sodium; Total 
Bilirubin; Direct Bilirubin (if total bilirubin is elevated above the upper limit of normal); 
Creatinine. 
 
6.1.5.3 Structured Follow-up (Arm A and B) 
To be performed as part of the structured follow-up. 
Every 3 months during the first 24 months after randomization: 
• 
ECOG Performance Status 
• 
Review Adverse Events (at each visit during trial intervention for Arm A) 
• 
Further anticancer therapy status (to be documented if and when new anticancer 
therapy (systemic and/or local) is initiated at the study site or if and when such 
information becomes available to the investigator, in case a new therapy is started 
somewhere else). All available information should be collected. 
• 
EQ5D5L Questionnaire 
• 
Tumor Imaging 
• 
Carcinoembryonic antigen 
Every 6 months for up to 60 months after randomization: 
• 
Survival status 
• 
EQ5D5L Questionnaire 
• 
Tumor Imaging 
• 
Carcinoembryonic antigen 
 
 Assessment of Safety 
The respective SmPCs of routine chemotherapy medications will be used as reference 
documents and will be provided to the investigators in the investigator's site file. 
6.2.1 Adverse Events and Laboratory Abnormalities Reporting 
It is the responsibility of the investigators to document all adverse events, pregnancy and 
overdose in the eCRF. Any serious adverse event (SAE) must be reported  immediately, 
without undue delay, but not later than 24 hours after obtaining knowledge to the CRO who 
will forward the SAEs to the Sponsor/Sponsor Representative within one working day.  
 

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6.2.1.1 Definitions 
6.2.1.1.1 
Adverse Event 
An adverse event (AE) is defined in the International Conference on Harmonization (ICH) 
Guideline for Good Clinical Practice as "any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment." (ICH E6: section 1.2).  
An adverse event can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease (including a worsening in the 
character, frequency, of severity of a pre-existing illness) temporally associated with the use 
of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
 
6.2.1.1.2 
Adverse Drug Reaction  
Adverse drug reactions (ADR) are all noxious and unintended responses to a medicinal 
product related to any dose administered” (European Directive 2001/20/EC).  
The phrase "responses to a medicinal product" means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship 
cannot be ruled out.  
A serious ADR (SADR) is an ADR that meets the definition of serious (provided below). 
 
6.2.1.1.3 
Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence (adverse event) 
that at any dose  
• 
results in death  
• 
is life-threatening (subject was at immediate risk of death at the time of the event)  
• 
requires in-patient hospitalization or prolongation of existing hospitalization  
• 
results in persistent or significant disability/incapacity  
• 
is a congenital anomaly/birth defect  
• 
is another significant medical condition/event  
A hospitalization meeting the regulatory definition for "serious" is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility. Any adverse 
event that does not meet one of the definitions of serious i.e. important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require interventions to prevent one of the other outcomes listed above (e.g. 
emergency room visit, outpatient surgery, or requires urgent investigation) may be considered 
by the investigator to meet the "other significant medical condition" criterion for classification 
as a serious adverse event. Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias.  

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Hospitalization for performing of protocol-required procedures or administration of study 
treatment or hospitalizations for procedures planned prior to study start and elective 
hospitalizations are not classified as an SAE, however any AE that occurs during this 
hospitalization and meets any of the above mentioned criteria of seriousness needs to be 
reported as SAE.  
Any second primary malignancy occurring in a patient during or after study treatment within 
the safety reporting period will be assessed as important medical event and thus has to be 
reported as SAE.  
Progression of the underlying malignant disease and symptoms caused by progression of the 
underlying tumor disease need not to be reported as SAE in this protocol, unless progression 
or symptoms of progression are assessed as causally related to study medication. 
 
6.2.1.1.4 
Unexpected Adverse Event / Suspected Unexpacted Serious Adverse 
Reaction 
An unexpected adverse event is any adverse drug event, the specificity or severity of which is 
not consistent with the current version of the respective SmPCs of routine chemotherapy 
medications. Also, reports which add significant information on specificity or severity of a 
known, already documented adverse event constitute unexpected adverse events. An event 
more specific or more severe than described in the current version of the respective SmPCs 
of routine chemotherapy medications would be considered "unexpected".  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction, the 
nature or severity of which is not consistent with the applicable safety reference document 
(SmPC). All suspected adverse reactions related to study medication which occur in this trial 
and are both unexpected and serious (SUSARs) are subject to expedited reporting.  
SAEs which are "serious", "related" and "unexpected" meet the criteria for SUSAR.  
In case of SUSARs a CIOMS report is completed and forwarded to the competent authorities, 
all participating investigators and the Sponsor. According to § 13 of the GCP guideline SUSAR 
reporting occurs immediately, but no later than 15 calendar days. Reporting of life-threatening 
or fatal SUSARs occurs immediately, but no later than 7 calendar days. 
 
6.2.1.2 Adverse Events Reporting 
All adverse events are documented by the participating site in the patient’s medical records 
and the eCRF. AEs are assessed from date of first study treatment until 4 weeks after the last 
dose of study therapy at every visit. For Arm B in which patients are not being actively treated, 
adverse events should be queried at every visit (planned and unplanned) during the first 7 
months from randomization, but at least twice (i.e. at the 3 and 6 months visit). Thereafter, 
adverse events should be queried every three months for both groups by an unbiased open 
question for up to two years after randomization. 
In addition to the documentation in the eCRF, all SAEs are reported by the site immediately, 
without undue delay, but not later than 24 hours after obtaining knowledge to the CRO by fax 
or email.  

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The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by patient are properly captured in the patients' medical records 
(source data).  
The following adverse event attributes must be assigned by the investigator:  
• 
Adverse event diagnosis or syndrome(s), preferably as term, if known, otherwise if not 
known signs or symptoms  
• 
Event description (with detail appropriate to the event)  
• 
Date of onset (if applicable, date of becoming serious)  
• 
Date of resolution  
• 
Seriousness (yes/no) / seriousness criterion (in case of AE fulfils criteria of SAE, SAE 
reporting is required)  
• 
Treatment required  
o 
None  
o 
Drug Treatment  
o 
Intensive Care 
o 
Other  
• 
Severity (Grade according to CTCAE version 5 or if not specified in CTCAE as follows): 
o 
Grade I: mild (awareness of sign, symptom, or event, usually transient, requiring 
 
no special treatment and generally not interfering with usual daily activities)  
o 
Grade II: moderate (discomfort that causes interference with usual activities; 
 
usually ameliorated by basic therapeutic maneuvers)  
o 
Grade III: severe (incapacitating with inability to do usual activities or 
 
significantly affects clinical status and warrants intervention. Hospitalization 
 
may or may not be required)  
o 
Grade IV: life-threatening (immediate risk of death; requires hospitalization and 
 
clinical intervention)  
o 
Grad V: death)  
• 
Assessment of relatedness to study treatment (related/not related)  
• 
Outcome: 
o 
Recovered/resolved  
o 
Recovering/resolving/ongoing  
o 
Recovered/resolved with sequelae  
o 
Not recovered/not resolved  
o 
Fatal  
o 
Unknown (only applicable if patient is lost to follow-up)  

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• 
Action taken regarding study drugs: 
• 
None  
o 
Dose reduced (new dose)  
o 
Dose increased  
o 
Temporarily discontinued (stop date, date of re-start)  
o 
Permanently discontinued (stop date)  
o 
Not applicable  
o 
Unknown.  
Medically significant adverse events considered related to the investigational product by the 
investigator, coordinating investigator or the Sponsor will be followed until resolved or 
considered stable. 
It will be left to the investigator’s clinical judgment to determine whether an adverse event is 
related or of sufficient severity to require the subject’s removal from treatment or from the 
study. A subject may also voluntarily withdraw from treatment due to what he or she perceives 
as an intolerable adverse event. If either of these situations arises, the subject should be 
strongly encouraged to undergo an end-of-treatment (EOT) assessment and be under medical 
supervision until symptoms cease or the condition becomes stable.  
All clinical adverse events (AEs) encountered during the clinical study will be reported on the 
AE page of the eCRF.  
Intensity of adverse events will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 5 (Appendix 2).  
Progression or deterioration of the malignancy under study (including new metastatic lesions 
and death due to disease progression) will be part of the efficacy assessment and should NOT 
be reported as AE or SAE. 
 
6.2.1.3 Laboratory Test Abnormalities  
Laboratory test results will be recorded on the laboratory results pages of the eCRF. Laboratory 
test value abnormalities as such should be considered as an AE in case they are:  
• 
Accompanied by clinical symptoms.  
• 
Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation).  
• 
Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).  
In general, it is the investigator’s responsibility to review all abnormal laboratory results and to 
determine if a given value represents a clinically significant change compared to previously 
obtained values and results in an adverse event (AE) or not.  

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Any laboratory result abnormality fulfilling the criteria for a serious adverse event (SAE) should 
be reported as such, in addition to being recorded as an adverse event in the eCRF. 
 
6.2.2 Handling and Reporting of Safety Parameters 
6.2.2.1 Serious Adverse Events 
For each patient any clinical adverse event or abnormal laboratory test value that is serious 
occurring during the course of the study from the date of first study treatment until up to 4 
weeks after the last dose of study treatment, must be reported immediately, without undue 
delay, but not later than 24 hours after recognition or receiving knowledge to CRO via fax or 
email with a completed SAE Report Form to the Sponsor and coordinating investigator. If 
missing information about a SAE cannot be collected, the SAE should be reported 
immediately, without undue delay, but not later than 24 hours and the missing information sent 
later as a follow-up report as soon as possible. 
The coordinating investigator as the sponsors authorized representative will medically review 
all SAE reports (second assessment of the SAE) within 3 calendar days, for fatal and life-
threatening SAEs within one calendar day, with regard to:  
• 
Relationship to study treatment  
• 
Expectedness  
• 
Change of risk-benefit relation of the study  
The Sponsor and the CRO will ensure compliance with all regulatory reporting requirements 
including the notification of the appropriate Ethics Committees, Competent Authorities and 
participating investigators of all serious adverse events occurring at the sites in accordance 
with national laws of Germany, ICH Good Clinical Practice and European/EMA requirements.  
Expectedness of any SAE will be assessed by means of the reference safety information in 
the current version of the respective SmPC for standard chemotherapy medications. Every 
SAE, being assessed by either the investigator or the sponsor (respectively the coordinating 
investigator) as related to study drug und assessed as being either unexpected or unexpected 
with regard to outcome or severity of the event will be reported as SUSAR to the competent 
authorities, responsible ethics committee and investigators of the trial in line with the national 
regulations in effect (German drug law [AMG] and GCP-V). 
Fatal or life-threatening SUSARs must be reported within 7 days, all others need to be reported 
within 15 days. Also, all events which can change the risk-benefit ratio of the study drug have 
to be reported within 15 days in the same way as SUSARs.  
Once a year throughout the clinical trial or on demand, the sponsor will provide the competent 
authorities and the responsible ethics committee with the annual safety report in the format of 
the Development Safety Update Report (DSUR) in accordance with European and national 
regulations (GCP-V).  
Misuse, abuse and overdose of study medication (i.e. higher dose than stipulated by the 
protocol) have to be reported to the Sponsor and the CRO within 15 days of identification. 

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Cases of misuse, abuse or overdose that lead to serious adverse reactions should be reported 
on an expedited basis with a completed and faxed or emailed SAE Report Form. 
 
6.2.2.2 Treatment and Follow-up of Adverse Events  
Adverse events, especially those for which the relationship to the study medication is related, 
should be followed up until they have returned to baseline status or stabilized. If a clear 
explanation is established, it should be recorded on the eCRF.  
 
6.2.2.3 Follow-up of Abnormal Laboratory Test Values  
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found. If a clear explanation is established, it should be 
recorded on the eCRF.  
 
6.2.2.4 Adverse drug reactions with Concomitant Medication  
The investigators must be aware that for all concomitant medications the regulations of post 
marketing reporting for suspected adverse drug reactions apply, i.e. reporting to the marketing 
authorization holder or the local regulatory bodies. 
 
6.2.2.5 Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the sponsor 
or designee. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious adverse events. If the pregnancy continues to term, the outcome (health of infant) must 
also be reported. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Institut für Klinische Krebsforschung IKF GmbH: 
IKF Safety facsimile number: +49 / (0)69 / 7601 – 3655 
or 
email: sae@ikf-khnw.de 

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FIRE-9 PORT 
 
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7 Accompanying Translational Research Project 
The accompanying translational research project aims to identify and characterize molecularly-
defined patient subgroups and to correlate their genetic and molecular tumor characteristics 
with clinical efficacy and toxicity using tumor specimen and blood-based biomarker candidates. 
Participation in translational research projects is optional for the patient and requires separate 
consent. If the patient does not consent or withdraws consent, this will have no impact on the 
study participation nor on his / her treatment outside this study.  
 
 Sampling Time Points, Materials and Analyses 
Tissue and blood samples should be sent to:  
  
Prof. Dr. med. Dominik Modest  
Keyword: PORT  
Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie  
Campus Virchow Klinikum (CVK) 
Geländeaddresse: Ostring 1; DG, Studienzentrale 
Charité – Universitätsmedizin Berlin 
Augustenburger Platz 1 
13353 Berlin 
 
7.1.1 Processing and Storage of blood samples  
• Streck tubes might be shipped without refrigeration at any time.  
• EDTA and serum blood should be processed with centrifugation, filled in sample tubes 
and stored at -20°C or below that temperature. Shipment of EDTA/Serum samples 
should be conducted in larger cohorts and coordinated with the sponsor representative 
to ensure arrival at workdays and continuous cooling. 
• An additional graphical illustration is part of the study documents for the processing and 
shipment of samples.  
 
7.1.2 Tissue Samples 
Formalin-fixed, paraffin embedded (FFPE) tissue blocks – blocks are preferred over slides – 
will be collected at baseline and after relapse of disease if a new biopsy or a new block of 
tissue is obtained within the clinical routine. Samples should be obtained by core or excisional 
biopsies (fine needle aspiration and bone metastasis samples are not acceptable) of a tumor 
lesion not previously irradiated. Tissue samples should be sent in pairs (if available) for any 
patient directly to the sponsor representative (see above). 
 

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FIRE-9 PORT 
 
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7.1.3 Blood Samples 
EDTA blood (10 ml), serum (10 ml) and Streck tubes (10 ml) samples are taken at Screening 
and every three months during the first 24 months after randomization and every 6 months 
thereafter - as long as no relapse occurs.  
 
7.1.4 Analyses 
The translational research projects might be adjusted or expanded taking the latest research 
data into account, but will consist of the following steps: 
1. 
Characterization of the initial resected/ablated tumor (primary and/or metastases) for 
DNA mutations and RNA expressions (for example panel NGS and mRNA expression 
analysis) 
2. 
Sequential central assessment of tumor markers and circulating tumor DNA (according 
to initial tumor characteristics), including three assessments during study intervention 
(baseline, after 3 months, after 6 months). 
3. 
Characterization of tumor specimen obtained after relapse of disease during or after 
study (if occurring and available) for DNA mutations and RNA expressions. 
4. 
Correlation of 1) with 3) and eventually also correlation of relapse tumor tissue with 
acquired changes in samples of 2)  
This paired sample collection including relapse specimen plus the longitudinal assessment of 
circulating tumor DNA will be performed in order to inform about early detection of relapse 
(potentially prior to radiographic correlate), relapse patterns (based on initial spread and the 
ablative technique) and molecular background of relapse (tumor evolution, secondary 
mutations, expressions). 

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FIRE-9 PORT 
 
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8 Statistical Analysis 
 Justification of Sample Size 
The primary endpoint will be PFS (progression-free survival, defined as progression/relapse 
or death from any cause) at 24 months after randomization. 
Our assumptions are based on the only available analysis of two pooled, early-stopped trials 
in the adjuvant/additive setting using fluoropyrimidine monotherapies [Mitry et al., 2008] that 
reported a hazard ratio for PFS in favor of active treatment of 0.76 (the originally reported 
hazard ratio was reported reversed as 1.32) that translated into a similar effect for the endpoint 
overall survival. This again support the validity of the primary endpoint PFS in this trial. We 
hypothesize a slightly larger effect for PFS in favor of active therapy due to the 2-3 drug 
regimens resulting in an estimated hazard ration of 0.70.  
For the control arm (surgery alone) with structured follow-up, a progression/relapse/death-free 
rate of 40% at time point 24 months was observed translating into a 60% 
progression/relapse/death-rate at this time (according to the reported control arm [Mitry et al., 
2008]). With a hazard ratio 0.70 (=IC C=0.0267/0.0382) favoring active treatment, the 
hypothesized relapse rate at 24 months in the intervention arm is assumed to be: 47%. With a 
power of 80%, a 2-sided alpha of 0,05, a total of 276 events need to be observed in order to 
detect a difference in progression-free survival of a hazard ratio of 0.70 – favoring active 
treatment vs. observation (Schoenfeld formula). Assuming an accrual time of 48 months and 
a follow-up time of 24 months, a drop-out/censoring rate of 40% after 24 months after 
randomization, a total of 480 patients (320/160 in the respective arms, rounded to receive 
integers and maintain the allocation ratio) is expected to yield the required number of events if 
the accrual rate is constant. The computation was done using the software R Version 3.5.1 
and the package Rpact. We account for additional 5% of patients that directly leave the study 
after randomization and never received the study medication. Thus, a total of 507 patients 
(480/507≈0,95) are planned to be recruited. 
 
 Analysis 
Statistical analysis is based on the International Conference on Harmonization (ICH) 
Guidelines “Structure and Content of Clinical Study Reports” and “Statistical Principles for 
Clinical Trials”. No interims analysis is planned. Prior to the final analysis, data will be verified 
with respect to completeness and plausibility (data cleaning). Inconsistencies and mistakes 
will be clarified with the study sites and will be removed. The data cleaning process starts soon 
after first patients are enrolled and monitored. Major protocol violations and special cases will 
be listed. Prior to the final analysis, a conference with coordinating investigator, statistician, 
and the steering committee of the study will discuss and define the statistical analysis plan 
(SAP) and the handling of special cases and major violations. This conference will also define 
those violations, which will result in the exclusion from the per protocol (PP) population or even 
from the intent-to-treat (ITT) population. Exclusion from the ITT group is limited to very special 
cases such as patients with the incorrect disease. 
 
 
 

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FIRE-9 PORT 
 
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Primary analysis: 
The null hypothesis to be tested in confirmatory analysis states that the hazard ratio for PFS 
comparing intervention versus control equals 1. This hypothesis will be tested by means of 
Cox-regression adjusting for the strata for randomization. The two-sided significance level is 
set to 0.05. The Cox-regression adjusted for additional factors provides a power advantage 
compared to the logrank test used for sample size calculation and this procedure thus provides 
a conservative approach. The primary analysis will be conducted based on the full analysis set 
which is defined as the Intent-to-treat population including all randomized patients. In a survival 
analysis setting, missing values are treated as non-informative censoring values so there is no 
need for imputation. 
 
Secondary analyses: 
As a sensitivity analysis to the primary efficacy analysis, the same test will be repeated on the 
per-protocol population. As another sensitivity analysis, the primary hypothesis will also be 
tested with the test for the average hazard ratio to potentially account for non-proportional 
hazards [Rauch et al., 2018]. Event probabilities of PSF will be estimated by Kaplan-Meier-
Curves. The above analyses will be repeated for overall survival (OS). The influence of 
treatments received after the period of intervention on (PFS and) OS will be assessed. Specific 
post-study treatments will be included in a Cox model as time-dependent explanatory 
variables. Longitudinal models will be fitted to examine the evolution over time of the two arms 
and to test potential differences between them. Circulating tumor DNA, tumors markers and 
molecular information as well as Quality of life/ patient reported outcomes will be evaluated 
exploratory. 
 
Safety analyses: 
Safety analysis will be performed in the safety set. Absolute and relative frequencies as well 
as unbiased event-rate estimates (Kaplan-Meier, Empirical cumulative incidence) of AEs, 
SAEs, event rates of grade 3 and 4 toxicities (NCI-CTCAE) and abnormal laboratory values/ 
increase/decrease between treatment arms will be reported at different time points together 
with 95%-confidence intervals. 
 
A detailed methodology for the statistical analysis will be described in the statistical analysis 
plan (SAP), which will be finalized before database lock. This also includes specification of 
validated statistical software to be used for analysis. 
 
8.2.1 Study Populations for Analysis 
The following data sets for analysis are defined: 
Intent-to-treat population (ITT): 
The intent-to-treat (ITT) population includes all randomized patients. Treatment assignment is 
based on the randomized treatment (primary population). The ITT population is the primary 

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FIRE-9 PORT 
 
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population for the description of the patient and treatment characteristics and is used for the 
primary efficacy analysis. 
Per-protocol (PP) population: 
This population will include all randomized patients fulfilling the inclusion and exclusion criteria 
and who received at least one cycle of active treatment with at least one documented 
structured follow-up visits (Arm A) or with at least one documented follow-up visit (Arm B). 
Treatment assignment is based on the treatment actually received. 
 
Safety analysis set: 
The safety population for chemotherapy related toxicities comprises all patients who received 
at least one administration of mFOLFOXIRI/mFOLFOX-6 after randomization. 
 
Several subgroup analyses including but not limited to prior systemic therapy (with vs. without 
prior systemic therapy), resection status (R1 vs. R0 resected lesions) and type of definite 
treatment of colorectal cancer metastases (ablated vs. purely resected lesions) are planned. 
In addition, and more explorative, subgroups might be defined based on circulating tumor DNA 
status at baseline (ctDNA positive vs. negative) and other molecular parameters. Further 
details will be specified in the SAP. 
 
 Further Analysis 
In addition, multiple types of machine learning (ML) models will be retrospectively applied on 
the data to evaluate the potential of ML-algorithms in predicting the occurrence of the primary 
as well as secondary endpoints on an exploratory basis. The ML models will use all categorical 
and numerical data outlined above and supervised and unsupervised learning models shall be 
tested. For analysis, model selection and hyperparameter optimization, the baseline dataset 
will be split into training and evaluation data using stratified k-fold crossvalidation. For 
supervised binary classification (e.g. PFS within 24 months) Logistic Regression, Support 
Vector Classifier and Neural Networks will be performed. Unsupervised learning algorithms 
will entail K-Nearest Neighbor or a Gaussian Mixture Model after principal component analysis. 
The evaluation of ML-algorithms with respect to their test performance criteria will be 
conducted using receiver operating characteristic (ROC) curves, which indicate the 
discriminatory power of a diagnostic test. The ROC curve describes the dependence of 
sensitivity (true positive rate) and 1-specificity (false positive rate) for different threshold values 
of the ML classifier. The Area Under the Curve (AUC) of the ROC will subsequently be applied 
to quantify the classification performance of each model at all classification thresholds. 
Depending on the balance of the dataset, precision-recall AUC will additionally be used for 
classifier performance testing. 
Data cleaning and preprocessing will be conducted with Python using the Anaconda/Jupyter-
Notebook (Anaconda Inc., Austin, TX, USA). ML algorithm calculation and testing will be 
performed with SKLearn [Buitinck et al., 2013]. Modelling of Neuronal Networks in particular 
will furthermore require Tensor Flow [Abadi et al., 2016]. 

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FIRE-9 PORT 
 
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9 Study Medication 
This section provides an overview on the study medication used. It is not intended to replace 
the careful reading of the summary of product characteristics (SmPC) for each component, 
which contains details on drug characteristics, storage, application, mode of action and 
adverse reactions. All substances within the FOLFOX / FOLFOXIRI regimen are market 
approved in Germany/Europe for at least one kind of tumor. Moreover, the regimens are 
standard of care for patients with of lower stages of colorectal cancer. Therefore, the protocol 
requires limited documentation of concomitant medication with regard to FOLFOX / 
FOLFOXIRI in this trial. If patients receive concomitant medication, the product characteristics 
need to be checked by the investigator with respect to potential drug interactions. In case of 
any doubt, the lead coordinating investigator shall be consulted. The investigator or the 
pharmaceutical expert in delegation is responsible for the safe storage, preparation, release, 
and documentation of the study medication with respect to standard procedures and national 
guidelines. All medication shall be distributed according to the prescription of the investigator 
 
 mFOLFOX-6 
9.1.1 Oxaliplatin 
Oxaliplatin (trade name: e.g. Eloxatin®) is presented as a clear, colourless concentrate in glass 
vials of 20 mL containing 100 mg active compound and to be diluted for preparation of an 
infusion solution. Oxaliplatin will be administered in 500mL of 5% glucose solution as a two-
hour i.v. infusion. Oxaliplatin should always be administered before 5-FU. For further 
information see the respective SmPC (Summary of Product Characteristics, Fachinformation). 
Oxaliplatin is a cytotoxic anticancer drug and, as with other potentially toxic compounds, 
caution should be exercised when handling and preparing oxaliplatin solutions. The use of 
gloves is recommended.  
If oxaliplatin concentrate, initial diluted solution, or infusion solution should come into contact 
with skin, immediately and thoroughly wash with soap and water. If oxaliplatin concentrate, 
initial diluted solution, or infusion solution should come into contact with mucosa, immediately 
and thoroughly wash with water.  
Do not combine with alkaline medications or media that cause oxaliplatin to degrade. Do not 
administer other agents simultaneously by the same line. Flush line after oxaliplatin 
administration before using the line to administer other agents. Do not use preparation / 
administration needles or intravenous administration sets containing aluminium parts, as 
aluminium has been reported to cause degradation of platinum compounds. 
 
9.1.1.1 Possible Adverse Effects of Oxaliplatin 
Nausea/vomiting, diarrhea, leukopenia, thrombocytopenia, anemia, increase of liver enzymes, 
alopecia, peripheral neurotoxicity. Please refer to the respective SmPC for further details. 
 

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9.1.2 Leucovorin  
Leucovorin (calcium folinate; e.g. Leucovorin 10mg/ml Pfizer) is administered intravenously 
according to the respective package insert and local routine. 
 
9.1.2.1 Possible Adverse Effects of Leucovorin 
Rare adverse effects related to Leucovorin are: Central nervous and/or gastrointestinal 
disturbances, allergic reactions. Please refer to the respective SmPC for further details. 
 
9.1.3 5-Fluorouracil 
5-Fluorouracil (e.g. 5-FU; e.g. 5-FU 50mg/ml Medac) is administered intravenously as 
described in section 10 (Therapy schema), according to the respective package insert and 
local routine at the respective study site.  
Fluorouracil (5-FU) must not be given in combination with brivudin, sorivudin and analogues. 
Brivudin, sorivudin and analogues are potent inhibitors of the 5-FU-metabolising enzyme 
dihydropyrimidine dehydrogenase (DPD). Fluorouracil (5-FU) must not be given to patients 
homozygotic for dihydropyrimidine dehydrogenase [mutations] (DPD). Where applicable, 
determination of DPD enzyme activity is indicated before starting treatment with 5-
fluorpyrimidines. 
 
9.1.3.1 Possible Adverse Effects of 5-Fluorouracil 
Nausea/vomiting, diarrhea, mucositis, hand-foot-skin-reactions, disturbances in cardiac 
function, skin alterations, alopecia, hematotoxicity. Please refer to the respective SmPC 
(Fachinformation) for further details. 
 
 mFOLFOXIRI 
See section above for details on Oxaliplatin (Section 9.1.1), Leucovorin (Section 9.1.2) and 5-
Fluorouracil (Section 9.1.3). 
 
9.2.1 Irinotecan 
Irinotecan is in topoisomerase inhibitor and works by blocking topoisomerase 1 which results 
in DNA damage and cell death. Irinotecan is administered intravenously according to the 
respective package insert and local routine. 
 
9.2.1.1 Possible Adverse Effects of Irinotecan 
Common side effects include diarrhea, vomiting, bone marrow suppression, alopecia, 
shortness of breath, and fever. Other severe side effects include blood clots, colon 
inflammation, and allergic reactions. Please refer to the respective SmPC for further details. 

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10 Administrative and Regulatory Details 
 Regulatory and Ethical Compliance 
This clinical trial was designed and shall be implemented and reported in accordance with the 
protocol, the AMG (Arzneimittelgesetz), the ICH Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC), 
and with the ethical principles laid down in the Declaration of Helsinki.  
Before recruitment into the clinical trial, each patient will be informed that participation in the 
study is completely voluntary, and that he or she may withdraw his or her participation in the 
trial at any time without any declaration of reasons. This will not lead to any disadvantage for 
the respective patient. If the withdrawal is caused by an adverse drug event, the patient should 
inform the Investigator about this fact.  
 
 Registration and Request for Authorization of the Trial 
According to GCP-V, the trial has to be submitted to and to be authorized/approved by the 
competent authority (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) and the 
Ethics Committee(s) responsible for the trial. The respective local authorities will be informed 
about the trial and the participation of individual trial sites. 
The competent authority and the competent Ethics Committee will be informed on the course 
of the study with respect to safety aspects to be announced as well as on the termination of 
the trial and the trial results according to GCP-V. 
 
 Ethics Committee  
Prior to start of the trial the study protocol and all additionally relevant documents will be sent 
by the Sponsor or designee to the competent Ethics Committee in order to receive the 
committee’s opinion. The trial is only allowed to start after a positive vote of the Ethics 
Committee has been received. During the course of the study the Sponsor or designee will 
inform the Ethics Committee about all amendments to the study protocol as well as on all 
SUSARs emerging from the trial according to GCP-V. In addition, the competent ethical 
committee will receive a DSUR once a year. 
All subsequent protocol amendments and amendments to the informed consent form will be 
submitted to the competent Ethics Committee to obtain an updated vote before implementation 
of the changes. Serious or unexpected adverse events occurring during the trial likely to affect 
the safety of the subjects or the conduct of the trial will also be reported to the Ethics 
Committee. 
In addition, the competent Ethics Committee will be informed on the course of the study with 
respect to the termination of the trial and the trial results. 
 

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 Informed Consent 
It is the Investigator’s responsibility to obtain witnessed written informed consent from the 
patient after adequate explanation of the aims, methods, anticipated benefits and potential 
hazards of the trial and before any trial specific procedures are performed. The patient should 
be given a copy of the informed consent documentation. The wet ink copy of the signed and 
dated informed consent must be retained in the institution’s records and is subject to inspection 
by representatives of the Sponsor or representatives from regulatory agencies. 
 
 Insurance 
A clinical trials insurance is contracted in accordance with the local law before submission of 
the study to the relevant authorities. A copy of the confirmation and the conditions of the 
insurance will be handed out to every trial subject together with the informed consent form. 
 
 Confidentiality 
By signing this protocol, the Investigator affirms to the Sponsor that information furnished to 
the Investigator by the Sponsor or designee will be maintained in confidence, and such 
information will be divulged to the local Ethics Committee or similar or expert committee; 
affiliated institution and employees, only under an appropriate understanding of confidentiality 
with such board or committee, affiliated institution and employees. Data generated by this trial 
will be considered confidential by the Investigator, except to the extent that it is included in a 
publication as provided in Section 10.12 of this protocol.  
 
 Confidentiality of Subject Records 
By signing this protocol, the Investigator agrees that the Sponsor (or designee), EC, or 
regulatory authority representatives may consult and/or copy trial documents in order to verify 
worksheet/case report form data. By signing the consent form, the subject agrees to this 
process. If trial documents will be photocopied during the process of verifying worksheet/case 
report form information, the subject will be identified by the screening or trial subject number 
only; full names/initials will be masked prior to transmission to the Sponsor or designee. 
By signing this protocol, the Investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations. 
 
 Confidentiality of Investigator Information 
By signing this protocol, the Investigator recognizes that certain personal identifying 
information with respect to the Investigator, and all Sub-Investigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of regulatory submissions, 
and as required by law. This information may include: 
1. Name, address, telephone number and e-mail address; 
2. Hospital or clinic address and telephone number; 

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3. Curriculum vitae or other summary of qualifications and credentials; and 
4. Other professional documentation. 
Additionally, the investigator’s name and business contact information may be included when 
reporting certain serious adverse events to regulatory authorities or to other Investigators. By 
signing this protocol, the Investigator expressly consents to these uses and disclosures. 
As this is a multicenter trial, in order to facilitate contact between Investigators, the Sponsor or 
designee may share an Investigator’s name and contact information with other participating 
Investigators upon request. 
 
 Compliance with Financial Disclosure Requirements 
The Investigator/Sub-Investigator(s) agree to provide his/her financial interests in and/or 
arrangements with the Sponsor on a Financial Disclosure Form provided by the Sponsor or 
designee. 
 
 Quality Management System 
10.10.1 Quality Control and Quality Assurance 
The Standard Operating Procedures (SOPs) of the Sponsor or designee or its designated sub-
contractors (if applicable) are used for conduction of the trial as specified in the respective 
agreements between the parties. 
 
10.10.2 Audits and Inspections 
In case of an audit/inspection by the Sponsor or designee or an appropriate authority, the 
investigator will make all relevant documents available. If an inspection visit by a regional 
authority is announced, the respective trial site should inform the Sponsor or designee as early 
as possible in order to allow for an appropriate preparation and support. 
 
10.10.3 Monitoring 
It is understood that an outside monitor and other authorized personnel may contact and visit 
the Investigator, and that they will be allowed direct access to source data/documents for trial-
related monitoring, audits, EC review and regulatory inspection. Direct access is defined as 
permission to examine, analyse, verify and reproduce any records and reports that are 
important to evaluation of a clinical trial. All reasonable precautions within the constraints of 
the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities 
and Sponsor’s proprietary information will be exercised (Guideline for Good Clinical Practice, 
ICH Harmonized Tripartite Guideline, adopted July 1996: Chapter 5.15.1 and 1.21, 
respectively). 
It is the monitor’s responsibility to inspect the case report forms at regular intervals throughout 
the trial to verify adherence to the protocol: the completeness, accuracy, and consistency of 
the data; and adherence to Good Clinical Practice guidelines. The monitor should have access 

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to patient charts, laboratory reports and other patient records needed to verify the entries on 
the case report forms. Where local rules do not allow direct access to the source data, the 
monitor will verify entries in the case report form by asking direct questions of a person or 
persons with authorized access to the source data. The Investigator agrees to cooperate with 
the monitor to ensure that any problems detected during the course of these monitoring visits 
are resolved. 
A monitoring plan with relevant details will be issued and regularly updated throughout the trial. 
An adjustment of monitoring activities to Covid-19 pandemic will be done due to actual 
recommendations and legal requirements. If on-site monitoring will not be possible at a certain 
point due to the pandemic, continuous monitoring of the data base will take place. Field 
monitors will be in close contact with the study sites to reschedule the planned on-site visits to 
the next possible date. Where remote monitoring can take place without loss of quality and 
oversight, e.g. in case of site initiation, it can replace regular on-site monitoring. 
 
 Data Management 
Data collection and capture, creation of queries and data analysis will be performed by the 
Sponsor or designee or its designated sub-contractors (if applicable). Good Clinical Practice 
(GCP)-compliant handling of the data is secured by adequate SOPs. Archiving of data and 
results electronically recorded will be at least 15 years after the end of this study (according to 
legal guidelines).  
 
10.11.1 Plausibility Check, Data Cleaning and Coding 
Qualified members of the Sponsor or designee or its designated sub-contractors (if applicable) 
regularly perform plausibility checks and data cleaning according to the data-cleaning plan. 
Some of the raw data of the eCRF also needs coding (e.g., surgical procedures, toxicities) 
according to the data-coding plan. Before data base closure, data cleaning and manual 
plausibility checks have to be performed for the relevant contents (defined by the data-cleaning 
plan), and all open questions have to be resolved. 
 
 Publication and Registration of the Trial 
The results of this trial will be published by the Coordinating Investigator and/or Sponsor after 
final analysis has been performed. Publication will be independent of the nature of the results 
obtained (whether they were positive or negative). The manuscript written for publication, 
together with the materials provided by the statistician can be accepted as the final study 
report. 
This clinical trial will be registered at a primary register of the WHO, e.g. at 
www.clinicaltrials.gov. 
 

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 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be established, consisting of experts in clinical 
trials and medical oncology. The DSMB will receive regular information on safety results of the 
trial (SAEs/SUSARs) and recommend on the continuation, modification or early termination of 
the clinical trials at each meeting and according to the criteria defined by the sponsor. 
Furthermore, the DSMB will review the yearly safety report (DSUR) and provide 
recommendations to the sponsor.  
Detailed working procedures are defined in the “Working Procedure for the Data Safety 
Monitoring Board (DSMB)”. 

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11 References 
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leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated 
metastatic colorectal cancer. GERCOR. Eur J Cancer, 1999; 35(9), 1343-1347. 
Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant 
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Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for 
Pancreatic Cancer. N Engl J Med 2018; 379(25): 2395-406. 
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Folprecht G, Gruenberger T, Bechstein W, et al. Survival of patients with initially unresectable 
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Gonzalez M, Poncet A, Combescure C, et al. Risk factors for survival after lung metastasectomy in 
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Grothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemotherapy for Stage III Colon 
Cancer. N Engl J Med 2018; 378(13): 1177-88. 
Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus 
bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): 
a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15(10): 1065-75. 

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Howlader N, Krapcho M, Neyman N et al. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 
Populations); Bethesda M: National Cancer Institute 2011. 
Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is 
associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 
2009; 27(22): 3677-83. 
Luo LX, Yu ZY, Huang JW, Wu H. Selecting patients for a second hepatectomy for colorectal 
metastases: an systemic review and meta-analysis. Eur J Surg Oncol 2014; 40(9): 1036-48. 
Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for 
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Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly 
leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal 
cancer (FOLFOX6). GERCOR. Eur J Cancer 1999; 35(9), 1338-1342. 
Maindrault-Goebel F, de Gramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in 
bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in 
pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group 
(GERCOR). Ann Oncol 2000; 11(11), 1477-1483. 
Maindrault-Goebel F, De Gramont A, Louvet C, et al. High-dose intensity oxaliplatin added to the 
simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for 
metastatic colorectal cancer (FOLFOX 7). European Journal of Cancer 2001; 37(8), 1000-1005. 
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Modest DP, Denecke T, Pratschke J, et al. Surgical treatment options following chemotherapy plus 
cetuximab or bevacizumab in metastatic colorectal cancer-central evaluation of FIRE-3. Eur 
J Cancer 2018; 88: 77-86. 
Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery 
versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 
Intergroup trial 40983): a randomised controlled trial. Lancet 2008; 371(9617): 1007-16. 
Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery 
versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): 
long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol 2013; 14(12): 1208-
15. 
Patel D, Townsend AR, Karapetis C, et al. Is Survival for Patients with Resectable Lung Metastatic 
Colorectal Cancer Comparable to Those with Resectable Liver Disease? Results from the 
South Australian Metastatic Colorectal Registry. Ann Surg Oncol 2016; 23(11): 3616-22. 
Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in 
patients with resectable colorectal liver metastasis: the New EPOC randomised controlled 
trial. Lancet Oncol 2014;15(6):601-11. 
Rauch G, Brannath W, Bruckner M, et al. The Average Hazard Ratio - A Good Effect Measure for 
Time-to-event Endpoints when the Proportional Hazard Assumption is Violated? Methods Inf 
Med 2018; 57(3): 89-100. 
Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland 
e.V. (Hrsg). Krebs in Deutschland für 2015/2016. Berlin, 2019; 12. Ausgabe. 
Saad ED, Katz A, Hoff PM, et al. Progression-free survival as surrogate and as true end point: 
insights from the breast and colorectal cancer literature. Ann Oncol. 2010;21(1):7-12. 
Schmiegel W, Buchberger B, Follmann M, et al. S3-Leitlinie – Kolorektales Karzinom. Z Gastroenterol 
2017; 55(12): 1344-498. 

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Schmoll HJ, Van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients 
with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 
2012; 23(10), 2479-2516. 
Soerjomataram I, Lortet-Tieulent J, Parkin DM, et al. Global burden of cancer in 2008: a systematic 
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50. 
Siegel R, Naishadham D & Jemal A Cancer statistics, 2012. CA Cancer J Clin 2012; 62(1), 10-29 
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in 
advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22(2), 229-237. 
Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of 
patients with metastatic colorectal cancer. Ann Oncol 2016; 27(8): 1386-422. 
 
 

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12 Appendices 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time. 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 
In bed > 50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
 

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Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html) 
 

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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 
For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Contraception Requirements 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below during the treatment period and for at least 180 days after the last administration of 
study drug.  
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to use highly effective methods of contraception consistently during the treatment period 
and for at least 180 days after the last administration of study drug (i.e. mandatory condom 
use, mandatory use of effective methods of contraception for female partners of males 

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participating in the study as described in the table below, refrain from sperm donation for male 
participants during the treatment period and for at least 180 days after the last administration 
of study drug). 
Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen-containing) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of < 1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently 
and correctly).  
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 

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Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. If applicable, this test should be repeated a maximum of 24 hours before the first dose. 
Following initiation of treatment, pregnancy testing will be performed at monthly intervals 
during treatment and until the end of relevant systemic exposure to the study drug, in 
accordance with the CTFG guidance on contraception. 
 
 

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Appendix 4: Evaluation of radiologic images 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. CT scans are recommended to have slice thickness of < 5 mm. MRI 
is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV contrast 
because of allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI 
(without IV contrast) will be used to evaluate the patient at baseline and during the study 
should be guided by the tumor type under investigation and the anatomic location of the 
disease. For patients who develop contraindications to contrast after baseline contrast CT is 
done, the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be 
performed should also be based on the tumor type and the anatomic location of the disease, 
and should be optimized to allow for comparison with the prior studies if possible. Each case 
should be discussed with the radiologist to determine if substitution of these other approaches 
is possible. As the primary endpoint of the trial is based on detection of relapse/progression 
of disease, different and changing modalities are permitted and unlikely to introduce bias. 
 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, cytology and histology if clinically indicated and 
performed can be used to prove tumor relapse/progression. If relapse is proven/suspected by 
ultrasound, confirmation by CT/MRI should in any case be obtained.  
 
IDENTIFICATION OF RELAPSE OR PROGRESSION 
The definite decision to diagnose a relapse/progression should be made by the investigator, 
taking perspectives of the radiologist and/or the interdisciplinary tumor conference into 
account – if applicable. Relapse/progression can be diagnosed by solid metastases in organs 
like liver or lung or indirect signs (progressive ascites). In unclear cases, confirmation by 
biopsy might be considered, if possible. As long as uncertainty concerning the remission 
status must be stated, continuation of study therapy is recommended.  
All potential new lesions should be evaluated as such. Measurements of all new lesions (or 
local progression) and involved organs is required and should be reported in the eCRF. 
Lymph nodes, particularly in local and timely connection to interventions, as site of relapse 
may only be considered definite lesions if they present with a short diameter of 15 mm or 
longer. All other relapses in lymph nodes require individual reporting and/or consultation with 
the sponsor representative. The total number of involved organs should be determined and 
also the total number of lesions (in case of more than 10 lesions, estimations are permitted) 
 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression/relapse; therefore, 
some comments on detection of new lesions are important. There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion should be 

Charité Universitätsmedizin Berlin 
 
Prof. Dr. med. Dominik Modest 
FIRE-9 PORT 
 
28-Sep-2021 
EudraCT no. 2020-006144-18 
 
Protocol Version 3.0 
 
Confidential 
 Page 79 of 79 
unequivocal, that especially not represent something other than active tumor. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a "new" cystic lesion, which 
it is not. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeated scans confirm 
there is definitely a new lesion, progression should be declared using the date of the initial 
scan.