METIMMOX: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by OXaliplatin
Phase: PHASE2
Conditions: Colorectal Cancer Metastatic
Sponsor: University Hospital, Akershus

METIMMOX: COLORECTAL CANCER METASTASIS 
– SHAPING ANTI-TUMOR IMMUNITY BY OXALIPLATIN 
 
Protocol Acronym:   METIMMOX 
Bristol-Myers Squibb Protocol Identification Number:   CA209-9M8 
EudraCT Number:   2017-001845-29 
ClinicalTrials ID:   NCT03388190 
Regional Committee for Medical and Health Research Ethics of South-East Norway 
 
Reference Number:   2017/1850 
 
SPONSOR: 
Tormod Fladby, Director of Research and 
Innovation, Professor, MD PhD 
Akershus University Hospital, P.O. Box 1000, 
1478 Lørenskog, Norway 
Tel : (+47) 928 17764 
E-mail: tormod.fladby@ahus.no 
 
PRINCIPAL INVESTIGATOR: 
Anne Hansen Ree, Professor, MD PhD 
Department of Oncology, Akershus University 
Hospital, P.O. Box 1000, 1478 Lørenskog, 
Norway 
Tel : (+47) 482 57968 
E-mail: a.h.ree@medisin.uio.no 
 
PRINCIPAL INVESTIGATOR – 
TRANSLATIONAL STUDY 
PROGRAM: 
Kjersti Flatmark, Professor, MD PhD 
Department of Tumor Biology – Institute for 
Cancer Research, Oslo University Hospital, 
P.O.Box 4950 Nydalen, 0424 Oslo, Norway 
Tel : (+47) 911 68466 
E-mail: kjersti.flatmark@rr-research.no 
 
 
PROTOCOL VERSION 2.1 – 2-January-2018 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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CONTACT DETAILS 
Coordinating Investigator: 
Christin Johansen, RN 
Department of Oncology, Akershus University Hospital, P.O.Box 
1000, 1478 Lørenskog, Norway 
Tel : (+47) 679 66016 
E-mail: christin.johansen@ahus.no 
 
Participating Department – Oncology: 
Eva Hofsli, MD PhD 
Department of Oncology, St. Olavs Hospital – Trondheim 
University Hospital, P.O.Box 3250 Sluppen, 7006 Trondheim, 
Norway 
Tel : (+47) 926 06454 
E-mail: eva.hofsli@ntnu.no 
 
 
 
  
Participating Department – Oncology: 
Halfdan Sørbye, Professor, MD PhD 
Department of Oncology, Haukeland University Hospital, P.O.Box 
1400, 5021 Bergen, Norway 
Tel : (+47) 928 53862 
E-mail: halfdan.sorbye@helse-bergen.no 
 
 
  
Participating Department – Oncology: 
Christian Kersten, MD PhD 
Department of Oncology, Hospital of Southern Norway, P.O.Box 
416 Lundsiden, 4604 Kristiansand, Norway 
Tel : (+47) 913 39443 
E-mail: Christian.Kersten@sshf.no 
 
 
  
Participating Department – Oncology: 
Marianne G. Guren, MD PhD 
Department of Oncology, Oslo University Hospital, P.O.Box 4950 
Nydalen, 0424 Oslo, Norway 
Tel : (+47) 997 13594 
E-mail: UXARUR@ous-hf.no 
 
Participating Department – Oncology: 
Hanne M. Hamre, MD PhD 
Department of Oncology, Akershus University Hospital, P.O.Box 
1000, 1478 Lørenskog, Norway 
Tel : (+47) 986 74519 
E-mail: hanne.m.hamre@ahus.no 
 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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Participating Department – Radiology: 
Anne Negård, MD PhD 
Department of Radiology, Akershus University Hospital, P.O.Box 
1000, 1478 Lørenskog, Norway 
Tel : (+47) 419 06371 
E-mail: anne.negard@ahus.no 
 
Participating Department – Statistics: 
Jūratė Šaltytė Benth, PhD 
Health Services Research Center, Akershus University Hospital, 
P.O.Box 1000, 1478 Lørenskog, Norway 
Tel : (+47) 482 24431 
E-mail: jurate.saltyte-benth@medisin.uio.no 
Data Management and Monitoring: 
Clinical Trial Unit 
Oslo University Hospital, P.O.Box 4950 Nydalen, 0424 Oslo, 
Norway 
Tel : (+47) 2306 6030 
Participating Department 
– Translational Study Program: 
Kathrine Røe Redalen, PhD 
Department of Oncology, Akershus University Hospital, P.O.Box 
1000, 1478 Lørenskog, Norway 
Tel : (+47) 924 37646 
E-mail: k.r.redalen@medisin.uio.no 
 
Participating Department 
– Translational Study Program: 
Jonn Terje Geitung, Professor, MD PhD 
Department of Radiology, Akershus University Hospital, P.O.Box 
1000, 1478 Lørenskog, Norway 
Tel : (+47) 957 06455 
E-mail: j.t.geitung@medisin.uio.no 
Participating Department 
– Translational Study Program: 
Sebastian Meltzer, MD PhD 
Department of Oncology, Akershus University Hospital, P.O.Box 
1000, 1478 Lørenskog, Norway 
Tel : (+47) 936 08514 
E-mail: sebastian.meltzer@medisin.uio.no 
 
Participating Department 
– Cost Modelling Study Program: 
Eline Aas, PhD 
Health Services Research Center, Akershus University Hospital, 
P.O.Box 1000, 1478 Lørenskog, Norway 
Tel : (+47) 411 41294 
E-mail: eline.aas@medisin.uio.no 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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SIGNATURE PAGE 
Title 
METIMMOX: Colorectal Cancer METastasis – Shaping Anti-Tumor IMMunity by OXaliplatin 
Protocol ID no. 
METIMMOX – CA209-9M8 
EudraCT no. 
2017-001845-29 
ClinicalTrials ID 
NCT03388190 
Ethics Committee 
no. 
2017/1850 
 
I hereby declare that I will conduct the study in compliance with the Protocol, International Conference 
on Harmonization – Good Clinical Practice, and the applicable regulatory requirements: 
Name 
Title 
Role 
Signature 
Date 
Tormod Fladby 
Director of Research 
and Innovation, 
Professor, MD PhD 
Sponsor 
 
 
Anne Hansen Ree 
Professor, MD PhD 
Principal Investigator 
 
 
Christin Johansen 
RN 
Coordinator 
 
 
Eva Hofsli 
MD PhD 
Clinical Investigator 
 
 
Halfdan Sørbye 
Professor, MD PhD 
Clinical Investigator 
 
 
Christian Kersten 
MD PhD 
Clinical Investigator 
 
 
Marianne G. Guren 
MD PhD 
Clinical Investigator 
 
 
Hanne M. Hamre 
MD PhD 
Clinical Investigator 
 
 
Anne Negård 
MD PhD 
Study Radiologist 
 
 
Jūratė Šaltytė Benth 
PhD 
Study Statistician 
 
 
 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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PROTOCOL SYNOPSIS 
METIMMOX: Colorectal Cancer METastasis – Shaping Anti-Tumor IMMunity by OXaliplatin 
Sponsor 
Akershus University Hospital 
Phase and study type 
Multicenter open-label randomized phase 2 study 
Investigational medical 
products 
Control arm: the Nordic FLOX regimen 
Experimental arm: repeat sequential FLOX and nivolumab 
 
 
Centers 
Akershus University Hospital 
St. Olavs Hospital – Trondheim University Hospital 
Haukeland University Hospital 
Hospital of Southern Norway 
Oslo University Hospital 
 
Study period 
 
Estimated date of first patient enrolled: 1 March 2018 
Anticipated recruitment period: 12 months 
Estimated date of last patient completed: 1 September 2020 
Treatment duration 
Expected treatment duration per patient: 
Experimental arm: 18 months (until failure of treatment strategy) 
Control arm: 9 months (until failure of treatment strategy) 
Follow-up 
Expected follow-up period per patient: 
Experimental arm: 30 months (12 months following failure of treatment strategy) 
Control arm: 21 months (12 months following failure of treatment strategy) 
Objectives 
Hypothesis: Most patients with metastatic colorectal cancer (CRC) harbor tumor that 
can be transformed into an immunogenic disease by oxaliplatin, and may thereby 
benefit from the addition of immune-modulating therapy to improve outcome of the 
current oxaliplatin-based standard-of-care. 
Primary objective: To determine progression-free survival (PFS), in terms of failure of 
treatment strategy, of sequential treatment with the Nordic FLOX regimen and 
nivolumab compared with the standard-of-care Nordic FLOX regimen in previously 
untreated microsatellite-stable (MSS) metastatic CRC. 
Secondary objectives: To determine safety and tolerability of sequential treatment 
with the Nordic FLOX regimen and nivolumab compared with the standard-of-care 
Nordic FLOX regimen. To monitor and compare quality-of-life (QoL) alterations during 
therapy courses. 

 
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End points 
Primary end point: PFS 
Secondary end points: safety (incidence of adverse events), tolerability (grading of 
adverse events), objective response rate, duration of response, secondary surgical 
curative resection rate, overall survival 
Study design 
Multicenter open-label randomized phase 2 study in previously untreated MSS 
metastatic CRC 
 
Main inclusion criteria  
 Patient has histologically verified CRC adenocarcinoma 
 Patient has radiologically measurable metastatic disease 
 Patient has a metastatic lesion that can be biopsied 
 Patient has not had previous systemic therapy for the metastatic disease 
 Patient is eligible for the Nordic FLOX regimen 
 
Main exclusion criteria 
 Patient has initially resectable metastatic disease for which neoadjuvant therapy 
is deemed superfluous 
 Patient does not consent to biopsy sampling 
 Patient has metastatic disease to lungs as the sole site 
 Patient has untreated or symptomatic brain metastasis (patient must be 
symptom-free without the use of corticosteroids) 
 Patient experiences a period of less than 6 months since discontinuation of 
adjuvant oxaliplatin-containing chemotherapy 
 Patient is ineligible for full chemotherapy doses (100% doses) at start of study 
treatment 
 Patient has had radiation therapy within 4 weeks of start of study treatment 
 Patient has a nervous system disorder worse than grade 1 of the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 
 Patient has any medical condition or has undergone any treatment within 4 
weeks of start of study treatment that will preclude him/her from cancer immune-
modulating therapy (treatment with Investigational Medical Product) 
 Patient has any medical condition that will preclude him/her from receiving a 
component of the FLOX regimen (treatment with Investigational Medical Product) 
 Patient has Eastern Cooperative Oncology Group performance status 2 or worse 
 Patient has serum/plasma C-reactive protein of 60 mg/L or higher 
 Patient does not meet the following requirements at baseline: adequate bone 
marrow function without current use of colony-stimulating factors (minimum 
values of neutrophils 1.5 x109/L, platelets 100 x109/L, hemoglobin 10 g/dL), 
adequate liver function (maximum values of AST/ALT 5 xULN and bilirubin 2 
xULN; albumin value of 30 g/L or higher; INR within normal level), adequate renal 
function (maximum creatinine value of 1.5 xULN) 
 Patient has any other reason, in the opinion of Clinical Investigator, not to 
participate in the study 
 

 
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Sample size 
100 patients (50 in each study arm) 
 
Efficacy assessments 
Radiologic assessment every 8 weeks (following 4 cycles of FLOX or the alternative 2 
cycles each of FLOX and nivolumab), according to the Response Evaluation Criteria 
in Solid Tumors (RECIST) and the RECIST consensus guideline for assessment of 
response to immune-modulating therapies (iRECIST). 
 
Safety assessments 
Recording of adverse events, according to CTCAE v4.0, will be done continuously 
and formally recorded at each new treatment cycle on active study therapy and every 
8 weeks in planned breaks from active study therapy; safety (incidence of adverse 
events) and tolerability (grading of adverse events) will be reported. 
Formal QoL assessments will be undertaken at study enrolment, completion of the 
active therapy of the first treatment sequence (after 16 weeks), and disease 
progression, using the consensus modules EORTC QLQ-C30, EORTC QLQ-CIPN20, 
and EQ-5D-5L. 
 
Other assessments 
Tertiary objective: To compare costs for the resource use (in diagnostic work-up, 
treatment, and any adverse events) for the sequential therapy with that of the 
standard-of-care, applying a model specifically developed for CRC. 
Exploratory objectives: 
1) Development of circulating marker tools: (a) To quantify phosphatase activity 
in serial peripheral blood mononuclear cells samples, collected 
corresponding to each change of therapy (from FLOX to nivolumab and 
reverse) in the sequential regimen, as surrogate measure of cytotoxic T 
lymphocyte activity. (b) To monitor alterations of circulating tumor DNA and 
exosomal miRNA in plasma samples collected at the same sampling points, 
as surrogate response marker. (c) To monitor factors reflecting systemic 
anti-tumor immunity in peripheral blood samples collected at the same 
sampling points, as marker of immunogenic cell death. 
2) Functional magnetic resonance (MR) imaging: To investigate responses of 
the tumor microenvironment in abdominal metastases caused by oxaliplatin 
and nivolumab by repeat functional MR imaging, undertaken corresponding 
to each change of therapy during the first two months of the sequential 
regimen, and correlate changes with RECIST/iRECIST measures and PFS. 
3) Histologic and molecular analyses: To investigate immune responses in 
liver/peritoneal metastases by histologic and molecular profiling of repeat 
liver/peritoneal biopsy samples, collected corresponding to each change of 
therapy during the first two months of the sequential regimen, and correlate 
changes with RECIST/iRECIST measures and PFS. 

 
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TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITIONS OF TERMS......................................................................................................... 12 
1 
INTRODUCTION ...................................................................................................................................................... 14 
1.1 
Background and rationale ................................................................................................................................... 14 
1.2 
Rationale for the chosen FLOX administration ................................................................................................... 14 
1.3 
Nivolumab........................................................................................................................................................... 16 
1.4 
Rationale for dose selection of nivolumab .......................................................................................................... 16 
2  
STUDY OBJECTIVES AND END POINTS .............................................................................................................. 17 
3 
OVERALL STUDY DESIGN ..................................................................................................................................... 19 
4 
STUDY POPULATION ............................................................................................................................................. 19 
4.1  
Selection of study population .............................................................................................................................. 19 
4.2 
Number of patients ............................................................................................................................................. 20 
4.3 
Inclusion criteria .................................................................................................................................................. 20 
4.4 
Exclusion criteria ................................................................................................................................................ 21 
4.5 
Patient stratification ............................................................................................................................................ 22 
4.6 
Risk/benefit assessment ..................................................................................................................................... 23 
5 
TREATMENT............................................................................................................................................................ 23 
5.1 
Drug handling ..................................................................................................................................................... 23 
5.2 
Drug accountability ............................................................................................................................................. 24 
5.3 
Drug labeling ...................................................................................................................................................... 24 
5.4 
Dosage, drug administration, and common toxicities ......................................................................................... 24 
5.5 
Duration of therapy ............................................................................................................................................. 25 
5.6 
Monitoring ........................................................................................................................................................... 26 
5.7 
Schedule modifications ....................................................................................................................................... 26 
5.7.1 
IMP (investigational medicinal products) schedule ....................................................................................... 26 
5.7.2 
Dose modifications for IMP .......................................................................................................................... 26 
5.7.2.1   Dose delay criteria for IMP .................................................................................................................... 26 
5.7.2.2   Criteria to resume dosing for IMP ......................................................................................................... 27 
5.7.2.3   Treatment discontinuation criteria for IMP ............................................................................................ 28 
5.7.2.4   Continuing nivolumab with suspected progression ............................................................................... 29 
5.7.2.5   Management algorithms for immuno-oncology agents ......................................................................... 29 
5.7.2.6   Management algorithms for the Nordic FLOX regimen ......................................................................... 29 
5.7.2.7   Treatment of IMP-related infusion reactions ......................................................................................... 29 
5.8  
Concomitant treatments ..................................................................................................................................... 30 
5.8.1 
Prohibited and/or restricted treatments ........................................................................................................ 30 
5.8.2 
Permitted therapy ......................................................................................................................................... 30 
5.9  
Subject numbering .............................................................................................................................................. 31 

 
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6 
STUDY FLOW CHART ............................................................................................................................................ 32 
7 
STUDY PROCEDURES ........................................................................................................................................... 35 
7.1 
Informed consent ................................................................................................................................................ 35 
7.2 
Inclusion and exclusion criteria ........................................................................................................................... 35 
7.3 
Medical history .................................................................................................................................................... 35 
7.3.1 
Prior medications .......................................................................................................................................... 35 
7.3.2 
Concomitant medications ............................................................................................................................. 35 
7.3.3 
Other diseases ............................................................................................................................................. 35 
7.3.4 
Prior treatment details .................................................................................................................................. 35 
7.3.5 
Subsequent anti-cancer therapy status ........................................................................................................ 36 
7.4 
Safety assessments ........................................................................................................................................... 36 
7.5 
Physical examination .......................................................................................................................................... 36 
7.5.1 
Full physical examination ............................................................................................................................. 36 
7.5.2 
Directed physical examination ...................................................................................................................... 36 
7.5.3 
Vital signs ..................................................................................................................................................... 37 
7.5.4 
ECOG performance status ........................................................................................................................... 37 
7.6 
Tumor imaging and assessment of disease procedures .................................................................................... 37 
7.6.1 
Evaluation of efficacy ................................................................................................................................... 37 
7.6.2 
Measurability of tumor lesions at baseline .................................................................................................... 37 
7.6.2.1 
Definitions ..................................................................................................................................... 37 
7.6.2.2 
Methods of measurements ........................................................................................................... 38 
7.6.3 
RECIST version 1.1 ...................................................................................................................................... 38 
7.6.4 
iRECIST ....................................................................................................................................................... 39 
7.6.5 
Frequency of tumor re-evaluation................................................................................................................. 40 
7.6.6. 
Date of progression ...................................................................................................................................... 41 
7.6.7 
Reporting of tumor response ........................................................................................................................ 41 
7.6.8 
Response duration ....................................................................................................................................... 41 
7.6.9 
Stable disease duration ................................................................................................................................ 41 
7.7 
Other study procedures  ..................................................................................................................................... 41 
7.7.1 
Screening period .......................................................................................................................................... 41 
7.7.2 
Treatment period .......................................................................................................................................... 41 
7.7.3 
Post-treatment visits ..................................................................................................................................... 41 
7.7.3.1 
Safety follow-up visit ..................................................................................................................... 41 
7.7.3.2 
Follow-up visits ............................................................................................................................. 42 
7.7.3.3 
Survival follow-up ......................................................................................................................... 42 
7.7.4 
Withdrawal or discontinuation ...................................................................................................................... 42 
7.8 
End of study........................................................................................................................................................ 42 
7.9 
Study termination ................................................................................................................................................ 43 

 
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7.10 Ancillary study procedures ................................................................................................................................. 43 
7.10.1 Repeat quality-of-life recording .................................................................................................................... 43 
7.10.2 Repeat collection of serum and plasma ....................................................................................................... 43 
7.10.3 Repeat collection of PBMC .......................................................................................................................... 44 
7.10.4 Repeat functional MR imaging ..................................................................................................................... 44 
7.10.5 Repeat collection of metastatic tissue .......................................................................................................... 44 
8 
SAFETY MONITORING AND REPORTING ............................................................................................................ 45 
8.1 
Definitions ........................................................................................................................................................... 45 
8.1.1 
Non-serious adverse event(s) ...................................................................................................................... 45 
8.1.2 
SAE (serious adverse events) ...................................................................................................................... 45 
8.2 
SAE (serious adverse events) collection and reporting ...................................................................................... 46 
8.3 
Disease progression or recurrence..................................................................................................................... 47 
8.4 
Laboratory test abnormalities ............................................................................................................................. 47 
8.5 
Pregnancy .......................................................................................................................................................... 47 
8.6 
Overdose ............................................................................................................................................................ 47 
8.7 
Potential drug-induced liver injury (DILI) ............................................................................................................. 48 
8.8 
Other safety considerations ................................................................................................................................ 48 
8.9 
AE (adverse events) recording ........................................................................................................................... 48 
8.10 Reporting procedure ........................................................................................................................................... 48 
8.10.1 AE (adverse events) and SAE (serious adverse events) ............................................................................. 48 
8.10.2 SUSAR (suspected unexpected serious adverse reactions) ........................................................................ 49 
8.10.3 Annual safety report ..................................................................................................................................... 49 
8.10.4 Clinical study report ...................................................................................................................................... 49 
8.11 Procedures in case of emergency ...................................................................................................................... 49 
9 
DATA MANAGEMENT AND MONITORING ............................................................................................................ 49 
9.1 
Database management ...................................................................................................................................... 49 
9.2  
CRF (case report forms) ..................................................................................................................................... 49 
9.3 
Source data ........................................................................................................................................................ 50 
9.4 
External Data and Safety Monitoring Committee ................................................................................................ 50 
9.5 
Study monitoring ................................................................................................................................................. 50 
9.6 
Confidentiality ..................................................................................................................................................... 51 
10 STATISTICAL METHODS AND DATA ANALYSIS ................................................................................................. 51 
10.1 Determination of sample size ............................................................................................................................. 51 
10.2 Randomization .................................................................................................................................................... 52 
10.2.1 Randomization procedure ............................................................................................................................ 52 
10.2.2 Blinding......................................................................................................................................................... 52 
10.3 Populations for analysis ...................................................................................................................................... 52 
10.4 Statistical analysis of clinical end points ............................................................................................................. 52 

 
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10.4.1 Main statistical analyses ............................................................................................................................... 52 
10.4.2 Interim analyses ........................................................................................................................................... 52 
10.4.3 Descriptive statistics ..................................................................................................................................... 53 
10.4.4 Primary analysis ........................................................................................................................................... 53 
10.4.5 Secondary analyses ..................................................................................................................................... 53 
10.5 Analysis of other end points ............................................................................................................................... 54 
10.6 Statistical software .............................................................................................................................................. 54 
11 STUDY MANAGEMENT .......................................................................................................................................... 54 
11.1  Study documentation .......................................................................................................................................... 54 
11.2  Protocol adherence ............................................................................................................................................ 54 
11.3 Study Conduct Group ......................................................................................................................................... 54 
11.4 Study amendments ............................................................................................................................................. 54 
11.5 Investigator Site File ........................................................................................................................................... 54 
11.6 Audit and inspections ......................................................................................................................................... 55 
12 ETHICAL AND REGULATORY REQUIREMENTS ................................................................................................. 55 
12.1 Compliance with laws and regulations................................................................................................................ 55 
12.2 ICF (informed consent form) ............................................................................................................................... 55 
12.3 Ethics Committee ............................................................................................................................................... 55 
12.4 Confidentiality ..................................................................................................................................................... 56 
13 STUDY FUNDING .................................................................................................................................................... 56 
14 TRIAL INSURANCE ................................................................................................................................................. 56 
15 PUBLICATION POLICY ........................................................................................................................................... 56 
16 REFERENCES ......................................................................................................................................................... 56 
17 APPENDICES .......................................................................................................................................................... 60 
Appendix 1 – Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 ...................................................... 60 
Appendix 2 – RECIST for immune-modulating therapies (iRECIST) ............................................................................. 60 
Appendix 3 – Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 ................................................ 61 
Appendix 4 – Eastern Cooperative Oncology Group (ECOG) performance status........................................................ 61 
Appendix 5 – Management algorithms for adverse events of immuno-oncology agents and regimens ........................ 62 
Appendix 6 – Management algorithms for adverse events caused by the Nordic FLOX regimen ................................. 62 
Appendix 7 – EORTC QLQ-C30 specimen questionnaire ............................................................................................. 63 
Appendix 8 – EORTC QLQ-CIPN20 questionnaire ....................................................................................................... 63 
Appendix 9 – EQ-5D-5L questionnaire user guide ........................................................................................................ 63 
Appendix 10 – CIOMS Suspect Adverse Reaction Report form .................................................................................... 63 
 
 

 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Explanation 
ADL 
activity of daily life 
AE 
adverse event(s) 
BMS 
Bristol-Myers Squibb 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form(s) 
CRT 
chemoradiotherapy 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DILI 
drug-induced liver injury 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
EDSMC 
External Data and Safety Monitoring Committee 
Flt3L 
fms-like tyrosine kinase 3 ligand 
GCP 
Good Clinical Practice 
HR 
hazard ratio 
IB 
Investigator’s Brochure 
ICB 
immune checkpoint blockade 
ICD 
immunogenic cell death 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
iCPD 
immune-confirmed progressive disease 
iCR 
immune-complete response 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product(s) 
iPR 
immune-partial response 

 
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irAE 
immune-related adverse event(s) 
IRB 
Institutional Review Board 
iSD 
immune-stable disease 
IV 
intravenous(ly) 
iRECIST 
RECIST for immune-modulating therapies 
iUPD 
immune-uncomfirmed progressive disease 
LARC 
locally advanced rectal cancer 
MR 
magnetic resonance 
MSI 
microsatellite-instable 
MSS 
microsatellite-stable 
NACT 
neoadjuvant chemotherapy 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed death receptor 1 
PD-L1 
ligand of PD-1 
PFS 
progression-free survival 
PR 
partial response 
QoL 
quality-of-life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event(s) 
SC 
subcutaneous(ly) 
SD 
stable disease 
SmPC 
summary of product characteristics 
SOP 
standard operating procedure 
SSCRR 
secondary surgical curative resection rate 
SUSAR 
suspected unexpected serious adverse reaction 
TME 
tumor microenvironment 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
 

 
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1 
INTRODUCTION 
1.1 
Background and rationale 
Advanced colorectal cancer – the public health and clinical challenges 
Colorectal cancer (CRC), owing to an aging population, is a disease common in both sexes and among all adult age 
groups but with a significant rise in incidence from the age of 60 [Ferlay et al., 2013]. Due to the overall increase in age 
of populations, it is a disease that is becoming more common over time. In 2014, the CRC incidence rate in the 
Norwegian population of 5.2 million persons added up to almost 4,200 individuals (www.kreftregisteret.no/en/). About half 
of CRC patients proceed to metastatic disease. Generally, no curative treatment for multi-organ metastasis exists. In the 
past two decades, several new systemic therapies such as cytotoxic and biologically targeted agents have come into 
routine use for advanced CRC, extending patients’ life and, importantly, alleviating their symptoms. Still, unresectable 
metastases particularly in abdominal cavity organs remain the cause of high morbidity and dismal survival [Hadden et 
al., 2016]. New insights into the biology of early systemic tumor propagation may show a path to the next milestone in 
CRC management, which will be the control of metastatic progression. 
In recent years, the potential for using the immune system to combat tumor progression has gained much attention. 
Tumor immunogenicity includes both tumor antigen recognition and the action of cytotoxic immune cells, and therefore 
the abnormality of a malignant tumor may make it a target it for immune-mediated elimination. However, a tumor is also 
‘self’. Protective mechanisms against auto-immunity will therefore impede tumor immune surveillance. This 
counterbalance between tumor and the immune system creates a state of equilibrium, or immune tolerance, which can 
be edited therapeutically. Immune-modulating therapy focuses on how to circumvent tumor-induced immune-
suppressive mechanisms and invoke a tumor-directed immune response. So far, this concept has proven successful in 
the treatment of highly immunogenic tumors. Less immunogenic tumors, such as CRC and many other entities, will need 
additional stimulation to breach the immune tolerance in order for patients to achieve durable and beneficial treatment 
responses. 
The tumor microenvironment and its immune attributes 
The tumor microenvironment (TME) consists of stromal elements, of which the immune cells have preferentially adopted 
activities that support immune tolerance [Whiteside et al., 2016]. Tumor cell expression of the ligand of programmed 
death receptor 1 (PD-1), PD-L1, renders the tumor cells more effective in binding to PD-1 on cytotoxic T lymphocytes 
[Smyth et al., 2016]. This causes silencing of this tumor cell-killing T cell population via elevation of intracellular PTEN 
phosphatase activity [Riley, 2009; Patsoukis et al., 2013]. Antibodies against PD-1 or PD-L1, which are approved for 
treatment of metastatic renal, urothelial, or non-small cell lung carcinoma, melanoma, and classic Hodgkin lymphoma, 
unleash the binding of PD-L1 from PD-1, which causes abrogation of PTEN activity and cytotoxic T cell activation. This 
phenomenon is commonly referred to as immune checkpoint blockade (ICB). However, the efficient activation of tumor-
targeting T lymphocytes also requires their priming for tumor antigens by antigen-presenting dendritic cells, which 
ultimately leads to full anti-tumor immunity. 
In CRC, the influence of the TME with its immune effectors for disease outcome is increasingly acknowledged [Galon et 
al., 2014; Anitei et al., 2014]. The recent studies demonstrating favorable survival following ICB in metastatic disease 
from mismatch repair-deficient, or microsatellite-instable (MSI), tumors with a high density of immunogenic neo-antigens 
[Le et al., 2015; Le et al., 2017] are already regarded as landmark contributions to the concept of possible immune 
modulation in advanced CRC. Nevertheless, the great majority of CRC patients suffer from mismatch repair-proficient, or 
microsatellite-stable (MSS), disease with a low mutational load and consequently, low antigenicity [Cancer Genome 
Atlas Network, 2012; Goldstein et al., 2014]. 
Immunogenic cell death by oxaliplatin 
The concept referred to as immunogenic cell death (ICD) essentially implies cytotoxic damage of tumor cells by either 
radiation or systemic therapies and the resulting priming of tumor-targeting T lymphocytes via capture and presentation 
of shed tumor antigens by dendritic cells [Galluzzi et al., 2015]. Preclinical studies have highlighted oxaliplatin as an ICD-
inducing agent [Tesniere et al., 2010; Zitvogel et al., 2010]. In mouse models, oxaliplatin has been shown to sensitize 
CRC and other adenocarcinomas to ICB therapy via enhanced tumor infiltration of cytotoxic T lymphocytes [Gou et al., 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 15 of 63 
2014; Pfirschke et al., 2016]. Increasing clinical evidence also supports the notion that oxaliplatin is able to induce ICD 
[Pol et al., 2015] and thereby invoke efficacious anti-tumor immunity. 
 
Our prospective study Locally Advanced Rectal Cancer – Radiation Response Prediction (NCT00278694) enrolled 
almost 100 patients with locally advanced rectal cancer (LARC) from October 2005 through March 2010, who were 
followed for five years (until August 2015). The patients were given curative intention neoadjuvant treatment before 
surgery [Ree et al., 2015]. Estimated five-year progression-free survival (PFS) was 61% and almost all of the recorded 
PFS events were metastatic disease progression [Dueland et al., 2016]. 
 
 
 
 
 
 
 
The treatment protocol consisted of oxaliplatin-based induction neoadjuvant chemotherapy (NACT; two cycles of the 
Nordic FLOX regimen1) followed by long-course chemoradiotherapy (CRT) and final surgery. NACT was found to be 
highly tolerable, with dose adjustments required for only 9% of patients [Dueland et al., 2016]. Importantly, Nordic FLOX 
is a cost-effective regimen in terms of inexpensive chemotherapeutics and short administration time with a relatively low 
requirement for oncology nurse staffing. It remains a mainstay in first-line therapy of metastatic CRC. 
In the LARC-RRP study, we made a set of remarkable observations. First, in a study population with considerable locally 
advanced disease (41% organ-invasive T4 cases and a majority of patients with lymph node involvement), five-year 
overall survival (OS) was as high as 83% [Dueland et al., 2016]. Next, the short-course NACT alone led to substantial 
tumor volume reduction, as measured by magnetic resonance (MR) volumetry [Flatmark et al., 2016]. And most 
noteworthy, patients who during the two induction FLOX cycles experienced a pronounced increase in circulating 
immune factors had significantly better PFS than patients without such immune responses [Meltzer et al., 2016; Kalanxhi 
et al., 2017]. For example, we assessed circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L) at baseline and 
following induction NACT and sequential CRT, with both modalities containing oxaliplatin. Flt3L is a factor that both 
reflects the direct cytotoxic effect of chemotherapy and causes expansion of the pool of antigen-presenting dendritic 
cells. The data indicated that induction of high circulating Flt3L by the two FLOX cycles and maintenance by oxaliplatin 
at mildly myelosuppressive doses during the CRT may favor survival without metastatic progression in high-risk T4 
cases [Kalanxhi et al., 2017]. In summary, low-cost and easy-to-administer oxaliplatin-based treatment was associated 
with favorable long-term outcome in a LARC population given curative intention pelvic radiation and surgery for locally 
advanced tumors commonly prone to metastatic progression. These findings suggest that systemic tumor-targeting 
effects may have been invoked by oxaliplatin. 
Figure 2 – the LARC-RRP study. 
Study patients received intensified 
neoadjuvant treatment consisting of 
oxaliplatin-containing induction 
NACT followed by CRT and pelvic 
surgery. Any progress to metastatic 
disease was recorded for five years 
after surgery. Serial serum and 
plasma samples were collected at 
sampling points indicated by tubes. 
Figure 1 – the ICD concept. 
Cytotoxic damage by oxaliplatin (1) 
causes release of tumor antigens 
from the dying tumor (2). These are 
taken up (3) by dendritic cells (DC) 
and presented to cytotoxic T cells (4), 
resulting in their activation and clonal 
proliferation (5). This will in principle 
enable specific T cell targeting of any 
tumor manifestation systemically (6).  

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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Moreover, in the recently concluded prospective study Oslo Randomized Laparoscopic Versus Open Liver Resection for 
Colorectal Metastasis Study (NCT01516710), 254 patients with resectable CRC liver metastases were enrolled and will 
be followed for five years [Fretland et al., 2017]. Approximately half of study patients received neoadjuvant FLOX. The 
ongoing exploration of oxaliplatin-induced effects in the surgical specimens indicates strong influx of T cells (CD3-
positive) and particularly cytotoxic T cells (CD8-positive), but not FoxP3-positive regulatory T cells, following neoadjuvant 
FLOX (3–8 cycles). 
 
1 The Nordic FLOX regimen: oxaliplatin 85 mg/m2 (over 30–60 minutes) on day 1; bolus (over <5 minutes) 5-fluorouracil 
500 mg/m2 and 30 minutes later bolus (over <10 minutes) folinic acid on days 1 and 2; IV administration every 2 weeks. 
1.2 
Rationale for the chosen FLOX administration 
Administration of the FLOX regimen will be according to the schedule that was used in the NORDIC-VII Study [Tveit et 
al., 2012], which in recent years has also been implemented in clinical practice. 
Please refer to the summary of product characteristics (SmPC) of each drug component of FLOX for reference safety 
information. If drug-related toxicities are observed in the this study, the guidelines outlined in Paragraph 5.7 will apply. 
1.3 
Nivolumab 
Nivolumab is a fully human monoclonal antibody that binds to PD-1 with nanomolar affinity and a high degree of 
specificity. Nivolumab is currently (as per May 2017) approved in Norway for treatment of metastatic renal, urothelial, 
non-small cell lung, or head-and-neck carcinoma, melanoma, and classic Hodgkin lymphoma based on clinical studies 
showing improved survival. Please refer to the Investigator’s Brochure (IB) version 16 (as of 23 June 2017), Chapter 5.6 
(Reference Safety Information), for detailed information on safety of nivolumab in humans. 
1.4 
Rationale for dose selection of nivolumab 
As detailed in the IB, nivolumab is safe and well tolerated up to 10 mg/kg Q2W dose level. Furthermore, in non-small cell 
lung cancer, nivolumab at a dose of 10 mg/kg Q3W has been shown to be safe when given concomitantly with 
chemotherapeutic agents such as cisplatin, pemetrexed, paclitaxel, docetaxel, or even some of these in combination. 
Finally, a flat dose of 240 mg Q2W has been shown to be similar to 3 mg/kg Q2W, and infusion time can be shortened to 
30 minutes. 
According to the IB for nivolumab version 16, the safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected 
to be similar to the 3 mg/kg Q2W dosing regimen. The 240 mg Q2W dose was selected since it is identical to a dose of 3 
mg/kg for subjects weighing 80 kg, the observed median body weight in nivolumab-treated cancer patients. Using a 
population pharmacokinetics model, the overall distributions of nivolumab exposures are comparable after treatment with 
either 3 mg/kg or 240 mg nivolumab. The predicted range of nivolumab exposures (median and 90% prediction intervals) 
resulting from a 240 mg flat dose across the 35–160 kg weight range is maintained well below the corresponding 
exposures observed with the 10 mg/kg Q2W dosage. Across various tumor types, nivolumab has been shown to be safe 
and well tolerated up to a dose of 10 mg/kg Q2W. Given the similarity of nivolumab pharmacokinetics across tumor types 
and the similar exposures predicted from administration of 240 mg Q2W flat dose and the 3 mg/kg Q2W regimen, it is 
expected that the safety and efficacy profile of the two regimens will be similar. Hence, the 240 mg Q2W flat dose 
regimen has been incorporated into currently ongoing clinical studies. 
Figure 3 – anti-tumor immune activation 
in liver metastases. Histologic sections of 
surgical specimens from two 
representative patients with liver-
metastatic CRC, stained with hematoxylin 
& eosin (H&E) or antibodies detecting 
various T lymphocyte populations within 
the TME (Dagenborg et al., manuscript in 
preparation). 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 17 of 63 
If drug-related toxicities are observed in the this study, the guidelines outlined in Paragraph 5.7 will apply. 
2  
STUDY OBJECTIVES AND END POINTS 
Hypothesis: Most patients with metastatic CRC harbor tumor that can be transformed into an immunogenic disease by 
oxaliplatin, and may thereby benefit from the addition of immune-modulating therapy to improve outcome of the current 
oxaliplatin-based standard-of-care. 
 
 
Objectives 
End points 
Primary 
To determine PFS, in terms of 
failure of treatment strategy, on 
sequential treatment with the 
Nordic FLOX regimen and 
nivolumab2 compared with the 
standard-of-care Nordic FLOX 
regimen in previously untreated 
MSS metastatic CRC. 
2 Nivolumab is an ICB agent. 
 PFS: radiologic assessment every 8 
weeks (following 4 cycles of FLOX or 
the alternative 2 cycles each of FLOX 
and nivolumab), according to the 
Response Evaluation Criteria in Solid 
Tumors (RECIST) and the RECIST 
consensus guideline for assessment 
of response to immune-modulating 
therapies, iRECIST (c.f., Appendices 
1 and 2). 
Secondary 
To determine safety and 
tolerability of sequential 
treatment with the Nordic FLOX 
regimen and nivolumab 
compared with the standard-of-
care Nordic FLOX regimen. 
 
 
Safety: incidence of adverse events 
(AE), as reported according to 
Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 
(c.f., Appendix 3) recorded on 
onboing basis, and summarized every 
4 weeks on active study therapy and 
every 8 weeks in planned breaks from 
active study therapy. 
 
Tolerability: AE grading, as assessed 
by CTCAE v4.0 recorded on onboing 
basis, and summarized every 4 
weeks on active study therapy and 
every 8 weeks in planned breaks from 
active study therapy. 
 
To determine objective 
response rate (ORR), duration 
of response (DOR), secondary 
surgical curative resection rate 
(SSCRR), and OS. 
 
ORR: the percentage of patients with 
a confirmed complete or partial 
response. 
 
DOR: the time from the first 
documentation of a complete or 
partial response to disease 
progression. 
 
SSCRR: the percentage of patients 
with a confirmed resection of 
metastatic disease with 
microscopically free margin (R0). 
 
OS: the time from randomization to 
death of any cause. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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To monitor and compare 
quality-of-life (QoL) alterations 
during therapy courses. 
 
QoL: assessment undertaken at study 
enrolment, completion of the active 
therapy of the first treatment 
sequence (after 16 weeks), and 
disease progression, using the 
consensus modules EORTC QLQ-
C30, EORTC QLQ-CIPN20, and EQ-
5D-5L (http://groups.eortc.be/qol/ , 
http://www.euroqol.org/). 
Tertiary 
To compare costs for the 
resource use (in diagnostic 
work-up, treatment, and any 
AE) for the sequential therapy 
with that of the standard-of-
care, applying a model 
specifically developed for CRC. 
 
Cost estimate: model described in 
Joranger P et al., Med Decis Making 
2015; 35, 256–65. 
Exploratory 
To develop circulating 
biomarkers of cytotoxic T 
lymphocyte activity. 
 
Surrogate measure of cytotoxic T 
lymphocyte activity: phosphatase 
activity in serial peripheral blood 
mononuclear cells (PBMC) samples, 
collected corresponding to each 
change of therapy (from FLOX to 
nivolumab and reverse) of the 
sequential regimen. 
 
To develop circulating 
biomarkers of tumor response. 
 
Surrogate response marker: 
alterations of circulating tumor DNA 
(ctDNA)  and exosomal miRNA in 
plasma samples, collected 
corresponding to each change of 
therapy in the sequential regimen. 
 
To develop circulating 
biomarkers of ICD. 
 
Measures of circulating immune 
factors and T cell phenotypes in serial 
serum/plasma/whole blood samples 
collected corresponding to each 
change of therapy in the sequential 
regimen. 
 
To develop functional MR 
imaging biomarkers. 
 
TME responses in abdominal 
metastases: repeat functional MR 
imaging, undertaken corresponding to 
each change of therapy (from FLOX 
to nivolumab and reverse) during the 
first two months of the sequential 
regimen (three recordings in total), 
and correlate such changes with 
RECIST/iRECIST measures and 
PFS. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 19 of 63 
 
To develop histologic and 
molecular tumor biomarkers. 
 
Immune responses in liver/peritoneal 
metastases: histologic and molecular 
profiling in repeat liver/peritoneal 
biopsy samples collected 
corresponding to each change of 
therapy (from FLOX to nivolumab and 
reverse) during the first two months of 
the sequential regimen (three biopsy 
procedures in total), and correlate 
such changes with RECIST/iRECIST 
measures and PFS. 
3 
OVERALL STUDY DESIGN 
The METIMMOX study is a multicenter open-label randomized phase 2 trial in first-line treatment of MSS metastatic 
CRC using the standard-of-care Nordic FLOX regimen (control arm) or sequential therapy with the Nordic FLOX regimen 
and nivolumab (experimental arm), to investigate whether the experimental arm shows superiority in PFS, safety, 
tolerability, and QoL. 
Study period 
 
Estimated date of first patient enrolled: 1 March 2018 
Anticipated recruitment period: 12 months 
Estimated date of last patient completed: 1 September 2020 
Treatment duration 
Expected treatment duration per patient: 
Experimental arm: 18 months (until failure of treatment strategy) 
Control arm: 9 months (until failure of treatment strategy) 
 
 
Follow-up 
Expected follow-up period per patient: 
Experimental arm: 30 months (12 months following failure of treatment strategy) 
Control arm: 21 months (12 months following failure of treatment strategy) 
 
4 
STUDY POPULATION 
4.1  
Selection of study population 
Centers across Norway will participate. The Institutions are: 
 
Akershus University Hospital, Lørenskog, Norway (catchment population of 500,000). 
 
St. Olavs Hospital – Trondheim University Hospital, Trondheim, Norway (catchment population of 450,000). 
 
Haukeland University Hospital, Bergen, Norway (catchment population of 450,000). 
 
Hospital of Southern Norway, Kristiansand, Norway (catchment population of 290,000). 
 
Oslo University Hospital, Oslo, Norway (catchment population of 500,000). 
All citizens of Norway have equal access to public health services. As a consequence, there will be no selection of 
patients onto the METIMMOX study other than that based on specific inclusion and exclusion criteria. This population-
based study accrual will provide a unique opportunity to investigate the generalizability of the study concept across a 
majority of patients with metastatic CRC. Importantly, algorithms for personalized allocation of first-line treatments in 
patients with metastatic CRC are uniform across Scandinavian countries and also incorporated in the respective national 
guidelines for management of CRC. Finally, there is no other study currently planned for this CRC population that might 
compete for patients. 

 
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As seen from the above list of Institutions, the total catchment population from the participating Norwegian centers is 
close to 2.2 million, or more than 40% of the nation’s population. It is therefore reasonable to assume an annual figure of 
almost 850 metastatic CRC cases among these centers. Therefore, if the study manages to enroll well over one tenth of 
these patients, the study accrual phase should last approximately one year. 
This project will actively use the Norwegian Clinical Research Infrastructures Network (www.norcrin.no) and their 
resources in the planning for and conducting the study. For example, this enables the access to the Viedoc system, 
which includes web-based case report forms (CRF) with an ancillary eDatabase, randomization procedures, and 
validation of data, along with study monitoring, all of which meet regulatory requirements for clinical therapy trials. 
4.2 
Number of patients 
100 patients will be included in this trial (50 in each study arm). 
4.3 
Inclusion criteria 
All the following conditions must apply to the prospective patient at screening prior to receiving study treatment: 
 
Patient has histologically verified CRC adenocarcinoma (also comprising the mucinous adenocarcinoma and signet-
ring cell carcinoma entities). 
 
Patient is ambulatory with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (c.f., Appendix 
4). 
 
Patient is at least 18 years of age. 
 
Patient has radiologically measurable metastatic disease. 
 
Patient has an intra-abdominal metastatic lesion that can be biopsied. 
 
Patient has not had previous systemic therapy for the metastatic disease. 
 
Patient is eligible for the Nordic FLOX regimen. 
 
Patient has the following laboratory values, as measured in serum/plasma within 14 days prior to study entry, 
indicative of adequate organ function: 
o Hemoglobin at least 10.0 g/dL. 
o Neutrophils at least 1.5 x109/L (without current use of colony-stimulating factors). 
o Platelets at least 100 x109/L. 
o C-reactive protein less than 60 mg/L. 
o AST/ALT no higher than 2xULN when patient does not have metastatic disease in the liver or no higher than 
5xULN when patient has metastatic disease in the liver. 
o Bilirubin no higher than 1.5xULN when patient does not have metastatic disease in the liver or no higher than 
2xULN when patient has metastatic disease in the liver. 
o Albumin no lower than 30 g/L. 
o INR within normal level. 
o Creatinine no higher than 1.5xULN. 
 
Woman of childbearing potential (WOCBP)3 must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. 
 
WOCBP will use an adequate method4 to avoid pregnancy for a period of 26 weeks (which includes the required 30 
days plus the time required for nivolumab to undergo five half-lives) after the last therapy dose, irrespective of study 
arm. 
 
Woman is not breastfeeding. 

 
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 
Male who is sexually active with WOCBP must agree to follow instructions for method(s) of contraception4 for a 
period of 26 weeks (which includes the required time to ensure duration of sperm turnover plus the time required for 
the investigational drugs to undergo five half-lives) after the last therapy dose, irrespective of study arm. 
 
Signed informed consent form (ICF) and expected cooperation of the patients for the treatment and follow-up must 
be obtained and documented according to International Conference on Harmonization (ICH) – Good Clinical 
Practice (GCP) and national/local regulations. 
3 WOCBP is defined by the Clinical Trial Facilitation Group’s document “Recommendations related to contraception and 
pregnancy testing in clinical trials” version 2014-09-15 (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf). A woman is considered WOCBP, i.e., 
fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined 
as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single measurement of the 
follicle-stimulating hormone level is insufficient. 
4 Highly effective birth control methods are defined by the same recommendations. They include: 
 
Combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
 
Progesterone-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Sexual abstinence 
4.4 
Exclusion criteria 
Patient will be excluded from the study if she/he meets any of the following criteria: 
 
Patient has initially resectable metastatic disease for which neoadjuvant therapy is deemed superfluous. 
 
Patient does not consent to biopsy sampling. 
 
Patient has metastatic disease to lungs as the sole site. 
 
Patient has untreated or symptomatic brain metastasis (patient must be symptom-free without the use of 
corticosteroids). 
 
Patient has experienced a period of less than 6 months since discontinuation of adjuvant oxaliplatin-containing 
chemotherapy. 
 
Patient is ineligible for full chemotherapy doses (100% doses) at start of study treatment. 
 
Patient has had radiation therapy against the only measurable lesion within 4 weeks of start of study treatment. 
 
Patient has a medical condition treated with anticoagulant medication that cannot be replaced by low molecular 
weight heparin during active study treatment. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 22 of 63 
 
Patient has a nervous system disorder worse than CTCAE grade 1. 
 
Patient has any medical condition that will preclude him/her from cancer immune-modulating therapy, such as: 
o Active or chronic hepatitis B or hepatitis C. 
o Known history of human immunodeficiency virus or acquired immunodeficiency-related illnesses. 
o Diagnosis of immunodeficiency or medical condition requiring systemic steroids or other forms of 
immunosuppressive therapy. 
o Autoimmune disease that has required systemic therapy within the past 2 years. 
o Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study 
therapy. 
o Active infection or chronic infection requiring chronic suppressive antibiotics. 
o Known history of previous diagnosis of tuberculosis. 
 
Patient with current or prior use of immunosuppressive medication within 28 days before the first dose of study 
therapy, with the exceptions of intranasal corticosteroids or systemic corticosteroids at physiological doses that do 
not exceed 10mg/day of prednisone or an equivalent corticosteroid. 
 
Patient has any medical condition or needs to use medication, as listed in the SmPC of each Investigational Medical 
Product (IMP), that will preclude him/her from receiving treatment with IMP, such as: 
o Pernicious anemia or anemias due to vitamin B12 deficiency (SmPC-listed contraindications for folinic acid). 
o Other SmPC-listed contraindications for folinic acid and SmPC-listed contraindications for the other IMPs are 
covered by other exclusion criteria. 
 
Patient has undergone treatment with any IMP that may interfere with the study treatment within 4 weeks prior to 
first administration of study drug. 
 
Patient has known hypersensitivity to any of the study IMP components. 
 
Patient has ECOG performance status 2 or worse. 
 
Patient has serum/plasma CRP of 60 mg/L or higher. 
 
Patient does not meet the following requirements at baseline: adequate bone marrow function without current use of 
colony-stimulating factors (minimum values of neutrophils 1.5 x109/L, platelets 100 x109/L, hemoglobin 10 g/dL), 
adequate liver function (maximum values of AST/ALT 5xULN and bilirubin 2xULN; albumin value of 30 g/L or higher; 
INR within normal level), adequate renal function (maximum creatinine value of 1.5xULN). 
 
Patient has history of other prior malignancy, with the exception of curatively treated basal cell or squamous cell 
carcinoma of the skin, cervical cancer stage IB, stage I prostate cancer considered not necessary to treat, and 
another malignancy that was treated with curative intent more than 5 years ago and has not relapsed later. 
 
Patient has significant cardiac, pulmonary, or other medical illness that would limit activity of daily life (ADL) or 
survival. 
 
Patient is pregnant or breastfeeding. 
 
Patient has any other reason, in the opinion of Clinical Investigator, not to participate in the study. 
4.5 
Patient stratification 
Subjects will be stratified according to sidedness5 and (K)RAS/BRAF mutation status of the primary tumor (right-sided 
versus left-sided and (K)RAS/BRAF wild-type versus mutation) of two reasons. Firstly, patients in good performance 
status (ECOG 0–1) with (K)RAS/BRAF wild-type tumor (which frequently is left-sided) will commonly and according to 
national guidelines be offered an irinotecan-containing regimen with the addition of an EGFR inhibitor. A block-
randomization within each study stratum will ensure that this therapeutic option does not compromise enrolment onto 
any of the other groups (c.f., Paragraph 10.1). Secondly, stratification will enable outcome analysis (PFS) within each of 
the defined groups, among which the study treatment may show differential effects. Ideally, tumor MSS status should be 
determined to avoid inclusion of MSI cases; however, the current logistics of this analysis at hospitals commonly 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 23 of 63 
precludes it from being undertaken swiftly enough before the commencement of active therapy. In order to meet this 
challenge, tumor MSS status will be determined as per current practice. It is expected that approximately 5% of enrolled 
patients will harbor non-MSS tumor [Cancer Genome Atlas Network, 2012; Goldstein et al., 2014], and the statistical 
power analysis (c.f., Paragraph 10.2.1) has been adjusted to enable removal of these few cases before data analysis. 
5 Sidedness is defined as follows: right-sided, primary tumor in cecum, ascending colon, or transverse colon; left-sided, 
primary tumor in splenic flexure, descending or sigmoid colon, or rectum. 
4.6 
Risk/benefit assessment 
Study patients will in general benefit from follow-up of their disease and treatment within the frame of a prospective trial. 
Safety and efficacy for control arm patients (c.f., Paragraph 5.5) are well known from a number of previous studies and 
routine clinical practice over two decades. 
For experimental arm patients (c.f., Paragraph 5.5), particular hazards and benefits may prevail. Patients suffering from 
MSS metastatic CRC do not possess an inherently immunogenic disease and may experience untoward effects from 
sequential nivolumab following the short-course treatment with FLOX. In addition, these patients will receive half the 
number of FLOX cycles over a defined treatment period compared to the standard-of-care. Each of these aspects may 
occasion detrimental treatment responses. Also, keeping in mind that the repeat sequential treatment is a novel design 
with no safety data known as of yet, new and unexpected toxicities may appear. 
On the other hand, experimental arm patients will have an unprecedented opportunity to receive treatment, in terms if 
ICB, that is currently not available for the vast majority of patients with metastatic CRC. If the study hypothesis prevails 
and oxaliplatin treatment transforms MSS metastatic CRC into an immunogenic disease, there is an opportunity for 
durable treatment effects from the sequential ICB, similar to those observed with single-agent ICB in MSI metastatic 
CRC [Le et al., 2015; Le et al., 2017]. It is also conceivable that sequential ICB may dampen common side effects of the 
FLOX regimen, which might ultimately result in tolerability to a higher number of FLOX cycles than usual for the 
standard-of-care. 
5 
TREATMENT 
For this study, nivolumab (Opdivo®), oxaliplatin, 5-fluorouracil, and folinic acid (Leucovorin) are defined as IMP. 
5.1 
  Drug handling 
With regard to nivolumab, the drug will be provided by Bristol-Myers Squibb (BMS) as flat dosing kits, each containing 
240 mg of the drug (two vials of 100 mg each and one vial of 40 mg). In the event of availability constraints of 40-mg 
vials, 100-mg vials will be provided for dispense. The Hospital Pharmacy of Mid Norway Trust (Sykehusapoteket, 
Trondheim) will be used as vendor to provide import, labeling, storage, and dispatch of the drug from BMS to each 
participating center in Norway in accordance with the environmental conditions (temperature, light, humidity) as 
determined by BMS. At each center, the product storage manager at the study pharmacy will ensure that nivolumab is 
stored and dispensed in accordance with these conditions. If concerns regarding the quality or appearance of nivolumab 
arise, the study drug will not be dispensed and BMS will be contacted immediately. Please refer to the BMS IB for 
nivolumab regarding drug-related information such as handling, storage, infusion, etc. 
At each center, oxaliplatin, 5-fluorouracil, and folinic acid will be provided by the study pharmacy as per routine practice. 
IMP documentation will be maintained. This includes all processes required to ensure that the drugs are accurately 
administered. Also, it includes documentation of drug storage, administration, and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., diluents, administration sets). 
Infusion-related supplies (e.g., bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose injection) will be supplied 
by each study site and purchased locally if permitted by local regulations. 
The IMPs will be stored in a secure area according to local regulations. It is the responsibility of the investigators to 
ensure that IMPs are only dispensed to study subjects. The IMPs will be dispensed only from official study sites by 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 24 of 63 
authorized personnel according to local regulations. Please refer to the current IB version and/or pharmacy reference 
sheets for complete storage, handling, dispensing, and infusion information for nivolumab. The infusion will be 
administrated by nurses with experience in treatment with immunotherapy. 
The Nordic FLOX regimen is standard-of-care; thus, drug administration will be according to each participating 
department’s standard operating procedure (SOP). Likewise, expenses for the actual drugs and their administration will 
be covered by the participating departments’ standard budget. 
5.2 
 Drug accountability 
The responsible site personnel will confirm receipt of study drug and will use the study drug only within the framework of 
this study and in accordance with this protocol. Receipt, distribution, and destruction (if any) of the study drug will be 
properly documented according to Sponsor’s agreed and specified procedures. Any destruction of nivolumab will be 
reported back to BMS. 
Pertaining to each of the study drugs, Clinical Investigator will prescribe the actual dose and treatment cycle in sufficient 
detail within a predefined study-specific form in the Hospital’s electronic prescription system. Each prescription will be 
documented in an electronic logbook at the study pharmacy, which will identify which study patient has received which 
study drug (name, dose, batch number, shelf life, and amount). The study pharmacy will apply procedures that 
guarantee the traceability of this information. 
5.3 
 Drug labeling 
The IMP (nivolumab), as dispatched from the Hospital Pharmacy of Mid Norway Trust, will have a label permanently 
affixed to the outside of the vials/kits and will be labeled according with ICH GCP and national regulations, stating that 
the material is for clinical trial / investigational use only and should be kept out of reach of children. 
Labeling of IMP should be done according to Eudralex volume 4, Annex 13 (http://ec.europa.eu/health/files/eudralex/vol-
4/2009_06_annex13.pdf). 
For Norway, labeling is required according to Chapter 4.4 in “Forskrift om klinisk utprøving av legemidler til mennesker” 
(http://www.lovdata.no/for/sf/ho/xo-20091030-1321.html). However, because the infusion bags for all four IMPs will be 
dispensed and administered by authorized personnel at the study sites, immediately following the prescription by Clinical 
Investigator, the Norwegian Medicines Agency is entitled to make an exception from the labeling requirements. 
Nevertheless, all IMP bags will have an affixed label with blank lines for:  
 
patient’s initials 
 
patient’s enrolment code 
 
protocol code 
 
date dispensed 
 
name of prescribing doctor 
 
name of Principal Investigator 
5.4 
  Dosage, drug administration, and common toxicities 
FLOX: oxaliplatin 85 mg/m2 (over 30–60 minutes) on day 1; bolus (over <5 minutes) 5-fluorouracil 500 mg/m2 and 30 
minutes later bolus (over <10 minutes) folinic acid on days 1 and 2; IV administration every 2 weeks. 
Common toxicities are acute allergic reactions (laryngopharyngeal dystonia, anaphylaxia), moderate nausea and 
vomiting, diarrhea, hand-foot-syndrome, hyperpigmentation, mucositis, fatigue, neuropathy, febrile neutropenia, and 
thrombocytopenia. 
 
Nivolumab: 240 mg flat dose over 30 minutes, IV administration every 2 weeks. 

 
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In general, the use of ICB leads to a unique spectrum of side effects termed immune-related AE (irAE) or, occasionally, 
AE of special interest. The irAE include dermatologic, gastrointestinal, hepatic, endocrine, and other less common 
inflammatory events. These are believed to arise from general immunologic enhancement. Temporary immune 
suppression with corticosteroids, tumor necrosis factor-alpha antagonists, mycophenolate mofetil, or other agents can be 
an effective treatment in most cases. 
5.5 
  Duration of therapy 
The control arm will consist of intermittent treatment with the Nordic FLOX regimen in terms of 8 cycles (16 weeks) 
before a break until disease progression, when therapy is reintroduced and administered for another 8 cycles before a 
new break. This go-and-stop schedule, which is chosen because continuous FLOX treatment commonly causes 
unacceptable toxicity in the palliative setting, will be continued until progressive disease on ongoing therapy (defining 
PFS in terms of failure of treatment strategy), unacceptable toxicity, withdrawal of consent, or death, whichever occurs 
first. 
The estimated median PFS in the control arm is 9 months (i.e., 39 weeks), as detailed in Chapter 10. During this period, 
it is assumed that the ‘average’ patient will receive 1 full go-and-stop treatment sequence, consisting of 16 weeks of 
active therapy followed by 8 weeks of break until disease progression, before the second treatment period results in 
progressive disease after 16 weeks on ongoing therapy; hence, a PFS of 40 weeks. During the entire treatment, this 
patient will receive 2 sequences of active therapy, each containing 8 FLOX cycles. 
The experimental arm will consist of repeat 2 cycles of the Nordic FLOX regimen followed by 2 cycles of nivolumab for 
a total of 8 individual cycles (16 weeks) before a break until disease progression, when therapy is reintroduced and 
administered for another total of 8 individual cycles before a new break. This go-and-stop schedule will be continued until 
progressive disease on ongoing therapy (defining PFS in terms of failure of treatment strategy), unacceptable toxicity, 
withdrawal of consent, or death, whichever occurs first. 
 
The estimated median PFS in the experimental arm is 18 months (i.e., 78 weeks), as detailed in Chapter 10. During this 
period, it is assumed that the ‘average’ patient will receive 3 full go-and-stop treatment sequences, each consisting of 16 
weeks of active therapy followed by 8 weeks of break until disease progression, before the fourth treatment period 
results in progressive disease after 8 weeks on ongoing therapy; hence, a PFS of 80 weeks. During the entire treatment, 
this patient will receive 4 sequences of active therapy, each containing 4 cycles each of FLOX and nivolumab. 
The optimum duration of immune-modulating therapy is currently unknown. However, because such therapy engages 
the immune system to control the tumor, continuous treatment, as is required with other types of biologically targeting 
agents or systemic cytotoxic therapies, may not be necessary.  
Accumulating evidence from different clinical trials in different tumor types with nivolumab or nivolumab combined with 
the ICB drug ipilimumab indicates that most of the responses are generally occurring early, with a median time to 
response of 2–4 months [Brahmer et al., 2015; Borghaei et al., 2015; Hellmann et al., 2016; Larkin et al., 2015; Motzer et 
al., 2015]. A recent analysis in a melanoma study suggests the majority of patients who discontinue nivolumab and/or 
ipilimumab for toxicity maintain disease control in the absence of further treatment (Schadendorf D et al., reported at the 
2016 Annual Meeting of the European Association of Dermato-Oncology in Vienna, Austria). Furthermore, a limited 
duration of ipilimumab including only 4 induction doses resulted in long-term survival in patients with metastatic 
melanoma, with a sustained plateau in survival starting at around year 3 [Schadendorf et al., 2015]. 
Figure 4 – the experimental treatment arm. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 26 of 63 
For these reasons, in the present study, a total of 24 months of active sequential FLOX and nivolumab therapy will be 
administered, given the absence of disease progression (while the subject is on active therapy) or unacceptable toxicity 
at an earlier treatment time. After 24 months, FLOX alone may be administered as per the study dosing schedule in the 
control arm. Experimental arm subjects who complete a total of 24 months of active sequential FLOX and nivolumab 
therapy and have subsequent disease progression (on or off FLOX alone) may, at the discretion of Clinical Investigator, 
reinitiate sequential FLOX and nivolumab at the same dose and schedule given previously on study, and continue such 
treatment for up to 1 additional year. Continuation of treatment with FLOX beyond a total of 24 months of active 
sequential FLOX and nivolumab therapy (i.e., 12 months of active FLOX) is contingent on continued tolerance for FLOX. 
5.6 
  Monitoring 
Common vital signs (e.g., blood pressure, heart rate) are to be assessed before commencement of infusion of FLOX or 
nivolumab. For the former, the patient will receive premedication (typically ondansetron and dexamethasone) according 
to each participating department’s SOP. 
The risks related to nivolumab therapy must be thoroughly discussed with patients randomized to the experimental arm. 
These subjects will also be provided with a Patient Information Card upon starting treatment. They will further receive a 
prescription of prednisone in case of irAE, and be informed to contact Clinical Investigator swiftly in case of suspected 
irAE. 
5.7 
  Schedule modifications 
5.7.1 
IMP (investigational medicinal products) schedule 
Continuation of IMP treatment with suspected progression is permitted; c.f., Paragraph 5.7.2.4. Discontinuation from 
study treatment may result from any of the criteria listed in Paragraph 5.7.2.3. 
If required, subjects may receive IMP up to 3 days before or after the scheduled date. A cycle started more than 3 days 
after the intended dose date will be considered a delay. Subsequent dosing should be based on the actual date of 
administration of the previous drug cycle. 
Subjects will be monitored for infusion reactions during IMP administration. If an acute reaction is noted, subjects will be 
managed according to Paragraph 5.7.2.7. IMP doses may be interrupted, delayed, or discontinued as per requirement. 
5.7.2 
Dose modifications for IMP 
Dose modification is only allowed in case of dose-limiting toxicity; c.f., Appendices 5 and 6 for general guidelines for 
practical management. 
5.7.2.1   Dose delay criteria for IMP 
Dose delay criteria apply for all drug-related AE. A treatment delay up to 4 weeks, i.e., ≤6 weeks calculated from start of 
the previous therapy cycle, is allowed. A treatment delay beyond 6 weeks is not allowed (Paragraph 5.7.2.3). 
Tumor assessments should continue as per protocol schedule, even if dosing is delayed. 
Nivolumab administration will be delayed for the following reasons (in CTCAE grading): 
 
Any grade ≥2 non-skin drug-related AE, except for fatigue and laboratory abnormalities. 
 
Any grade 3 skin drug-related AE. 
 
Any grade 3 drug-related laboratory abnormality. 
 
Any AE, laboratory abnormality, intercurrent illness, or other reason which, in the judgment of Clinical Investigator, 
warrants delaying the dose of study medication. 
Subjects who require delay of nivolumab will be re-evaluated weekly, or more frequently if clinically indicated. Nivolumab 
dosing can be resumed on the established dosing schedule when retreatment criteria are met (Paragraph 5.7.2.2). 
FLOX administration will be delayed for the following reasons (in CTCAE grading): 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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 
Grade 2 diarrhea (increase of 4–6 stools per day over baseline; moderate increase in stoma output compared to 
baseline; not interfering with ADL). 
 
Grade 3 diarrhea (increase of 7 or more stools per day over baseline; incontinence; severe increase in stoma output 
compared to baseline; interfering with ADL). 
 
Grade 2 myelosuppression (neutrophils of 1.0 x109/L to less than 1.5 x109/L, or platelets of 50 x109/L to less than 75 
x109/L). 
 
Grade 3 myelosuppression (neutrophils of 0.5 x109/L to less than 1.0 x109/L, or platelets of 25 x109/L to less than 50 
x109/L). 
 
Grade 4 myelosuppression (neutrophils less than 0.5 x109/L, or platelets less than 25 x109/L). 
 
Grade 2 sensory neuropathy (sensory alteration or paresthesia persisting between two oxaliplatin doses with no or 
only minor improvement, moderate symptoms, limiting instrumental ADL). 
Subjects who require delay of FLOX will be re-evaluated weekly, or more frequently if clinically indicated. FLOX 
administration will be resumed when retreatment criteria are met (Paragraph 5.7.2.2). 
5.7.2.2   Criteria to resume dosing for IMP 
Subjects may resume treatment with study drug when the drug-related AE resolves to CTCAE grade ≤1 or baseline 
value, with the following exceptions: 
For nivolumab: 
 
Subjects may resume nivolumab treatment in accordance with the below criteria irrespective of whether FLOX or 
nivolumab was administered in the preceding cycle. 
 
Subjects may resume treatment in the presence of CTCAE grade 2 fatigue. 
 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before treatment is resumed.  
 
Subjects with drug-related endocrinopathies adequately controlled with only physiologic hormone replacement may 
resume treatment. 
 
Subjects who received systemic corticosteroids for management of any drug-related toxicity must be off 
corticosteroids or have tapered down to an equivalent dose of prednisolone ≤10 mg/day. 
For FLOX: 
 
Subjects may resume FLOX treatment in accordance with the below criteria (in CTCAE grading) irrespective of 
whether FLOX or nivolumab was administered in the preceding cycle. 
 
Grade 2 diarrhea; the following pertaining to both oxaliplatin and fluorouracil: interrupt until grade 1 or less, then 
100% dose first time, 75% dose second time, 50% dose third time. 
 
Grade 3 diarrhea; the following pertaining to both oxaliplatin and fluorouracil: interrupt until grade 1 or less, then 
75% dose first time, 50% dose second time, discontinue third time. 
 
Grade 2 myelosuppression; the following pertaining to both oxaliplatin and fluorouracil: interrupt until grade 1, then 
100% dose first time, 75% dose and consider support with granulocyte-colony stimulating factor (e.g., pegfilgrastim) 
second or subsequent times. 
 
Grade 3 myelosuppression; the following pertaining to both oxaliplatin and fluorouracil: interrupt until grade 1 or less, 
then 75% dose and consider support with granulocyte-colony stimulating factor (e.g., pegfilgrastim) first or 
subsequent times. 
 
Grade 4 myelosuppression; the following pertaining to both oxaliplatin and fluorouracil: interrupt until grade 1 or less, 
then 50% dose and consider support with granulocyte-colony stimulating factor (e.g., pegfilgrastim) first or 
subsequent times. 
 
Grade 2 sensory neuropathy; the following pertaining only to oxaliplatin: interrupt until grade 1 or less, then 75% 
dose first time, 50% dose second time, discontinue third time. 

 
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5.7.2.3   Treatment discontinuation criteria for IMP 
For nivolumab, treatment will be permanently discontinued for the following reasons (in CTCAE grading):  
 
Any grade 4 drug-related AE. 
 
Any grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not 
improve to grade 1 severity within the re-treatment period or requires systemic treatment. 
 
Any grade 3 non-skin, drug-related AE lasting >7 days, with the following exceptions for laboratory abnormalities, 
drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or infusion reaction of any 
duration (requires discontinuation). 
o Grade 3 drug-related endocrinopathies that are adequately controlled with only physiologic hormone 
replacement (do not require discontinuation). 
o Grade 3 drug-related laboratory abnormalities (do not require treatment discontinuation) except grade 3 drug-
related thrombocytopenia >7 days or associated with bleeding (requires discontinuation). 
 
Any drug-related liver function test abnormality that meets the following criteria (requires discontinuation): 
o AST or ALT >5xULN. 
o Total bilirubin >3xULN. 
 
Any grade 4 drug-related AE or laboratory abnormality, except for one of the following events (does not require 
discontinuation): 
o Grade 4 neutropenia ≤7 days. 
o Grade 4 lymphopenia or leukopenia. 
o Isolated grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis. Study Conduct Group (c.f., Paragraph 11.3) should be consulted for grade 4 
amylase or lipase abnormalities. 
o Isolated grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are 
corrected with supplementation/appropriate management within 72 hours of their onset. 
o Grade 4 drug-related endocrinopathy adverse events, such as adrenal insufficiency, ACTH deficiency, hyper- or 
hypothyroidism, or glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from Study Conduct Group. 
 
Any event that leads to delay in dosing lasting >6 weeks from start of the previous therapy cycle requires 
discontinuation, with the following exceptions: 
o Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events (allowed). 
o Dosing delays lasting >6 weeks from the previous dose that occur for non-drug-related reasons (may be 
allowed if approved by Study Conduct Group). 
o Prior to re-initiating treatment in a subject with a dosing delay lasting >6 weeks, Study Conduct Group must be 
consulted. Tumor assessments should continue as per protocol even if dosing is delayed. Periodic study visits 
to assess safety and laboratory studies should also continue every 6 weeks or more frequently if clinically 
indicated during such dosing delays. 
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of Clinical Investigator, presents a 
substantial clinical risk to the subject with continued nivolumab dosing. 
For detailed information, please refer to the IB for nivolumab. 
For FLOX, treatment will be permanently discontinued for the following reasons (in CTCAE grading): 
 
Grade 4 diarrhea (life-threatening consequences, urgent intervention indicated). 
 
Grade 3 sensory neuropathy (sensory alteration or paresthesia, severe symptoms, limiting self-care ADL). 

 
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5.7.2.4   Continuing nivolumab with suspected progression 
Accumulating evidence indicates that a minority of subjects treated with immune-modulating therapy may derive clinical 
benefit despite initial evidence of disease progression, such as inflammatory reaction simulating progression, so-called 
pseudo-progression. Subjects may, at the discretion of Clinical Investigator, continue study treatment in the setting of 
suspected progression until progression is confirmed, in accordance with the evaluation algorithm detailed for 
RECIST/iRECIST (c.f., Paragraph 7.6). If Clinical Investigator believes that the subject continues to derive clinical benefit 
by continuing treatment, the subject should continue monitoring/assessments according the same schedule as patients 
without tumor progression, with more frequent radiologic assessment if clinically indicated (see below). 
Subjects may continue study treatment beyond initial (suspected) progression only if they meet the following criteria: 
 
Subject is in stable performance status (ECOG 0–1) and tolerates study treatment. 
 
Treatment will not delay intervention to prevent imminent complications. 
 
There is overall clinical benefit as judged by Clinical Investigator. 
Radiographic assessment should be repeated after suspected progression as clinically required in order to determine 
whether there has been a decrease in the tumor size or continued progression. Potential for clinical benefit should be 
balanced by clinical judgment as to whether the subject is clinically deteriorating and unlikely to receive benefit from 
continued study treatment. Study treatment will be permanently discontinued upon confirmation of progression. 
5.5.2.5   Management algorithms for immuno-oncology agents 
These agents are associated with irAE that can differ in severity and duration from AE caused by other therapeutic 
classes. Nivolumab is considered an immuno-oncology agent in this protocol. Early recognition and management of irAE 
associated with immuno-oncology agents may mitigate severe toxicity. Management algorithms have been developed to 
assist investigators in assessing and managing the following groups of irAE: 
 
gastrointestinal 
 
renal 
 
pulmonary 
 
hepatic 
 
endocrinopathy 
 
skin 
 
neurological 
Refer to Appendix 5 for management details. 
5.7.2.6   Management algorithms for the Nordic FLOX regimen 
Refer to Appendix 6 for further details. 
5.7.2.7   Treatment of IMP-related infusion reactions 
For nivolumab infusion reactions, the following information will be taken into consideration: 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be immunogenic and induce 
infusion or hypersensitivity reactions. However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
Any CTCAE grade 3 or 4 infusion reaction will be reported within 24 hours as a serious adverse event (SAE) if it meets 
the criteria (c.f., Paragraph 8.1.2). Infusion reactions will be graded according to the CTCAE v4.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment standards and 
guidelines, as appropriate: 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not indicated): 
 
Remain with patient and monitor until recovery from symptoms. The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol (acetaminophen) 
325 to 1000 mg at least 30 minutes before additional nivolumab administrations. 

 
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For grade 2 symptoms (moderate reaction requiring therapy or infusion interruption but responding promptly to 
symptomatic treatment, such as antihistamines, non-steroidal anti-inflammatory drugs, narcotics, corticosteroids, 
bronchodilators, IV fluids; prophylactic medications indicated for ≤24 hours): 
 
Stop the nivolumab infusion, begin IV infusion of normal saline, and treat the subject with diphenhydramine 50 mg 
IV (or equivalent) and/or paracetamol (acetaminophen) 325 to 1000 mg; remain with patient and monitor until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If 
the infusion is interrupted, restart the infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor subject closely. If symptoms recur, no further nivolumab shall be administered at that visit. 
 
For future infusions, the following prophylactic premedications are recommended: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol (acetaminophen) 325 to 1000 mg should be administered at least 30 minutes 
before nivolumab infusion. If necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used. 
For grade 3 or 4 symptoms (severe reaction; grade 3: prolonged, i.e., not rapidly responsive to symptomatic medication 
and/or brief interruption of infusion; recurrence of symptoms following initial improvement; hospital admission indicated 
for other clinical sequelae, e.g., renal impairment, pulmonary infiltrates); grade 4: life threatening; pressor or ventilatory 
support indicated): 
 
Immediately discontinue infusion of nivolumab. Begin IV infusion of normal saline and treat the subject as follows: 
recommend bronchodilators, epinephrine 0.2–1 mg of a 1:1000 solution for SC administration or 0.1– 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 
100 mg IV (or equivalent), as needed. Subject should be monitored until Clinical Investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued. Clinical Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms. 
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized pruritus within 1 week 
after treatment), symptomatic treatment may be given (e.g., oral antihistamine or corticosteroids). 
For FLOX infusion reactions, management will be according to each participating department’s SOP. 
5.8  
Concomitant treatments 
It is expected that enrolled subjects will have systemic corticosteroids tapered as quickly as clinically appropriate during 
screening phase, and discontinued if possible prior to inclusion. 
All concomitant medication (including over-the-counter drugs) used by the patient will be recorded. 
Supportive care for all disease-related or treatment-related AE will be maximized for all subjects on this study. 
5.8.1 
Prohibited and/or restricted treatments 
Immunosuppressive agents, including systemic corticosteroids, are prohibited during study treatment unless utilized to 
treat a drug-related AE. Subjects with a condition requiring systemic treatment with either corticosteroids (>20 mg daily 
prednisolone, >3 mg dexamethasone daily, or equivalent) or other immunosuppressive medications (including within 14 
days of inclusion) are excluded. Subjects continuing to require supraphysiologic steroids (prednisolone >20 mg daily, >3 
mg dexamethasone daily, or equivalent) may not be enrolled. Inhaled or topical steroids and adrenal replacement steroid 
doses (≤20 mg daily prednisolone daily, ≤3 mg dexamethasone daily, or equivalent) are permitted in the absence of 
active autoimmune disease. 
Anticoagulant medication other than low molecular weight heparin is not permitted during active study treatment. 
Brivudine, sorivudine, or analogs (antiviral drugs) are contraindicated during the use of fluoropyrimidine analogs and 
therefore not permitted during study treatment and the initial 4 weeks of planned treatment breaks. 
5.8.2 
Permitted therapy 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption). Adrenal replacement steroid doses of >10 mg daily prednisone are permitted. A brief (less than 3 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 31 of 63 
weeks) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune 
conditions (e.g., delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
Steroid use should be minimized prior to inclusion. Systemic corticosteroid use or physiologic replacement doses of 
steroids are permitted, even >20 mg/day prednisolone equivalents, for: a) treatment-related AE or b) treatment of non-
autoimmune conditions (e.g., prophylaxis for contrast dye allergy, contact hypersensitivity). Details regarding 
corticosteroid use prior to and during the study will be collected (name of medication, doses utilized, start and stop dates, 
frequency of use, route of administration). Information regarding concomitant corticosteroid use may be analyzed with 
regard to study outcome measures. Subjects requiring chronic treatment with corticosteroids should be treated with 
histamine-2 receptor antagonists or proton pump inhibitors as prophylaxis for potential gastrointestinal adverse reactions 
(ulceration, perforation, hemorrhage) unless otherwise contraindicated. 
Support with granulocyte-colony stimulating factor (e.g., pegfilgrastim) in case of myelosuppression is permitted. 
Oral anticoagulant therapy is permitted during study treatment breaks. 
Concomitant medications are recorded at baseline and throughout the study treatment sequences. All medications 
(prescriptions or over-the-counter medications) continued at the start of the study or started during the study and 
different from the study drug will be documented. 
All treatments that Clinical Investigator considers necessary for a subject’s welfare may be administered at the discretion 
of Clinical Investigator in keeping with the community standards of medical care. All concomitant medication will be 
recorded, including all prescription, over-the-counter, and IV medications and fluids. If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be recorded. 
All concomitant medications received within 28 days before the first dose of study treatment and 30 days after the last 
dose of study treatment will be recorded. Concomitant medications administered later than 30 days after the last dose of 
study treatment should be recorded for SAE. 
5.9 
Subject numbering 
Each subject is identified in the study by a unique subject number that is assigned when subject signs the ICF and is 
randomized. Once assigned the subject number cannot be reused for any other subject. The study treatment will be 
dispensed/administered to the subject by authorized site personnel only.

 
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Page 32 of 63 
6 
STUDY FLOW CHART 
Trial period 
Screening 
phase 
Treatment sequence 1 
Scheduling window;                         
visit (V), cycle (C), day(D) 
V-1   
(D 
-15 
to 
D-1) 
V0   
(D 
-14 
to 
D0) 
V1   
C1   
D1 
(±3 
days) 
V2   
C2   
D1 
(±3 
days) 
V3   
C3   
D1 
(±3 
days) 
V4   
C4   
D1 
(±3 
days) 
V5   
C5   
D1 
(±3 
days) 
V6   
C6   
D1 
(±3 
days) 
V7   
C7   
D1 
(±3 
days) 
V8   
C8   
D1 
(±3 
days) 
Administrative procedures 
  
  
  
  
  
  
  
  
  
  
Informed consent 
X 
  
  
  
  
  
  
  
  
  
Inclusion/exclusion criteria 
  
X 
  
  
  
  
  
  
  
  
Tumor (K)RAS/BRAF                     
mutation status 3 
  
X 
  
  
  
  
  
  
  
  
Medical history 
  
X 
  
  
  
  
  
  
  
  
Prior 4 and concomitant 
medication review 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-study anticancer therapy 
status 
  
  
  
  
  
  
  
  
  
  
Questionnaires (QoL) 
  
X 
  
  
  
  
  
  
  
  
Clinical procedures 
Review adverse events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination 7 
  
X 8 
  
  
  
  
  
  
  
Directed physical examination 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and weight 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival follow-up 
  
  
  
  
  
  
  
  
  
  
Laboratory procedures 
Pregnancy test 9 
  
X 10 
  
  
X 10 
  
X 
  
X 10 
  
HIV, HBV, and HCV tests 
  
X 
  
  
  
  
  
  
  
  
Laboratory analyses 13 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine analysis 15 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment administration 
FLOX 
  
  
X 
X 
X 16 
X 16 
X 
X 
X 16 
X 16 
Nivolumab 
  
  
  
  
X 16 
X 16 
  
  
X 16 
X 16 
Evaluation procedure(s) 
CT 17 
  
X 18 
  
  
  
  
X 
  
  
  
Correlative study procedures 
Whole blood sampling 
  
  
X 
  
  
  
  
  
  
  
Plasma and serum sampling 
  
  
X 
  
X 
  
X 
  
X 
  
PBMC sampling 19 
  
  
X 
  
X 
  
X 
  
X 
  
Functional MR liver 
acquisition 19,20 
  
X 
  
  
X 
  
X 
  
  
  
Liver/peritoneal biopsy sampling 21 
  
X 
  
  
X 
  
X 
  
  
  
 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 33 of 63 
 
Trial period 
Break 
period 2 
End of 
study 
visit 
Withdrawal 
visit (if 
applicable) 
Post-treatment phase 
Scheduling window;                         
visit (V), cycle (C), day(D) 
Every 8 
weeks 
At the 
time of 
treatment 
discont. 
At the time 
of 
withdrawal 
Safety 
follow-up 
(approx. 
D30 after 
discont.) 
Follow-
up year 1 
after 
discont. 
(every 3 
months 
±7 days) 
Survival 
follow-up 
Administrative procedures 
  
  
  
  
  
  
Informed consent 
  
  
  
  
  
  
Inclusion/exclusion criteria 
  
  
  
  
  
  
Tumor (K)RAS/BRAF                     
mutation status 3 
  
  
  
  
  
  
Medical history 
  
  
  
  
  
  
Prior 4 and concomitant 
medication review 
X 
X 
X 
X 
  
  
Post-study anticancer therapy 
status 
  
  
  
X 
X 
  
Questionnaires (QoL) 
X 5 
X 
  
  
  
  
Clinical procedures 
Review adverse events 
X 
X 
X 6 
X 6 
X 6 
  
Full physical examination 7 
  
  
X 
  
  
Directed physical examination 
X 
X 
X 
  
  
  
Vital signs and weight 
X 
X 
X 
X 
  
  
ECOG performance status 
X 
X 
X 
X 
  
  
Survival follow-up 
  
  
  
  
  
X 
Laboratory procedures 
Pregnancy test 9 
X 11 
X 
X 
X 
X 12 
  
HIV, HBV, and HCV tests 
  
  
  
  
  
  
Laboratory analyses 13 
X 
X 14 
X 14 
X 14 
X 14 
  
Urine analysis 15 
X 
X 14 
X 14 
X 14 
X 14 
  
Treatment administration 
FLOX 
  
  
  
  
  
  
Nivolumab 
  
  
  
  
  
  
Evaluation procedure(s) 
CT 17 
X 
X 
  
  
  
  
Correlative study procedures 
Whole blood sampling 
  
  
  
  
  
  
Plasma and serum sampling 
X 
X 
  
  
  
  
PBMC sampling 19 
X 
X 
  
  
  
  
Functional MR liver 
acquisition 19,20 
  
  
  
  
  
  
Liver/peritoneal biopsy sampling 21 
  
  
  
  
  
  

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 34 of 63 
1 
Repeat after break period with disease progression, continue until progressive disease on ongoing therapy. 
2  Until disease progression. 
3 Analysis on primary or metastatic tumor. 
4  Only at visit 2. 
5  By completion of the active therapy of the first treatment sequence (after 16 weeks), i.e., at first visit in first treatment 
break. 
6  Until all study drug-related AE are resolved, have returned to baseline, or are deemed irreversible; reported for at 
least 100 days after last dose administration of IMP. 
7 To be undertaken if clinically indicated from V1 onward, but mandatory at the 30 days safety follow-up visit. 
8  May be omitted if full physical examination has been undertaken 14 days or less prior to the first dose of trial 
treatment. 
9  For WOCBP. 
10  Within 24 hours prior to the start of study drug. 
11  Every 4 weeks. 
12  Every 4 weeks; in the control arm, for 30 days after the last dose of study drug; in the experimental arm, for 160 days 
after the last dose of study drug. 
13  Laboratory tests: Hb, HCT, WBC (including differential counting), platelets, liver factors (ALT, AST, ALP, LDH, GGT, 
total bilirubin, total albumin, INR), creatinine or urea, Na, K, Ca, Mg, phosphate, glucose, TSH, free T4, CEA, Ca19.9, 
Ca125. 
14  Until all study drug-related abnormalities are resolved, have returned to baseline, or are deemed irreversible. 
15  Dipstick. 
16  FLOX in control treatment arm, nivolumab in experimental treatment arm. 
17  In addition to computed tomography (CT) scan, MR scans or other radiologic evaluations will be performed if 
indicated. 
18  Baseline CT scan must be taken within 28 days prior to the start of study drug. 
19  Participation is optional for study centers. 
20  Patient must not present contraindication to the procedure. Procedure must be done before a metastatic lesion in the 
liver/peritoneum is sampled. 
21 Baseline sampling is mandatory; follow-up sampling is optional. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 35 of 63 
7 
STUDY PROCEDURES 
The Study Flow Chart (Chapter 6) summarizes study procedures to be performed at each visit. Individual procedures are 
described in detail below. It may be necessary to perform these procedures at unscheduled times if deemed clinically 
necessary by Clinical Investigator. 
Furthermore, additional evaluation/testing may be deemed necessary by Sponsor and/or BMS for reasons related to 
subject safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., human 
immunodeficiency virus, hepatitis C), and thus local regulations may require that additional informed consent be obtained 
from the subject. In these cases, such evaluation/testing will be performed in accordance with those regulations. 
7.1 
Informed consent 
Clinical Investigator will obtain documented consent from each subject prior to participation in the trial. Consent must be 
documented by the subject’s dated signature on the ICF along with the dated signature of the person conducting the 
consent discussion. A copy of the signed and dated ICF will be given to the subject before participation in the trial. 
The initial ICF, any subsequent revised written ICF, and any written information provided to the subject must receive 
approval of Institutional Review Board (IRB) and Independent Ethics Committee (IEC) in advance of use. The subject will 
be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial. The communication of this information will be provided and documented via a revised 
ICF or addendum to the original consent form that captures the subject’s dated signature. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations, and Sponsor requirements. 
7.2 
Inclusion and exclusion criteria 
All inclusion and exclusion criteria will be reviewed by Clinical Investigator or a qualified designee to ensure that the 
subject qualifies for the trial.  
7.3 
Medical history 
A medical history will be obtained by Clinical Investigator or a 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 
Clinical Investigator. Details regarding the disease for which the subject has enrolled in this study will be recorded 
separately and not listed as medical history.   
7.3.1 
Prior medications 
Clinical Investigator or a qualified designee will review prior medication use, including any protocol-specified washout 
requirement, and record prior medication taken by the subject within 28 days before starting the trial. Treatment for the 
disease for which the subject has enrolled in this study will be recorded separately and not listed as prior medication. 
7.3.2 
Concomitant medications 
Clinical Investigator or a qualified designee will record medication, if any, taken by the subject during the trial.  
7.3.3 
Other diseases 
Clinical Investigator or a qualified designee will obtain prior and current details regarding disease status.  
7.3.4 
Prior treatment details 
Clinical Investigator or a qualified designee will review all prior cancer treatments including systemic treatments, 
radiation, and surgery. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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7.3.5 
Subsequent anti-cancer therapy status 
Clinical Investigator or a qualified designee will review all new anti-neoplastic therapy initiated after the last dose of trial 
treatment. If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30 day 
safety follow-up visit must occur before the first dose of the new therapy. Once new anti-cancer therapy has been 
initiated the subject will move into survival follow-up. 
7.4 
Safety assessments 
At baseline, a medical history will be obtained to capture relevant underlying conditions. The baseline examinations will 
include weight, height, ECOG status, blood pressure, heart rate, and temperature, and will be performed within 14 days 
prior to first dose. Baseline signs and symptoms are those that are assessed within 14 days prior to first dose of study 
drug. Concomitant medications including steroid dose will be collected within 14 days prior to first dose of study drug and 
through the study treatment period. 
Baseline local laboratory assessments will be done within 14 days prior to first dose and will include the following 
serum/plasma assessments: Hb, HCT, WBC (including differential counting), platelets, liver factors (ALT, AST, ALP, 
LDH, GGT, total bilirubin, total albumin, INR), creatinine or urea, Na, K, Ca, Mg, phosphate, glucose, TSH, free T4, CEA, 
Ca19.9, and Ca125. Additionally, urine analysis will be done. 
The following baseline local laboratory assessments should be done within 28 days prior to first treatment: hepatitis B 
and C testing, according to each Institution’s SOP. 
Pregnancy testing of WOCBP must be performed within 24 hours prior to Day 1 and then every 4 weeks. 
While on study treatment, the same local laboratory assessments as those of baseline will be done within 3 days prior to 
each dose. 
Subjects will be evaluated for safety and tolerability if they have received any study drug. Toxicity assessments will be 
continuous during the treatment phase and formally recorded at each new therapy cycle, and every 8 weeks during 
planned breaks from active study therapy, and should be done in person. Once subjects reach the survival follow-up 
phase, either in-person or documented telephone calls to assess the subject’s status are acceptable. 
AE and laboratory values will be graded according to CTCAE v4.0. 
The start and stop time of the study therapy infusions will be documented. 
Additional measures, including non-study required laboratory tests, will be performed as clinically indicated or to comply 
with local regulations. Laboratory toxicities (e.g., suspected drug-induced liver enzyme evaluations) will be monitored 
during the follow-up phase via local laboratories until all study drug-related toxicities resolve, return to baseline, or are 
deemed irreversible. 
Some of the assessments referred to in this section may not be captured as data in the CRF. They are intended to be 
used as safety monitoring by the treating physician. Additional testing or assessments may be performed as clinically 
necessary or where required by institutional or local regulations. 
7.5 
Physical examination 
7.5.1 
Full physical examination 
Clinical Investigator or a qualified designee will perform a complete physical examination during the screening period. 
Clinically significant abnormal findings should be recorded as medical history. A full physical examination will also be 
performed at the 30 days safety follow-up visit and if clinically indicated otherwise during the study. 
7.5.2 
Directed physical examination 
For study visits that do not require a full physical examination as per Study Flow Chart, Clinical Investigator or a qualified 
designee will perform a directed physical examination as clinically indicated prior to trial treatment administration.   

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
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7.5.3 
Vital signs 
Clinical Investigator or a qualified designee will take vital signs at screening, prior to the administration of each dose of 
trial treatment, and at treatment discontinuation as specified in Study Flow Chart. Vital signs should include temperature, 
pulse, weight, and blood pressure. Height will be measured at screening only. 
7.5.4 
ECOG performance status 
Clinical Investigator or a qualified designee will assess ECOG status at screening, prior to the administration of each 
dose of trial treatment, every 8 weeks during planned breaks from active study therapy, at discontinuation of trial 
treatment, and during follow-up, as specified in Study Flow Chart. 
7.6 
Tumor imaging and assessment of disease procedures 
7.6.1 
Evaluation of efficacy 
The imaging assessments will be performed by CT, typicall a thoracic/abdominal/pelvic CT scan. Tumor treatment 
response will be assessed according to RECIST v1.1 as the primary method and iRECIST as the secondary method. 
After baseline tumor assessments, evaluation of tumor response will be performed every 8 weeks (±7 days). Additional 
MR scans or other radiologic evaluations will be performed if indicated. 
All radiologic examinations will be transmitted to Study Radiologist at Akershus University Hospital within 1 working day 
after the scan is performed. A radiologist at the actual study center will evaluate the images for incidental findings that 
may have a therapeutic consequence (e.g., pulmonary embolism, immune therapy-related findings that require 
emergency actions). 
Study Radiologist will be blinded to patient treatment, but will be informed about treatment breaks in the go-and-stop 
schedule. Study Radiologist will primarily assess tumor measures according to RECIST v1.1. If disease progression is 
concluded by means of RECIST v1.1, Study Radiologist will also assess tumor measures according to iRECIST. The 
radiology report will detail the criteria used for Clinical Investigator to make a decision about further study treatment (c.f., 
Paragraph 5.7.2.4). 
PFS will be calculated from the day of randomization to first recorded disease progression according to RECIST v1.1 or 
iRECIST when applicable, or death. Patients who have not had disease progression at the time of final analysis will be 
censored at the date last known to be alive and progression-free. 
7.6.2 
Measurability of tumor lesions at baseline 
7.6.2.1 
Definitions 
 
Measurable disease: The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature will be confirmed by cytology/histology prior to treatment.  
 
Measurable lesions: Tumor lesions that can be accurately measured in at least one dimension (longest diameter to 
be recorded) as ≥10 mm with CT.  
o Bone lesions are considered measurable only if assessed by CT and have an identifiable soft tissue 
component that meets these requirements (soft tissue component ≥10 mm with CT).   
o Malignant lymph nodes must be ≥15 mm in the short axis to be considered measurable; only the short axis 
will be measured and followed. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Tumor lesions situated in 
a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion.  
 
Non-measurable lesions: All other lesions (or sites of disease), including small lesions, are considered non-
measurable disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, lymphangitic involvement of lung or skin and abdominal 
masses followed by clinical examination, are all non-measurable. Nodes that have a short axis <10 mm at baseline 
are considered non-pathological and should not be recorded or followed.  

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 38 of 63 
 
Target lesions: When more than one measurable tumor lesion or malignant lymph node is present at baseline, all 
lesions up to a maximum of 5 (or 3, if only three are present) lesions in total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions, and will be recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to reproducible repeat 
measurements. Note that pathological lymph nodes must meet the criterion of a short axis of ≥15 mm by CT and 
only the short axis of these nodes will contribute to the baseline sum. At baseline, the sum of the target lesions 
(longest diameter of tumor lesions plus short axis of lymph nodes; overall maximum of 5) is to be calculated and 
recorded. 
 
Non-target lesions: All non-measurable lesions (or sites of disease), including pathological nodes (those with short 
axis ≥10 mm but <15 mm), plus any measurable lesions over and above those listed as target lesions are 
considered non-target lesions. Measurements are not required, but these lesions should be noted at baseline and 
should be followed as present or absent. 
All baseline evaluations should be performed as closely as possible to the beginning of treatment and every 8 weeks 
during treatment and planned treatment breaks. 
7.6.2.2 
Methods of measurements 
CT of the thoracic/abdominal/pelvic cavities (preferably with IV contrast) is the best currently available and reproducible 
method to measure lesions selected for response assessment in metastatic CRC. This protocol has defined 
measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
 
Evaluation will be done every 8 weeks. 
 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. 
 
While on study, all target lesions recorded at baseline should have their actual measurements recorded on the CRF 
at each subsequent evaluation. 
 
If it is the opinion of Study Radiologist that the lesion has likely disappeared, the measurement should be recorded 
as 0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 
For lesions which fragment/split add together, the longest diameter of the fragmented portions will be measured. For 
lesions which coalesce, the maximal longest diameter for the ‘merged lesion’ will be measured. 
7.6.3 
RECIST version 1.1 
All patients will have their best response from the start of study treatment until the end of treatment, classified as such: 
 
Complete response (CR): Disappearance of all target and non-target lesions. Pathological lymph nodes must have 
short axis measures <10 mm (note: continue to record the measurement even if <10 mm and considered CR). 
Tumor markers must have normalized. Residual lesions (other than nodes <10 mm) thought to be non-malignant 
should be further investigated (by cytology or positron emission tomography) before CR can be accepted.  
 
Partial response (PR): At least a 30% decrease in the sum of measures (longest diameter for tumor lesions and 
short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non-target 
lesions must be non-PD.  
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum of diameters on study. 
 
Progressive disease (PD): At least 20% increase in the sum of diameters of measured lesions taking as references 
the smallest sum of diameters recorded on study (including baseline) and an absolute increase of ≥5 mm. 
Appearance of new lesions will also constitute PD (including lesions in previously unassessed areas). In exceptional 
circumstances, unequivocal progression of non-target disease may be accepted as evidence of disease 
progression, where the overall tumor burden has increased sufficiently to merit discontinuation of treatment, for 
example where the tumor burden appears to have increased by at least 73% in volume (which is the increase in 
volume when all dimensions of a single lesion increase by 20%). Modest increases in the size of one or more non-

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 39 of 63 
target lesions are not considered unequivocal progression. If the evidence of PD is equivocal (target or non-target 
lesions), treatment may continue until the next assessment, but on further documentation, the earlier date must be 
used. 
CR or PR may be claimed only if the criteria for each are met at a subsequent time point at least 8 weeks later. 
Assignments of timepoint response using RECIST v1.1: 
 
7.6.4 
iRECIST 
In the experimental arm, iRECIST will be used in the case of new lesion(s) or increase in size of known lesion(s), and if 
the patient is clinically deteriorating. This is categorized as immune-unconfirmed progressive disease (iUPD). An 
immune-confirmed progressive disease (iCPD) is only assigned if at next assessment after iUPD (4–8 weeks later) 
additional new lesions appear or an increase in size of new lesions is seen (≥5 mm for sum of new target lesion or any 
increase in new non-target lesion). The appearance of new lesions when none have previously been recorded can also 
confirm iCPD. 
However, if progression is not confirmed but instead tumor shrinkage occurs (compared with baseline), which meets the 
criteria of immune-complete response (iCR), immune-partial response (iPR), or immune-stable disease (iSD), then the 
bar is reset so that iUPD needs to occur again (compared with nadir values) and then be confirmed (by further growth) at 
the next assessment, for iCPD to be assigned. If no change in tumor size or extent from iUPD occurs, then the time point 
response would again be iUPD. This approach allows atypical responses, such as delayed responses that occur after 
pseudoprogression, to be identified, further understood, and better characterized. 
Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and, 
together with other lesions that are denoted as non-target lesions, followed until disease progression. 
For direct comparison of iRECIST with RECIST v1.1 [Seymour et al., 2017], please refer to Appendix 2. 
iCR or iPR may be claimed only if the criteria for each are met at a subsequent time point at least 8 weeks later. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 40 of 63 
Assignments of timepoint response using iRECIST: 
 
 
7.6.5 
Frequency of tumor re-evaluation 
Frequency of tumor re-evaluation will be every 8 weeks in both arms and during planned study treatment breaks. In the 
case of suspected clinical progression or iUPD according to iRECIST, the next evaluation may be preponed to after 4 
weeks. 
Evaluation will be with routine CT of the thoracic/abdominal/pelvic cavities, preferably with contrast in the case of 
adequate renal function. 
If brain or bone metastasis is suspected, supplemental MR evaluations may be undertaken. However, bone scans only 
need to be repeated when CR is identified in target disease or when progression in bone is suspected. 
All target and non-target sites are assessed at each evaluation. 
After discontinuation of protocol treatment, patients who have not progressed will still be re-evaluated every 8 weeks 
until end-of-study, as per protocol. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 41 of 63 
7.6.6. 
Date of progression 
This is defined as the first day when RECIST (v1.1) PD is observed in the control arm and after iRECIST iCPD is 
observed in the experimental arm. 
7.6.7 
Reporting of tumor response 
All patients included in the study must be assessed for response to treatment, even if there is a major protocol treatment 
deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following 
categories: CR/iCR, PR/iPR, SD/iSD, PD/iCPD, early death from malignant disease, early death from toxicity, or early 
death from other cause or unknown (not assessable, insufficient data). 
Early death is defined as any death occurring <30 days after randomization. Clinical Investigator will decide if the cause 
of death is malignant disease, toxicity, or other. 
Patients for whom response is not confirmed will be classified as Unknown, unless they meet the criteria for SD/iSD (or 
the criteria for PR/iPR in case of an unconfirmed CR/iCR). Patients’ response will also be classified as Unknown if 
insufficient data were collected to allow evaluation per these criteria. 
7.6.8 
Response duration 
This will be measured from the time of randomization, or until the first date that recurrent or progressive disease is 
objectively documented. Patients who have not had PD/iCPD at the time of final analysis will be censored at the date last 
known to be alive and progression-free. 
7.6.9 
Stable disease duration 
This will be measured from the time of randomization until the criteria for progression are met. Patients who have not 
had PD/iCPD at the time of final analysis will be censored at the date last known to be alive and progression-free. 
7.7 
Other study procedures 
7.7.1 
Screening period 
Approximately 7–14 days prior to subject allocation, potential subjects will be evaluated to determine that they fulfill the 
entry requirements. Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame. Screening 
procedures can not be completed earlier than 14 days prior to the first dose of trial treatment except for WOCBP, for 
whom a serum pregnancy test will be performed within 24 hours prior to the first dose of trial treatment. A urine test may 
be considered if serum test is not appropriate. 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results from assessments 
performed during the initial screening period are acceptable in lieu of a repeat screening test if performed within the 
specified time frame and the inclusion/exclusion criteria are met. 
7.7.2 
Treatment period 
Visit requirements are outlined in Chapter 6 – Study Flow Chart. Specific procedure-related details are provided in 
Chapter 7 – Study Procedures. 
7.7.3 
Post-treatment visits 
7.7.3.1 
Safety follow-up visit 
The mandatory safety follow-up visit will be conducted approximately 30 days after the last dose of trial treatment or 
before the initiation of a new anti-cancer treatment, whichever comes first. All AE that occur prior to the safety follow-up 
visit should be recorded. Subjects with an AE of CTCAE grade >1 will be followed until the resolution of the AE to grade 
0–1 or stabilization, or until the beginning of a new anti-neoplastic therapy, whichever occurs first. SAE that occurs within 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 42 of 63 
the full duration of the study (c.f., Paragraph 7.8) or before initiation of a new anti-cancer treatment will also be followed 
and recorded. 
7.7.3.2 
Follow-up visits 
When a subject discontinues study treatment, for whatever reason (PD/iCPD, unacceptable toxicity, or withdrawal of 
consent), the subject will move into the follow-up phase. The patient will be assessed every 3 months (±7 days) the first 
year after discontinuation to monitor disease status. Every effort will be made to collect information regarding disease 
status until the start of a new anti-neoplastic therapy, disease progression, death, or end of the study. Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
7.7.3.3 
Survival follow-up 
Once a subject discontinues study treatment or starts a new anti-cancer therapy, the subject moves into the survival 
follow-up phase. We will monitor survival status every 6–12 months (by phone call, subject visit, contact with patient’s 
general practitioner) until the end of the study. The survival status and, if applicable, the cause of death will be recorded. 
7.7.4 
Withdrawal or discontinuation 
When a subject discontinues or withdraws prior to trial completion, all applicable activities scheduled for the final trial visit 
will be performed at the time of discontinuation. Any AE which are present at the time of discontinuation will be followed 
in accordance with the safety requirements outlined in Chapter 8. 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion of Clinical 
Investigator should any untoward effect occur. In addition, a subject may be withdrawn by Clinical Investigator or 
Sponsor if enrolment into the trial is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons. A subject must be discontinued from the trial for any of the following reasons: 
 
AE/SAE as specifically described. 
 
The subject withdraws consent. 
 
Confirmed disease progression; c.f., Paragraph 7.6. 
 
Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of Clinical Investigator, indicates 
that continued participation in the study is not in the best interest of the subject. 
 
Intercurrent illness that prevents further administration of treatment. 
 
Clinical Investigator’s decision to withdraw the subject. 
 
The subject has a confirmed positive pregnancy test. 
 
Non-compliance with trial treatment or procedure requirements. 
 
The subject is lost to follow-up. 
 
Administrative reasons. 
After the end of treatment, each subject will be followed for 30 days for AE monitoring. Subjects who discontinue for 
reasons other than PD/iCPD will have post-treatment follow-up for disease status until disease progression, starting a 
non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. After documented disease progression, 
information on survival will be obtained until death, withdrawal of consent, or the end of the study, whichever occurs first. 
7.8 
End of study 
The end of study is defined as “last patient last visit”, in accordance with European Commission guidelines. However, as 
mentioned in Paragraph 5.5, accumulating evidence from a number of clinical trials in different tumor types with 
nivolumab indicates that patients may obtain durable responses, even if they discontinue nivolumab for toxicity. Such 
observations are acknowledged as general features of ICB [Emens et al., 2017] and may call for a redefinition of the 
end-of-study term during the study conduct. 

 
METIMMOX – CA209-9M8 version 2.1 – 2-January-2018 
Page 43 of 63 
7.9 
Study termination 
Early trial termination may be the result of one of the following criteria: 
 
Quality or quantity of data recording is inaccurate or incomplete. 
 
Poor adherence to protocol and regulatory requirements. 
 
Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard to subjects. 
 
Plans to modify or discontinue the development of the study drug. 
In the event of BMS decision to no longer supply study drug, ample notification will be provided so that appropriate 
adjustments to subject treatment can be made. 
The whole trial may be discontinued at the discretion of Principal Investigator or Sponsor in the event of any of the 
following: 
 
Occurrence of AE/SAE unknown to date in respect of their nature, severity, and duration. 
 
Medical or ethical reasons affecting the continued performance of the trial. 
 
Difficulties in the recruitment of patients. 
 
Cancellation of drug development. 
Sponsor and Principal Investigator will inform all investigators and the relevant Competent Authorities and Ethics 
Committees of the termination of the trial along with the reasons for such action. If the study is terminated early on 
grounds of safety, the Competent Authorities and Ethics Committees will be informed within 15 days. 
7.10 
Ancillary study procedures 
The below listed procedures do not represent a mandatory list of what are to be performed, but instead provide an 
overview of the current plans. The priority of analyses and assays will be subject to review during and after finalization of 
the trial. Additional investigations may be performed, reflecting ongoing developments in the field. Some assays will be 
performed only for selected patients because of costs and work load. 
For the precise timing of the various procedures described below, please refer to the Study Flow Chart – Chapter 6. 
7.10.1 
Repeat quality-of-life recording 
Formal QoL recording will undertaken at study enrolment, completion of the active therapy of the first treatment 
sequence (after 16 weeks), and disease progression, using the consensus modules EORTC QLQ-C30, EORTC QLQ-
CIPN20, and EQ-5D-5L (http://groups.eortc.be/qol/, http://www.euroqol.org/). Please refer to the information in 
Appendices 7–9. 
Participation in the QoL sub-study is mandatory for study centers. 
7.10.2 
Repeat collection of serum and plasma 
Up to ten tubes of 5–10 mL peripheral blood will be drawn immediately before start of treatment, after every completed 2 
therapy cycles (immediately before start of the next cycle or at treatment interruption) until disease progression, 
unacceptable toxicity, withdrawal of consent, death by any reason, or end-of-follow-up, whichever occurs first, and every 
8 weeks during planned treatment breaks. The tubes will be used to prepare EDTA plasma, citrate plasma, and serum, 
according to specified SOP documents (in Investigator Site File). A small volume of the whole blood collected 
immediately before start of treatment will be used for isolation of germ-line DNA. The samples will be stored at –80ºC at 
the local study center and dispatched to the study biobank at Akershus University Hospital upon request. 
The circulating biomarker study program will comprise ctDNA [Spindler et al., 2017], exosomal miRNA (published in the 
PhD thesis of S. Meltzer 2017, manuscript in preparation), and ICD factors [Kalanxhi et al., 2016; Meltzer et al., 2016; 
Kalanxhi et al., 2017]. 
Participation in the above-mentioned circulating biomarker sub-studies is mandatory for study centers. 

 
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7.10.3 
Repeat collection of PBMC 
Currently, no robust biomarker of cytotoxic T cell activity exists for clinical use, but PTEN phosphatase activity is high in 
T lymphocytes silenced by PD-1 binding to PD-L1 [Riley, 2009; Patsoukis et al., 2013]. Building on our long-standing 
collaboration with the Dutch biotechnology company PamGene International B.V. (www.pamgene.com), we will apply 
their recently developed phosphatase array [Hovestad-Bijl et al., 2016] on PBMC samples [Noé et al., 2016], as readily 
accessible surrogate tissue for the monitoring of cytotoxic T cell activity, at the proteomic facility at Department of Clinical 
Molecular Biology, Akershus University Hospital [Ree et al., 2015]. 
Moreover, together with Department of Cellular Therapy / Immunomonitoring Laboratory, Oslo University Hospital, ex 
vivo cytokine analysis, applying the ELISPOT assay, will be done on PBMC or specific subsets of CD4-positive and 
CD8-positive T cells. 
One tube of 10 mL peripheral blood will be drawn for this purpose immediately before start of treatment and after every 
completed 2 therapy cycles (immediately before start of the next cycle or at treatment interruption) until disease 
progression, unacceptable toxicity, withdrawal of consent, death by any reason, or end-of-follow-up, whichever occurs 
first, and every 8 weeks during planned treatment breaks. PBMC will be isolated by density-gradient centrifugation in 
Ficoll, stored at –80ºC at the local study center, and dispatched to the study biobank at Akershus University Hospital 
upon request. Please refer to the specified SOP document (in Investigator Site File). 
Participation in the above-mentioned circulating biomarker sub-studies is optional for study centers. 
7.10.4 
Repeat functional MR imaging 
Experiental arm patients will undergo repeat MR recordings of abdominal metastases at time points corresponding to 
each change of therapy (from FLOX to nivolumab and reverse) during the first two months of the sequential regimen 
(i.e., three recordings in total), using a discrete number of functional MR sequences with readouts reflecting TME 
biology. Specifically, we will apply our recently developed multi-echo contrast-enhanced sequence, which can predict 
metastatic progression with high diagnostic accuracy [Grøvik et al., 2016]. Importantly, the MR procedure must be done 
before a metastatic lesion is sampled by biopsy. Control arm patients may be exempt from MR imaging at the discretion 
of Clinical Investigator. Please refer to the specified SOP document (in Investigator Site File). 
Participation in the functional MR imaging biomarker sub-study is optional for study centers. 
7.10.5 
Repeat collection of metastatic tissue 
Experimental arm patients will undergo repeat sampling of core biopsies from liver/peritoneal metastases at time points 
corresponding to each change of therapy (from FLOX to nivolumab and reverse) during the first two months of the 
sequential regimen (i.e., three sampling procedures in total; one or both of the resampling procedures, i.e., others than 
that at baseline, are excused if the total number of three procudures is not feasible). Control arm patients will undergo 
biopsy sampling at baseline and may also be exempt from repeat sampling at the discretion of Clinical Investigator. For 
an individual patient, repeat sampling will preferentially be from the same lesion every time.  The sampling procedure will 
be ultrasound-guided. Ideally, to ensure that the material from the sampling locus is representative, a regular smear from 
a fine-needle aspirate will be assessed by a pathologist at site. Next, 1–3 core biopsies will be taken and tumor cell 
content estimated by tissue imprint prior to freezing in liquid nitrogen [Ree et al., 2017]. The samples will be dispatched 
to the study biobank at Akershus University Hospital upon request. Please refer to the specified SOP document (in 
Investigator Site File). 
The 1–3 biopsy samples will be utilized in the following priority: 1) histology/immune histochemistry, 2) RNA applications, 
and 3) DNA applications. Specifically, the total number of T cells (CD3-positive) will be determined, with identification of 
T cell subpopulations by their expression of specific proteins (CD8-positive cytotoxic and FoxP3-positive regulatory T 
cells), as recently shown in a pilot study (Dagenborg et al., manuscript in preparation). Also, CRC liver metastasis 
samples were recently analyzed by gene expression microarrays and indicated immune activity profiles in patients who 
had received neoadjuvant FLOX [Østrup et al., 2017]. Comprehensive gene mutation analysis will be done [Ree et al., 
2017]. Of note, a number of RNA-based methods will be applied to specifically investigate novel mechanisms of anti-
tumor immunity. Also, tumor PD-L1 expression, consensus molecular subtype, and mutation burden may be determined. 
Participation in the histologic and molecular investigational sub-studies is mandatory (baseline biopsy sampling; follow-
up biopsy sampling is optional) for study centers. 

 
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8 
SAFETY MONITORING AND REPORTING 
The investigators are responsible for the detection and documentation of events meeting the criteria and definition of AE 
or SAE. Each patient will be instructed to contact Clinical Investigator immediately should they manifest any signs or 
symptoms they perceive as serious. 
8.1 
Definitions 
An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a subject 
administered a study drug and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not cautionally related to the 
medicinal (investigational) product. 
The causal relationship to a study drug is determined by a physician and can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
 
Not related: There is not a reasonable causal relationship between study drug administration and the AE. 
The term “reasonable causal relationship” means there is evidence to suggest a causal relationship. AE can be 
spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject. 
8.1.1 
Non-serious adverse event(s) 
The term AE is used to include both SAE and non-serious AE. 
Non-serious AE are CTCAE grade ≤2 events or reactions listed in the the IB/SmPC of nivolumab. For FLOX, non-
serious AE are CTCAE grade ≤2 events. Non-serious AE do not need to be reported. Also, AE or SAE that are definitely 
due to disease progression do not need to be reported; c.f., Paragraph 8.3. 
If an abnormal laboratory value or vital sign is associated with clinical signs and symptoms, the sign/symptom should be 
reported as an AE and the associated laboratory result/vital sign will be considered additional information to be collected 
on the relevant CRF. 
The collection of non-serious AE information will begin at initiation of study drug and last until 100 days from the last 
dose of study drug (the 100-day injunction pertains to experimental arm patients only). Non-serious AE will be followed 
to resolution or stabilization, or reported as SAE if they become serious. Follow-up is also required for non-serious AE 
that cause interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. Identified non-serious AE will be recorded on a designated page of the CRF. 
8.1.2 
SAE (serious adverse events) 
An SAE is any untoward medical occurrence that at any dose: 
 
Results in death. 
 
Is immediately life-threatening. 
 
Requires in-patient hospitalization or prolongation of existing admission. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital abnormality or birth defect. 
 
Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of 
the outcomes listed above. Examples of such events include but are not limited to intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization. Potential drug-induced liver injury (DILI) is also considered an important medical event (see 
Paragraph 8.7 for the definition of potential DILI). 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug is an SAE. 

 
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Although pregnancy, overdose, cancer, and potential DILI are not always serious by regulatory definition, these events 
must be handled as SAE (see Paragraph 8.5 for reporting pregnancies). 
Any component of a study end point that is considered related to study therapy (e.g., death is an end point; if death 
occurred due to anaphylaxis, anaphylaxis must be reported) should be reported as SAE. 
Note: 
The following hospitalizations are not considered SAE in this study: 
 
A visit to the emergency room or other hospital department for <24 hours which does not result in admission 
(unless considered an important medical or life-threatening event). 
 
Elective surgery planned prior to signing consent. 
 
Admission for a planned medical/surgical procedure. 
 
Routine health assessment requiring admission for baseline/trending of health status (e.g., routine colonoscopy). 
 
Medical/surgical admission other than to remedy ill health and planned prior to entry into the study. Appropriate 
documentation is required in these cases. 
 
Admission encountered for another life circumstance that carries no bearing on health status and requires no 
medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, 
administrative reason). 
 
Admission for administration of anti-cancer therapy in the absence of any other SAE. 
8.2 
SAE (serious adverse events) collection and reporting 
For nivolumab, the IB represents the reference safety information to determine expectedness of SAE for expedited 
reporting. For the FLOX regimen, the SmPC of each of the drug components represents the reference safety 
information. Following the subject’s written consent to participate in the study, all SAE (in both study arms), whether 
related or not related to study drug, must be collected, including those thought to be associated with protocol-specified 
procedures. All SAE must be collected that occur during the screening period and within 100 days of the last dose of 
nivolumab. If applicable, SAE must be collected that relate to any later protocol-specified procedure. 
Clinical Investigator must report any SAE that occurs after these time periods and that is believed to be related to any 
IMP or protocol-specified procedure, pertaining to the full duration of the study (c.f., Paragraph 7.8), which is in 
accordance with European Commission guidelines. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If Clinical Investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of the 
study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship must be specified 
in the narrative section of the SAE report form. 
SAE, whether related or not related to study drug, and pregnancies, must be reported to Sponsor (or designee) within 24 
hours of awareness of the event. SAE will be recorded on the Suspect Adverse Reaction Report form by the Council for 
International Organizations of Medical Sciences (CIOMS), c.f. Appendix 10. Pregnancies will be recorded on a 
Pregnancy Surveillance Form. 
If only limited information is initially available, follow-up reports are required. All SAE must be followed to resolution or 
stabilization. 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, the SAE 
report must be updated and submitted within 24 hours to Sponsor (or designee) using the same procedure used for 
transmitting the initial SAE report. 
 
Sponsor’s representative for SAE notifications has the following address: 
a.h.ree@medisin.uio.no 
and 
Cell Phone: (+47) 482-57968 

 
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Sponsor will immediately forward SAE notifications (in experimental arm patients) to the following address: 
Worldwide.Safety@BMS.com 
or 
Facsimile Number: (+1) 609-818-3804 
 
8.3 
Disease progression or recurrence 
Disease progression can be considered as a worsening of a patient’s condition attributable to the disease for which the 
IMP is being studied. It may be an increase in the severity of the disease under study and/or increase in the symptoms of 
the disease. Expected progression of the disease under the study and/or expected progression of signs and symptoms 
of the disease under study, unless more severe in intensity or more frequent than expected for the patient’s condition, 
will not be reported as AE. Events which are definitely due to disease progression will not be reported as AE. However, if 
Clinical Investigator considers that there was a causal relationship between treatment with IMP or protocol 
design/procedures and the disease progression/recurrence, this will be reported as SAE. 
Death due to progressive disease will be recorded on a specific form in the CRF and not as SAE. Any new primary 
cancer (non-related to the cancer under study) will be considered for reporting as SAE. 
8.4 
Laboratory test abnormalities 
The following laboratory test abnormalities will be captured on the non-serious AE CRF page or SAE report form as 
appropriate:  
 
Any laboratory test result that is clinically significant or meets the definition of SAE. 
 
Any laboratory test result abnormality that requires the subject to have study drug discontinued or unintendedly 
interrupted. 
 
Any laboratory test result abnormality that requires the subject to receive specific corrective therapy. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the reporting investigator 
(e.g., anemia versus low hemoglobin value). 
8.5 
Pregnancy 
If, following initiation of the study drug, it is subsequently discovered that a study subject is pregnant or may have been 
pregnant at the time of study exposure, including during at least 5 half-lives after administration of nivolumab, Clinical 
Investigator must immediately notify Sponsor of this event and complete and forward a Pregnancy Surveillance Form 
(provided upon request from BMS) to Sponsor and BMS (in the case of an experimental arm patient) within 24 hours of 
awareness of the event and in accordance with SAE reporting procedures. 
In this case, the IMP will be permanently discontinued in an appropriate manner. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where 
applicable, offspring information must be reported on the Pregnancy Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to Sponsor and BMS (in 
the case of an experimental arm patient). Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. 
8.6 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both 
excessive and medically important. All occurrences of overdose must be reported as SAE. 

 
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8.7 
Potential drug-induced liver injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the reporting 
of a potential DILI event. All occurrences of potential DILI, meeting the defined criteria, must be reported as SAE. 
Potential DILI is defined as: 
1. ALT or AST elevation >3xULN 
and 
2. Total bilirubin >2xULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) 
and 
3. No other immediately apparent possible causes of ALT/AST elevation and hyperbilirubinemia, including but not limited 
to viral hepatitis, pre-existing chronic or acute liver disease, or administration of other drug(s) known to be hepatotoxic. 
8.8 
Other safety considerations 
Any significant worsening noted during interim or final physical examinations, radiology examination, or any other 
potential safety assessment required or not required by protocol should also be recorded as a non-serious AE or SAE, 
as appropriate, and reported accordingly. 
8.9 
AE (adverse events) recording 
If the patient has experienced an AE, Clinical Investigator will record the following information in the CRF: 
 
The nature of the AE will be described in precise standard medical terminology (i.e., not necessarily the exact words 
used by the patient). 
 
The duration of the event will be described in terms of event onset date and event ended date. 
 
The intensity of the AE will be defined according to CTCAE v4.0. 
 
The causal relationship of the event to the IMP will be assessed as one of the following: 
Unrelated: There is no temporal relationship to IMP administration (too early or late, or IMP not administered), or 
there is a reasonable causal relationship between non-investigational product, concurrent disease, or circumstance 
and the AE. 
Unlikely: There is a temporal relationship to IMP administration, but there is not a reasonable causal relationship 
between the IMP and AE. 
Possible: There is reasonable causal relationship between the IMP and AE. Dechallenge information is lacking or 
unclear. 
Probable: There is a reasonable causal relationship between the IMP and AE. The event responds to dechallenge. 
Rechallenge is not required. 
Definite: There is a reasonable causal relationship between the IMP and AE. 
 
Action taken. 
 
The outcome of the AE – whether the event is resolved or still ongoing. 
It is important to distinguish between serious and severe AE. Severity is a measure of intensity whereas seriousness is 
defined by the criteria in Paragraph 8.1.2. An AE of severe intensity needs not necessarily be considered serious. For 
example, nausea that persists for several hours may be considered severe nausea, but is not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild stroke, but would be an SAE. 
8.10 
Reporting procedure 
8.10.1 
AE (adverse events) and SAE (serious adverse events) 
All AE and SAE will be recorded in the patient's CRF. 

 
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SAE must be reported by Clinical Investigator to Sponsor by email and telephone to Principal Investigator, within 24 
hours after the site has gained knowledge of the SAE (c.f., Paragraph 8.2). Every SAE must be documented by Clinical 
Investigator on the SAE pages (to be found in Investigator Site File). The SAE report form must be completed, signed, 
and sent to Sponsor. The initial report shall promptly be followed by detailed, written reports if necessary. The initial and 
follow-up reports shall identify the trial subjects by unique code numbers assigned to the latter.  
Sponsor will keep detailed records of all SAE reported by the investigators and performs an evaluation with respect to 
seriousness, causality, and expectedness. 
8.10.2 
SUSAR (suspected unexpected serious adverse reactions) 
SUSAR will be reported to the Competent Authority and Ethics Committee according to national regulation. The following 
timelines should be followed (pertaining to both study arms): 
Sponsor will ensure that all relevant information about SUSAR that are fatal or life-threatening is recorded and reported 
as soon as possible to the Competent Authority and Ethics Committee, in any case no later than seven (7) days after 
knowledge by Sponsor of such a case, and that relevant follow-up information is subsequently communicated within an 
additional eight (8) days. 
All other SUSAR will be reported to the Competent Authority concerned and Ethics Committee as soon as possible but 
within a maximum of fifteen (15) days of first knowledge by the sponsor. 
SUSAR will be reported using the CIOMS form. 
8.10.3 
Annual safety report 
Once a year throughout the clinical study, Sponsor will provide the Competent Authority with an annual safety report. A 
final safety report will also be provided at study conclusion. The format will comply with national requirements. 
8.10.4 
Clinical study report 
The AE and SAE occurring during the study will be discussed in the safety evaluation part of the clinical study report. 
8.11 
Procedures in case of emergency 
Clinical Investigator is responsible for assuring that there are procedures and expertise available to cope with 
emergencies during the study.  
9 
DATA MANAGEMENT AND MONITORING 
9.1 
Database management 
All data will be collected and collated in the the web-based data management system, termed Viedoc, which includes 
web-based CRF with an ancillary eDatabase, randomization procedures, and validation of data, and which meets 
regulatory requirements for clinical therapy trials. This service will be purchased from the South-Eastern Norway 
Regional Health Authority’s Clinical Trial Unit, Oslo University Hospital. 
9.2  
CRF (case report forms) 
The designated investigator staff will enter the data required by the protocol into the electronic CRF. Clinical Investigator 
is responsible for assuring that data entered into the CRF is accurate and complete. The signature of Clinical 
Investigator will attest the accuracy of the data on each CRF. If any assessments are omitted, the reason for such 
omissions will be noted on the CRF. Corrections, with the reason, will also be recorded.  
After database lock, Principal Investigator will receive copies of the subject data for archiving at the investigational site. 

 
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9.3 
Source data  
The medical records for each patient will contain information which is important for the patient’s safety and continued 
care, and to fulfill the requirement that critical study data will be verifiable.  
To achieve this, the medical records of each patient should clearly describe at least: 
 
That the patient is participating in the study, e.g., by including the enrolment number and the study code or other 
study identification. 
 
Date when ICF was obtained from the patient and statement that patient received a copy of the signed and dated 
ICF. 
 
Results of all assessments confirming a patient’s eligibility for the study. 
 
Diseases (past and current, both the disease studied and others, as relevant). 
 
Treatments withdrawn/withheld due to participation in the study. 
 
Results of assessments performed during the study. 
 
ECOG performance status assessments conducted as part of the study. 
 
Treatments given, changes in treatments during the study, and the time points for the changes. 
 
Visits to the clinic and telephone contacts during the study, including those for study purposes only. 
 
Non-serious AE and SAE (if any), including causality assessments. 
 
Date of and reason for discontinuation from study treatment. 
 
Date of and reason for withdrawal from study. 
 
Date of death and cause of death, if available. 
 
Additional information according to local regulations and practice. 
9.4 
External Data and Safety Monitoring Committee 
The External Data and Safety Monitoring Committee (EDSMC) will oversee the trial during its entire course. EDSMC will 
consist of two board-certified specialists in oncology and one medical statistician, all of whom are independent from 
Sponsor and with no competing interests. EDSMC will review treatment response and safety data after each twentieth 
consecutive study patient has been accrued, or more frequently should there be a medical indication for a review 
identified by an EDSMC member or an investigator. 
EDSMC will have particular focus on data indicating unexpectedly good treatment responses (e.g., a ‘miraculous’ 
response leading to potential curation of patient), possible responses detrimental for experimental arm patients, and 
unexpected toxicities from the sequential therapy (i.e., SUSAR or SAE and SUSAR-like toxicities not foreseen and 
therefore not described in the study protocol). In case of such data, EDSMC will immediately confer with Study Conduct 
Group (c.f., Paragraph 11.3) about the immediate further conduct and management of the study. 
EDSMC actions related to interim analyses are detailed in Paragraph 10.4.2. If the number of PFS events in the 
experimental arm at any review is twice the number of PFS events in the control arm, EDSMC may consider early study 
termination. 
The EDSMC members will be: 
 
Dr. Marta Nyakas, MD PhD, Oslo University Hospital (expertise in clinical immune therapy studies) 
 
Dr. Svein Dueland, MD PhD, Oslo University Hospital (expertise in clinical CRC studies) 
 
Dr. Morten W. Fagerland, PhD, Oslo University Hospital (expertise in statistical methods in medical research) 
9.5 
Study monitoring 
Monitoring will be provided by the the South-Eastern Norway Regional Health Authority’s Clinical Trial Unit, Oslo 
University Hospital. Each local site will be visited on a regular basis by Monitor, who will check the following: 

 
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 
Informed consent process. 
 
Reporting of AE/SAE and all other safety data. 
 
Adherence to protocol. 
 
Maintenance of required regulatory documents. 
 
Study supply accountability. 
 
Facilities and equipment. 
 
Data completion on the relevant CRF documents, including source data verification. 
Monitor will review the relevant CRF documents for accuracy and completeness, and will ask the site staff to adjust any 
discrepancies as required.  
Sponsor’s representatives (e.g., monitors, auditors) and/or Competent Authorities will be allowed access to source data 
for source data verification in which case a review of those parts of the hospital records relevant to the study may be 
required. 
9.6 
Confidentiality 
Principal Investigator shall arrange for the secure retention of the patient identification and the code list. Patient files shall 
be kept for the maximum period of time permitted by each hospital. The study documentation (CRF, Investigator Site 
File, etc.) shall be retained and stored during the study and for 25 years after study closure. All information concerning 
the study will be stored in a safe place inaccessible to unauthorized personnel. 
10 
STATISTICAL METHODS AND DATA ANALYSIS 
10.1 Determination of sample size 
Calculation of sample size was performed for PFS – the primary end point – and based on PFS data from recent 
publications. A median PFS of 9 months was assumed for the standard-of-care (control arm) [Cartwright, 2012; Tveit et 
al., 2012; Cremolini et al., 2015]. Regarding the therapy concept of ICB, there is no PFS data published as yet for the 
setting of interest. In the study of patients with treatment-refractory metastatic CRC, median PFS was not reached in the 
cohort with mismatch repair-deficient disease at the time of reporting [Le et al., 2015]. In the study of previously 
untreated patients with advanced non-small cell lung cancer, which is a tumor entity with considerably poorer prognosis 
than advanced CRC, patients with PD-L1-positive tumors that were randomized to ICB showed median PFS of 10.3 
months compared to 6.0 months for standard chemotherapy [Reck et al., 2016]. 
Extrapolating to the setting of interest, with a median PFS of 9 months for standard-of-care, a median PFS twice as long 
(18 months) was entered for the sequential therapy. Assuming the exponential distribution of survival functions, the 
median PFS estimates were converted to hazard ratio (HR) of 0.5. Allowing for 10% censoring rate of subjects, the 
required sample size was estimated to be 40 patients in each arm to be able to show that HR of 0.5, implying the risk of 
a PFS event in the experimental group is 50% lower than in the control group, is significantly different from 1 with the 
power of 80% at significance level of 5%, given that log-rank test will be used. 
However, it was necessary with several adjustments of the above calculations to maintain sufficient power. First, the 
sample size was adjusted to enable removal of a maximum of 5% enrolled cases with non-MSS tumor before data 
analysis. Next, keeping in mind the condition of patients, it is not unlikely that some will be lost from the study before a 
valid PFS event has been reached. Also, a number of analyses stratified by primary tumor sidedness and (K)RAS/BRAF 
mutation status will be performed. Hence, to enable high enough power in the statistical analysis, the sample size was 
increased by an additional 20%. After incorporating the adjustments, the final sample size was estimated to be 100 
patients, 50 in each arm, with 1:1 randomization. 
With the total catchment populations of the participating centers (c.f., Paragraph 4.1) we envisage an accrual duration 
period of approximately 12 months to procure the sufficient number of study cases. As there is no PFS data published as 
of yet for the novel therapy concept of repeat sequential immunogenic chemotherapy and ICB, and further, the optimum 
duration of immune-modulating therapy is currently unknown (c.f., Paragraph 5.5), the study duration of the expected 

 
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longer-lasting arm (experimental arm) was estimated to 30 months (12 months following failure of treatment strategy). 
Because these estimates were pure conjecture, they were not entered into the sample size calculation. 
10.2 Randomization 
10.2.1 Randomization procedure 
The patients will be block-randomized into treatment arms with ratio 1:1 following a computer-randomized allocation 
sequence. The blocks will be defined according to sidedness and (K)RAS/BRAF mutation status of the primary tumor 
(right-sided versus left-sided and (K)RAS/BRAF wild-type versus mutation) (c.f., Paragraph 4.5). The allocation 
sequence will be generated by the web-based Viedoc system. 
10.2.2 Blinding 
Study Statistician (along with Study Radiologist) will not have access to the information on treatment arms before the 
study conduct is concluded and all analyses have been performed. An emergency unblinding for Study Statistician 
should not be required at any time of the study conduct since EDSMC will oversee the trial during its entire course (c.f., 
Paragraph 9.4). 
10.3 Populations for analysis 
The following study populations will be defined: 
 
Intention-to-treat population: Includes all randomized participants, regardless of protocol adherence. We expect 
about 5% of randomized patients to have non-MSS tumor. These patients will be excluded from the analysis post-
randomization. According to Fergusson and co-workers [Fergusson et al., 2002], such exclusion does not introduce 
bias and may be legitimate if an independent, blinded adjudication committee makes the decision on exclusion after 
evaluating all randomized patients. Sample size calculations include necessary adjustments to preserve the same 
power after exclusion of misdiagnosed patients. The sample size calculation has included necessary adjustments to 
maintain the same power after exclusion of patients with non-MSS tumor. 
 
Safety population: Includes all randomized participants who have received at least one dose of study medication 
and had at least one sequential safety-related observation. Subjects who withdraw from the study will be included in 
the safety analysis given the safety population criteria are otherwise met. A list of withdrawn subjects, preferably 
with the reasons for withdrawal, will be made. 
 
Per-protocol population: Includes all subjects who have adhered to all protocol-defined treatments and outcome 
assessments. 
We will account for all of the patients registered in the study. The number of patients who are not evaluable, or who die 
or withdraw before treatment has begun, will be specified. The distribution of follow-up time will be described and the 
number of patients lost to follow-up will be given. Start of follow-up will be defined as the date of randomization. 
10.4 Statistical analysis of clinical end points 
10.4.1 Main statistical analyses 
The main statistical analysis is planned after the last patient has fulfilled the pre-defined follow-up period. PFS will be 
calculated from the day of randomization to first recorded disease progression according to RECIST v1.1 or when 
applicable iRECIST, or death. Patients who have not had disease progression at the time of final analysis will be 
censored at the date last known to be alive and progression-free. The analyses will compare the treatment groups in 
total as well as groups stratified by primary tumor sidedness  and (K)RAS/BRAF mutation status. 
Deviation from the original statistical plan will be described and justified in the clinical study report. Amendments to plan 
can be done until the day of database lock. 
10.4.2 Interim analyses 
Interim analyses will particularly apply to data on safety, tolerability, possible detrimental effects, and curative outcomes, 
and will be based on purely clinical judgment by the EDSMC (c.f., Paragraph 9.4). In particular, CTCAE grade 3–5, PFS 

 
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measures considerably shorter than 9 months, CR/iCR, and secondary surgical curative resection events will be 
counted. These types of data will be reported as the number of events. 
10.4.3 Descriptive statistics 
Demographic and clinical characteristics will be presented as means and standard deviations, medians with minimum 
and maximum values, or frequencies and percentages, as appropriate. Further statistical analyses will be separated to 
primary analyses, including only comparison of primary end point between two treatment arms, and secondary analyses, 
including stratified analyses on primary and secondary end points as well as number of analyses on secondary end 
points. 
10.4.4 Primary analysis 
Median PFS time will be compared between study arms by drawing Kaplan-Meier survival curves and performing log-
rank test. HR with the corresponding 95% confidence interval (CI) and p-values will be estimated by Cox proportional 
hazards model. 
10.4.5 Secondary analyses 
Distribution of PFS times stratified by the primary tumor sidedness and (K)RAS/BRAF mutation status will be illustrated 
graphically by Kaplan-Meier curves and compared by log-rank test. To assess the hazard rates for disease progression 
within each strata, Cox proportional hazards model will be estimated and, if appropriate, adjusted for relevant covariates. 
The results will be presented as HR with the corresponding 95% CI and p-values. 
Safety: The number of SAE will be summarized and presented by trial arm and according to the MedDRA System Organ 
Class (www.meddra.org). In addition, information will be given on the number of SAE per participant, together with 
details on the causality, expectedness, and outcome of each SAE experienced. Summaries of SUSAR events will also 
be presented by trial arm. 
Tolerability: Summaries by trial arm will be produced to show the proportion of participants experiencing each grade of 
CTCAE toxicities overall and during each treatment cycle. For more detailed summaries, this information will also be 
broken down into the different types of toxicities. 
QoL: This will be summarized for each treatment arm at study enrolment, completion of the active therapy of the first 
treatment sequence (after 16 weeks), and disease progression, using the consensus modules EORTC QLQ-C30, 
EORTC QLQ-CIPN20, and EQ-5D-5L. The data will be illustrated graphically and presented as mean scores with 95% 
CI at separate time points. The differences in QoL between two treatment arms throughout the study period will be 
assessed by estimating a linear mixed model with fixed effects for time and treatment arm and the interaction between 
these two. Random effects for patients will be included. A significant interaction will quantify differences between the 
groups and serve as an omnibus test. 
Safety and tolerability in the treatment arms will be compared by χ2 or Fisher’s exact test, as appropriate. 
ORR is defined as the percentage of patients with a confirmed CR or PR. The proportion of participants achieving at 
least PR will be summarized with corresponding 95% CI for each treatment arm. The difference between the trial arms in 
the proportion of participants achieving at least PR will also be presented with corresponding 95% CI. The difference 
between participants achieving at least PR and remaining participants will be assessed using logistic regression 
adjusting for treatment group and stratification factors. Odds ratios with corresponding 95% CI and p-values will be 
presented for all variables incorporated in the model. 
SSCRR is defined as the percentage of patients with a confirmed resection of metastatic disease with microscopically 
free margin (R0). Corresponding analyses as those to be performed for ORR will be applied for SSCRR. 
DOR is defined as the time from the first documentation of CR/iCR or PR/iPR to disease progression. DOR Kaplan-
Meier curves will be drawn and compared by log-rank test. The median DOR with corresponding 95% CI will be 
presented by treatment group. Stratified analyses will be performed as well. The Cox proportional hazards model, 
adjusting for the stratification factors, will also be used to compare DOR between the treatment groups. HR, 95%CI and 
p-values will be presented for all variables incorporated in the model. 
OS is defined as the time from randomization to death of any cause. The same analyses as for DOR will be performed 
for OS. 

 
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The assumptions for the statistical method considered will be assessed by using standard techniques. In the case the 
assumptions are not met, the necessary adjustments for methods specified above will be introduced and reported. 
10.5 Analysis of other end points 
Cost modeling and validation will apply a model specifically developed for CRC by Investigator at Health Services 
Research Center, Akershus University Hospital [Joranger et al., 2015]. 
For exploratory analyses, appropriate statistical methods will be applied to analyze the various outcome measures. 
10.6 Statistical software 
SPSS Statistics, SAS, STATA, and GraphPad Prism (the most recent versions for all) are relevant software for statistical 
analyses of the study data. 
11 
STUDY MANAGEMENT 
11.1  
Study documentation 
All investigators must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented, including but not limited to the protocol, protocol amendments, ICF, and documentation of IRB approval. 
11.2  
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. All significant protocol deviations will be 
recorded and reported in the clinical study report. 
11.3 Study Conduct Group 
This will consist of the following investigators: 
 
Professor Anne Hansen Ree, Akershus University Hospital 
 
Professor Kjersti Flatmark, Oslo University Hospital 
 
Professor Halfdan Sørbye, Haukeland University Hospital 
 
Dr. Christian Kersten, Hospital of Southern Norway 
These investigators will communicate about study issues on regular basis and promptly whenever requested by other 
investigators or BMS. 
11.4 
Study amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study protocol must 
be reported to and approved by the Competent Authority and Ethics Committee according to EU and national 
regulations. 
11.5 Investigator Site File 
This will contain the following: 
 
letters 
 
all forms 
 
research protocol 
 
information for the subjects 

 
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 
questionnaires 
 
SOP documents for exploratory sub-studies 
 
information about the participating site and respective contact persons 
 
safety information 
 
progress reports and study results 
11.6 
Audit and inspections 
Authorized representatives of a Competent Authority, Ethics Committee, and BMS may visit the centers to perform 
inspections, including source data verification. Likewise, the representatives from Sponsor may visit the centers to 
perform an audit. The purpose of an audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported according to the protocol, ICH-GCP, and any applicable regulatory requirements. Principal 
Investigator, in cooperation with the actual Clinical Investigator, will ensure that the inspectors and auditors will be 
provided with access to source data and documents. 
12 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Compliance with laws and regulations 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and the principles of the Declaration 
of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater 
protection to the individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting), in addition with the EU Clinical Trial Directive 
(2001/20/EC). The protocol will also have been registered in the ClinicalTrials database (www.ClinicalTrials.gov) before 
inclusion of the first patient. 
12.2 
ICF (informed consent form) 
The definition of informed consent is given in Paragraph 7.1. 
The ICF will contain separate sections that address any hazards related to the biopsy sampling and how a possible 
complication may delay the commencement of the treatment, and also the use of samples in the study biobank and of 
the study-specific MR sequences for exploratory research. Clinical Investigator or a designee will explain to each patient 
the objectives of the exploratory research. The patient’s ICF signature documents his/her agreement to allow specimens 
to be used for exploratory research. 
The consent forms should be revised whenever there are changes to study procedures or when new information 
becomes available that may affect the willingness of patient to participate. The final revised IRB/IEC-approved consent 
forms must be provided to Sponsor for health authority submission purposes. 
Patients must be reconsented to the most current version of the consent form (or to a significant new information/findings 
addendum in accordance with applicable laws and IRB/IEC policy) during their participation in the study. For any 
updated or revised consent form, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the updated/revised consent form for continued 
participation in the study. 
A copy of each signed ICF must be provided to the patient. All signed and dated ICF documents must remain in each 
patient’s study file or Investigator Site File and must be available for verification by study monitors at any time. 
12.3 
Ethics Committee  
This protocol, the ICF, any information to be given to the patient, and relevant supporting information have been 
submitted to the Ethics Committee and have been reviewed and approved according national regulations. This will also 
be valid for any amendments and/or new versions of the study protocol (amended protocol). 

 
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12.4 
Confidentiality 
Sponsor will maintain confidentiality standards by coding each patient enrolled on the study through assignment of a 
unique patient identification number. This means that patient names are not included in data sets. 
Patient medical information obtained by this study is confidential and may be disclosed to third parties only as permitted 
by the ICF (or separate authorization for use and disclosure of personal health information) signed by the patient, unless 
permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate medical personnel responsible 
for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of the Competent 
Authority, Sponsor, and Monitor. 
13 
STUDY FUNDING 
The study has received funding from the Norwegian Cancer Society (Grant 182496) with associated funding from the 
University of Oslo. BMS supports the study through the provision of nivolumab at no cost for the investigators. 
14 
TRIAL INSURANCE 
The investigators have insurance coverage for this study through membership of the Drug Liability Association. 
15 
PUBLICATION POLICY 
Upon study completion and finalization of the study report, the results of this study will be submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
The results of this study will also be submitted to the Competent Authority and the Ethics Committee according to EU 
and national regulations. 
All personnel who have contributed significantly to the planning and performance of the study may be included in the list 
of authors, according to the Vancouver Protocol: Uniform Requirements for Manuscripts Submitted to Biomedical 
Journal. 
16 
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17 
APPENDICES 
Appendix 1 – Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Please click on links below or copy and paste them into your browser: 
http://recist.eortc.org/recist-1-1-2/ 
http://recist.eortc.org/wp-content/uploads/2015/03/RECISTGuidelines.pdf 
http://www.radiologytutor.com/index.php/cases/oncol/139-recist 
 
Appendix 2 – RECIST for immune-modulating therapies (iRECIST) 
Comparison of RECIST v1.1 and iRECIST: 
 

 
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Appendix 3 – Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
Please click on links below or copy and paste them into your browser: 
HTTPS://EVS.NCI.NIH.GOV/FTP1/CTCAE/CTCAE_4.03_2010-06-
14_QUICKREFERENCE_5X7.PDF 
https://www.uptodate.com/contents/common-terminology-criteria-for-adverse-events 
 
Appendix 4 – Eastern Cooperative Oncology Group (ECOG) performance status 
 

 
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Appendix 5 – Management algorithms for adverse events of immuno-oncology agents 
and regimens 
Please refer to the content of the specific document provided by BMS. 
 
Appendix 6 – Management algorithms for adverse events caused by the Nordic FLOX 
regimen 
The below criteria come to use each time a new series of FLOX cycles is commenced (irrespective of study treatment 
arm). 
CTCAE grade 
Description 
Oxaliplatin 
Fluorouracil 
Diarrhea, grade 2 
Increase of 4-6 stools per day over 
baseline; moderate increase in 
stoma output compared to baseline; 
not interfering with ADL 
Interrupt until grade 1, then 
100% dose first time, 75% 
dose second time, 50% 
dose third time 
Interrupt until grade 1, then 
100% dose first time, 75% 
dose second time, 50% 
dose third time 
Diarrhea, grade 3 
Increase of 7 or more stools per day 
over baseline; incontinence; severe 
increase in stoma output compared 
to baseline; interfering with ADL 
Interrupt until grade 1, then 
75% dose first time, 50% 
dose second time, 
discontinue third time 
Interrupt until grade 1, then 
75% dose first time, 50% 
dose second time, 
discontinue third time 
Diarrhea, grade 4 
Life-threatening consequences, 
urgent intervention indicated 
Discontinue 
Discontinue 
Myelosuppression, grade 2 Neutrophils of 1.0 to less than 1.5, 
or platelets of 50 to less than 75 
Interrupt until grade 1, then 
100% dose first time, 75% 
dose and consider support 
with granulocyte-colony 
stimulating factor (e.g., 
pegfilgrastim) second or 
subsequent times 
Interrupt until grade 1, then 
100% dose first time, 75% 
dose and consider support 
with granulocyte-colony 
stimulating factor (e.g., 
pegfilgrastim) second or 
subsequent times 
Myelosuppression, grade 3 Neutrophils of 0.5 to less than 1.0, 
or platelets of 25 to less than 50 
Interrupt until grade 1, then 
75% dose and consider 
support with granulocyte-
colony stimulating factor 
(e.g., pegfilgrastim) first or 
subsequent times 
Interrupt until grade 1, then 
75% dose and consider 
support with granulocyte-
colony stimulating factor 
(e.g., pegfilgrastim) first or 
subsequent times 
Myelosuppression, grade 4 Neutrophils of less than 0.5, or 
platelets less than 25 
Interrupt until grade 1, then 
50% dose and consider 
support with granulocyte-
colony stimulating factor 
(e.g., pegfilgrastim) first or 
subsequent times 
Interrupt until grade 1, then 
50% dose and consider 
support with granulocyte-
colony stimulating factor 
(e.g., pegfilgrastim) first or 
subsequent times 
Sensory neuropathy, 
grade 2 
Sensory alteration or paresthesia 
persisting between two oxaliplatin 
doses with no or only minor 
improvement, moderate symptoms, 
limiting instrumental ADL 
Interrupt until grade 1, then 
75% dose first time, 50% 
dose second time, 
discontinue third time 
NA 
Sensory neuropathy, 
grade 3 
Sensory alteration or paresthesia, 
severe symptoms, limiting self-care 
ADL 
Discontinue 
NA 
Units of measurement: neutrophils, x109/L; platelets, x109/L. 
Abbreviations: ADL, activity of daily life; CTCAE, Common Terminology Criteria for Adverse Events; NA; not applicable. 

 
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Appendix 7 – EORTC QLQ-C30 specimen questionnaire 
Please click on the link below or copy and paste it into your browser. A Norwegian version is available in Investigator 
Site File. 
http://groups.eortc.be/qol/sites/default/files/img/slider/specimen_qlq-c30_english.pdf 
 
Appendix 8 – EORTC QLQ-CIPN20 questionnaire 
The form can be requested from justyna.mierzynska@eortc.be. A Norwegian version is available in Investigator Site 
File. 
Chemotherapy-induced peripheral neuropathy (CIPN) is a major, potentially dose-limiting side effect of various 
chemotherapeutic agents. The CIPN20 is a 20-item quality of life questionnaire, which has been developed to elicit 
patients’ experience of symptoms and functional limitations related to CIPN. The CIPN20 has 3 subscales: a sensory, a 
motor, and an autonomic subscale. In combination with the more classical, physician-based clinical rating scales, the 
CIPN20 should yield a more complete picture of the nature, frequency, and severity of CIPN in a wide range of oncology 
patient populations. 
 
Appendix 9 – EQ-5D-5L questionnaire user guide 
Please click on the link below or copy and paste it into your browser. A Norwegian version of the questionnaire is 
available in Investigator Site File. 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf 
 
Appendix 10 – Council for International Organizations of Medical Sciences (CIOMS) 
Suspect Adverse Reaction Report form 
Please click on the link below or copy and paste it into your browser: 
http://www.basg.gv.at/fileadmin/_migrated/content_uploads/CIOMS_form.pdf