Conditions: Colon Cancer
Keywords: Aspirin colon cancer stage II stage III PIK3CA double-blind placebo Adjuvant Treatment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1040
Healthy volunteers: no

Brief summary:
Following complete resection of their primary tumor, potentially eligible stage II or stage III colon cancer patients will undergo central PIK3CA testing. Patients with somatic mutations will be 2:1 randomized to daily aspirin 100 mg versus placebo for a a maximum of 3 years or until disease recurrence, patient death or withdrawal of consent, whichever occurs first. Patients will be followed up for at least 3 years from the date of surgery.

The intake of aspirin or placebo is independent of adjuvant chemotherapy, and does not impact on the indication to give (or not to give) adjuvant chemotherapy.

Detailed description:
Colorectal cancer is the third most common malignancy for both women and men and is responsible for almost 10% of all cancer death. Despite complete removal of the tumor and use of adjuvant chemotherapy, up to 25% of patients with stage II colon cancer and up to 50% of patients with stage III disease will suffer from recurrences, which is associated with poor prognosis.

Several retrospective observations have documented a favorable effect of long-term intake of oral aspirin for the prevention of colorectal cancer in different clinical situations. Regular intake of aspirin after the diagnosis of colorectal cancer may also be associated with a lower risk of colorectal cancer-specific and overall mortality. Two recent publications in prestigious medical journals provided retrospective evidence that patients with PIK3CA-mutated colon cancer may derive a very substantial benefit from daily oral aspirin. Both analyses showed a roughly 85% reduction of the risk for tumor relapse compared to patients who did not take aspirin. However, a potential selection bias in these retrospective analyses cannot be excluded with certainty. These extremely interesting and intriguing findings must be confirmed in a randomized controlled trial to potentially change clinical practice.

The trial objective is to demonstrate a statistically significant and clinically relevant disease-free survival benefit in stage II and III PIK3CA mutated colon cancer patients taking daily adjuvant aspirin for 3 years.

Patients with resected colon cancer stage II or stage III bearing somatic mutations in exon 9 or 20 of PIK3CA will be 2:1 randomized to daily adjuvant aspirin 100 mg versus placebo for a maximum of 3 years or until disease recurrence, patient death or withdrawal of consent, whichever occurs first. Patients will be followed up for at least 3 years from the date of surgery. The intake of aspirin or placebo is independent of adjuvant chemotherapy, and does not impact on the indication to give (or not to give) adjuvant chemotherapy.

Arms:
arm 1: Asprin 100 mg daily for maximum 3 years standard chemo if indicated arm 2: Placebo daily for maximum 3 years standard chemo if indicated

Interventions: intervention 1: Aspirin intervention 2: Placebo
Intervention descriptions: intervention 1: Aspirin 100 mg daily intervention 2: Placebo

Protocol document:
Prot_SAP_000.pdf: 
SAKK 41/13-Aspirin                                        Version 4.0, 11.11.2021                                                        Page 1 of 59 
SAKK - SWISS GROUP FOR CLINICAL CANCER RESEARCH 
Protocol SAKK 41/13-Aspirin 
Adjuvant aspirin treatment in PIK3CA mutated colon 
cancer patients. A randomized, double-blinded, 
placebo-controlled, phase III trial. 
Protocol version: 
Version 4.0: amended version incl. amendments 1-3, 11.11.2021 
Activation date:  
April 26, 2016 
SNCTP No. SNCTP000001339 
 
 
EudraCT No. 2015-001482-57  
Copyright © 2015 by SAKK 
Study type: 
Clinical trial with Investigational Medicinal Product (IMP)  
Categorization: 
Risk category B according to the Human Research Act (HRA) and its 
ordinance KlinV/Oclin 
Coordinating Investigator: 
Prof. Dr. med Ulrich Güller, MHS, FEBS  Phone: +41 58 636 27 77 
 
Medical Oncology 
 
 
Spital STS AG Thun 
ulrich.gueller@spitalstsag.ch 
Supporting Coordinating: 
PD Dr. med Dr. rer nat Markus Joerger Phone: +41 76 559 10 70 
Investigators 
Medical Oncology 
Fax: +41 71 494 63 25 
 
Cantonal Hospital, St. Gallen 
markus.joerger@kssg.ch 
 
Dr. med Dr. Daniel H. Horber 
Phone: +41 71 494 35 69 
  
Medical Oncology 
Fax: +41 71 494 63 25 
 
Cantonal Hospital, St. Gallen 
daniel.horber@kssg.ch 
 
Prof. Dr. med Arnaud Roth 
Phone: +41 22 372 77 44 
  
Surgical Oncology 
Fax: +41 22 372 77 45 
 
University Hospital, Geneva 
arnaud.roth@hcuge.ch 
Central pathologist: 
Prof. Wolfram Jochum  
Phone: +41 71 494 21 01 
 
Pathology Institute 
Fax: +41 71 494 28 94 
 
Cantonal Hospital, St. Gallen 
wolfram.jochum@kssg.ch 
Statistician: 
Dr. Stefanie Hayoz  
Phone: +41 31 508 42 20
 
SAKK CC, Bern  
stefanie.hayoz@sakk.ch 
Clinical Project Manager: 
Dr. Karin Rothgiesser 
Phone: +41 31 508 41 57
 
SAKK CC, Bern  
karin.rothgiesser@sakk.ch 
 
 
Sponsor:  
Swiss Group for Clinical Cancer Research 
  
Bern, Switzerland 
Internet-based registration: 
www.sakk.ch/edc 


Adjuvant aspirin for colon cancer 
 
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Trial information: 
SAKK CC  
Phone: +41 31 389 91 91 
 
Effingerstrasse 33                                
    
 
CH – 3008 Bern 
                              trials@sakk.ch 
Opening hours: 
                              Mon-Fri 8:00 am to 5:00 pm 
SAKK Portal: 
portal.sakk.ch 
 
 
CONFIDENTIALITY 
The information contained in this document is confidential and the property of SAKK (or “sponsor”). 
The information may not - in full or in part - be transmitted, reproduced, published, or disclosed to 
others than the applicable Competent Ethics Committee(s) and Regulatory Authority(/ies), involved 
pharmaceutical companies and any other stakeholders without prior written authorization from the 
sponsor except to the extent necessary to obtain informed consent from those who will participate 
in the study. The study is performed along applicable transparency rules and is published on publicly 
available registries (e.g. SNCTP, clinicaltrials.gov)  




Adjuvant aspirin for colon cancer 
 
Page 4 of 59                                                     Version 4.0, 11.11.2021                                               SAKK 41/13-Aspirin 
PROTOCOL SIGN-OFF PAGE PROTOCOL VERSION 4.0 FOR THE 
PRINCIPAL INVESTIGATOR 
 
 
SAKK 41/13-Aspirin. Adjuvant aspirin treatment in PIK3CA mutated colon cancer patients. A 
randomized, double-blinded, placebo-controlled, phase III trial. 
 
Principal Investigator in:  ____________________________________________________  
Having read and understood protocol version 4.0, I agree to conduct the trial as specified in the 
protocol, current version of the World Medical Association Declaration of Helsinki, the ICH-GCP 
guidelines and the local legally applicable requirements. Version 4.0 may only be implemented after 
the responsible ethics committee and the competent authority have accepted amendment 3. 
Name:  ________________________  
Title: 
 ___________________________  
Date: 
 ________________________  
Signature:  ___________________________  
 


SAKK 41/13-Aspirin                                        Version 4.0, 11.11.2021                                                        Page 5 of 59 
ABBREVIATIONS 
AE 
Adverse event 
ASR 
Annual safety report 
CEA 
Carcinoembryonic antigen 
CI 
Confidence interval  
COX-2 
Cyclooxygenase-2  
CDM 
Clinical Data Manager 
CPM 
Clinical Project Manager 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CSS 
Cancer-specific survival 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DCN 
Drug code number 
DFS 
Disease-free survival 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESMO 
European Society of Medical Oncology 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
HFV 
Humanforschungsverordnung 
HLA 
Human leukocyte antigen 
HR  
Hazard ratio  
HRA 
Human Research Act 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational medicinal product 
KlinV 
Verordnung über klinische Versuche in der Humanforschung  
KOFAM 
Koordinationsstelle Forschung am Menschen 
MSI 
Microsatellite instability  
NCI 
National Cancer Institute  
NSAID 
Non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OClin 
Ordonnance sur les essais cliniques dans le cadre de la recherche sur l’être humain 
ORH  
Ordonnance relative à la recherche sur l'être humain 
OTC 
Over-the-counter 
OS  
Overall survival 
PIK3CA 
phosphatidylinositol-4,5-biphosphonate 3-kinase 
PD 
Progressive disease 
PP 
Per protocol 
PQC 
Product quality complaint 


Adjuvant aspirin for colon cancer 
 
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PS 
Performance status 
RSI 
Reference safety information 
SAE 
Serious adverse event 
SAKK 
Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung 
SAKK CC 
SAKK Coordinating Center 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SDL 
Source data location 
SDV 
Source data verification 
SGG//SSG 
Schweizerische 
Gesellschaft 
für 
Gastroenterologie/ 
Société 
Suisse 
de 
Gastroentérologie/ Società Svizzera di Gastroenterologia  
SNCTP 
Swiss National Clinical Trials Portal 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TTR 
Time to recurrence  
ULN 
Upper limit of normal 
UPN 
Unique patient number 
WHO 
World Health Organization 


SAKK 41/13-Aspirin                                        Version 4.0, 11.11.2021                                                        Page 7 of 59 
TABLE OF CONTENTS 
PROTOCOL SIGN-OFF PAGE 
3 
ABBREVIATIONS 
5 
TABLE OF CONTENTS 
7 
1 TRIAL OVERVIEW SAKK 41/13-ASPIRIN 
10 
2 INTRODUCTION AND BACKGROUND 
14 
2.1 
Disease background 
14 
2.2 
Therapy background 
14 
2.3 
Rationale for performing the trial 
14 
2.4 
Choice of aspirin dosage 
15 
2.5 
Choice of design and comparator 
15 
2.6 
Choice of study population 
16 
3 OBJECTIVES AND ENDPOINTS 
17 
3.1 
Objective 
17 
3.2 
Endpoints 
17 
3.3 
Additional research questions 
17 
4 TRIAL DESIGN 
17 
4.1 
Methods of minimizing bias 
18 
5 TRIAL DURATION AND TERMINATION 
18 
6 SELECTION OF PATIENTS 
20 
6.1 
Inclusion criteria 
20 
6.2 
Exclusion criteria 
20 
7 REGISTRATION AND RANDOMIZATION 
22 
7.1 
Pre-registration procedure (PIK3CA mutation screening) 
22 
7.2 
At registration and randomization 
22 
7.3 
Blinding procedure and allocation of a drug code number (DCN) 
23 
7.4 
After randomization 
23 
7.5 
Unblinding procedures 
23 
8 DRUG SUPPLY AND HANDLING 
25 
8.1 
Drugs in protocol 
25 
8.2 
Drug supply and handling of aspirin and placebo 
25 
8.3 
Product quality complaint handling 
26 
8.4 
Other drugs for anticancer treatment outside protocol 
27 
9 TRIAL TREATMENT 
28 
9.1 
Treatment overview 
28 
9.2 
Therapy with aspirin/placebo 
28 
9.3 
Treatments not permitted during trial treatment phase 
28 
9.4 
Treatment duration 
29 
9.5 
Concomitant adjuvant chemotherapy 
29 
9.6 
Precaution 
29 
10 ADVERSE 
EVENT 
REPORTING, 
DOSE 
MODIFICATIONS 
AND 
SUPPORTIVE 
TREATMENT 
30 
10.1 Definition of adverse event (AE) 
30 
10.2 Reporting of AEs 
30 
10.3 Aspirin-related adverse events 
31 
10.4 Safety parameters 
31 


Adjuvant aspirin for colon cancer 
 
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10.5 General remarks on dose modifications and treatment interruption 
31 
11 SAFETY REPORTING 
32 
11.1 Definition of serious adverse event (SAE) 
32 
11.2 Definition of serious adverse reaction (SAR) 
32 
11.3 Definition of suspected unexpected serious adverse reactions (SUSARs) 
32 
11.4 Reporting of SAEs and pregnancy 
32 
11.5 Procedure for reporting individual SAEs by the investigator 
33 
11.6 Reporting of individual SAEs and SUSARs by the sponsor 
33 
11.7 Reporting of safety signals 
34 
11.8 Periodic reporting on safety to principal investigators and regulatory authorities 
34 
12 EVALUATIONS AND INVESTIGATIONS BEFORE, DURING AND AFTER TRIAL 
TREATMENT 
35 
12.1 Pretreatment evaluations and procedures 
35 
12.2 Evaluations during trial treatment 
35 
12.3 Evaluations in the follow-up phase 
37 
13 CRITERIA OF EVALUATION AND DEFINITION OF ENDPOINTS 
39 
13.1 Criteria of evaluation 
39 
13.2 Definition of Endpoints 
39 
14 DOCUMENTATION 
40 
14.1 CRFs and reports 
40 
14.2 Notes for special handling of CRFs 
40 
14.3 Source data 
40 
15 STATISTICAL CONSIDERATIONS 
41 
15.1 Sample size estimation 
41 
15.2 Interim efficacy analyses 
42 
15.3 Statistical analyses 
42 
15.4 Handling of missing data and drop-outs 
42 
16 QUALITY OF LIFE 
43 
17 PATHOLOGY 
43 
17.1 Local pathology 
43 
17.2 Central PIK3CA mutation analysis 
44 
17.3 Pathology samples banking 
44 
18 TRANSLATIONAL RESEARCH 
45 
18.1 Rationale and aims 
45 
18.2 Samples and schedule of sampling 
47 
18.3 Sample biobanking 
48 
19 DIAGNOSTIC SUBSTUDY 
48 
20 ECONOMIC EVALUATION 
48 
21 INDEPENDENT RESPONSE REVIEW 
48 
22 ETHICAL CONSIDERATIONS 
49 
22.1 Risks/benefits 
49 
22.2 Trial categorization 
49 
22.3 Patient information and informed consent 
49 
22.4 Premature withdrawal 
50 
22.5 Patient information at trial unblinding 
50 
23 ADMINISTRATIVE CONSIDERATIONS 
51 


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23.1 Insurance 
51 
23.2 Monitoring and auditing 
51 
23.3 Quality control and quality assurance 
51 
23.4 Trial activation procedure 
52 
23.5 Local trial records 
52 
23.6 Trial registration 
53 
23.7 Participation of local and foreign sites 
53 
23.8 Modifications of the protocol 
53 
23.9 Trial termination 
53 
24 PUBLICATION 
54 
25 CONFIDENTIALITY 
54 
25.1 Copyright 
54 
25.2 Confidentiality 
54 
26 REFERENCES 
55 
27 APPENDICES 
58 
Appendix 1 
TNM Classification 
58 
Appendix 2 
Calculation of creatinine clearance 
59 
Appendix 3 
WHO performance status 
59 
Appendix 4 
New York Heart Association (NYHA) classification 
59 
 
 
 


Adjuvant aspirin for colon cancer 
 
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1 
TRIAL OVERVIEW SAKK 41/13-ASPIRIN 
SAKK 41/13-Aspirin. Adjuvant aspirin treatment in PIK3CA mutated colon cancer patients.  
A randomized, double-blinded, placebo-controlled, phase III trial. 
 
Sponsor: Swiss Group for Clinical Cancer Research (SAKK) 
Trial registry No.:  Swiss National Clinical Trial Portal (SNCTP): SNCTP000001339 
 
Cancer Clinical Trials Registry (ClinicalTrials.gov): NCT02467582  
 
European Clinical Trials Database (EudraCT): 2015-001482-57 
Coordinating investigator: Prof. Dr. med. Ulrich Güller, Spital STS AG Thun, Switzerland 
TRIAL TYPE AND CATEGORISATION 
Clinical trial with IMP (including placebo as comparator). 
Aspirin is a medication with marketing authorization in Switzerland and EU as an analgesic, anti-
inflammatory and antipyretic drug and, at low dose, for the prevention and treatment of 
cardiovascular and cerebrovascular diseases. In this trial, low dose aspirin (i.e. 100 mg) will be used 
daily during 3 years for the adjuvant treatment of colon cancer. According to the Swiss HRA and its 
corresponding ordinance KlinV/Oclin on clinical trials, this trial is classified as category B. 
OBJECTIVE 
The trial objective is to demonstrate a statistically significant and clinically relevant disease-free 
survival benefit in stage II and III PIK3CA mutated colon cancer patients taking daily adjuvant aspirin 
for maximum 3 years. 
ENDPOINTS 
Primary endpoint: 
 
Disease-free survival (DFS) 
Secondary endpoints: 
 
Time to recurrence (TTR) 
 
Overall survival (OS) 
 
Cancer-specific survival (CSS) 
 
Adverse events (AEs)  
Additional research questions: 
Patient’s tumor will be investigated for the identification of predictive and prognostic markers for the 
response to adjuvant therapy with aspirin and for the assessment of the biology of aspirin-mediated 
response. 
 
 


SAKK 41/13-Aspirin                                        Version 4.0, 11.11.2021                                                        Page 11 of 59 
TRIAL DESIGN 
International, multicenter, randomized, double-blinded, placebo-controlled, phase III trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The concomitant use of adjuvant chemotherapy for stage III and high risk stage II colon cancer 
according to international treatment guidelines is allowed (chemotherapy regimens include 
intravenous 5-fluorouracil or oral capecitabine either alone or in combination with intravenous 
oxaliplatin). 
SELECTION OF PATIENTS  
Refer to section 6 for the full list of inclusion/exclusion criteria  
 
Histologically confirmed diagnosis of adenocarcinoma of the colon 
 
Stage II (pT3/T4 N0 cM0) or stage III (pTx pN+ cM0) disease 
 
Presence of predefined, activating PIK3CA mutation in exons 9 or 20  
 
Complete curative tumor resection (R0) within 14 weeks maximum before registration 
 
Adequate performance status (PS 0-2) and hematological values 
 
No multiple adenocarcinomas of the colon  
 
No rectal cancer 
 
No severe or uncontrolled cardiovascular disease 
 
No upper gastrointestinal bleeding within 12 months prior to registration; no bleeding disorder 
that is an absolute contraindication to the use of aspirin  
 
No regular intake of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs) 
or cyclooxygenase (COX)-2 inhibitors 
 
No systemic rheumatic diseases or degenerative disorders affecting the musculoskeletal system 
with a relevant risk of requiring treatment with NSAIDs in the future 
 
No concurrent treatment with other experimental drugs, no administration of concomitant drugs 
contraindicated for use with the trial drug (the concomitant use of adjuvant chemotherapy for 
Stage II or stage III colon cancer 
PIK3CA testing 
mutated PIK3CA 
RANDOMIZATION 
2:1 
Aspirin 100 mg 
daily for maximum 3 years 
Standard chemo if indicated 
Placebo 
daily for maximum 3 years 
Standard chemo if indicated 
Follow up 
at least 3 up to 10 years from the date of surgery 


Adjuvant aspirin for colon cancer 
 
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stage III and high risk stage II colon cancer according to international treatment guidelines is 
allowed)  
TRIAL DURATION 
Duration of accrual: Initially planned 3 years, actual duration until premature closure of the trial (see 
section 5) 4.5 years  
Duration of trial therapy (per patient): maximum 3 years (or until recurrence, death or consent 
withdrawal) 
Duration of the follow-up (per patient): at least 3 years (from the date of surgery) 
Duration of trial (in total): 7.5 years 
The trial may be stopped early based on the results of two interim efficacy analyses or if new scientific 
data become available which change assessment of risk/benefit.  
TRIAL SCHEDULE 
Trial activation: Q2 2016  
First patient in: Q2 2016  
Last patient in: Q2 2019 (initially planned); Q4 2020 (after premature closure) 
Last patient last treatment: Q2 2022 (initially planned); Q2 2021 (after premature closure) 
Last patient last visit: Q2 2029 (initially planned); Q4 2023 (planned after premature closure) 
TRIAL PRODUCT 
Aspirin® (acetylsalicylic acid) is a salicylate drug that has analgesic, anti-inflammatory, antipyretic 
and antiplatelet properties. Aspirin is part of a group of medications called non-steroidal anti-
inflammatory drugs, but differs from most other NSAIDs in the mechanism of action.  
The comparator used in this trial is placebo, and both, aspirin or placebo are taken orally once daily. 
TRIAL TREATMENT 
Patients with resected colon cancer stage II or stage III bearing somatic mutations in exon 9 or 20 
of PIK3CA will be 2:1 randomized to daily adjuvant aspirin 100 mg versus placebo for a maximum 
of 3 years or until disease recurrence, patient death or withdrawal of consent, whichever occurs first. 
Patients will be followed up for at least 3 years from the date of surgery. 
The intake of aspirin or placebo is independent of adjuvant chemotherapy, and does not impact on 
the indication to give (or not to give) adjuvant chemotherapy. 
MEASUREMENTS AND PROCEDURES  
Following complete resection of their primary tumor, potentially eligible stage II or stage III colon 
cancer patients will undergo PIK3CA testing. Mutation screening will be performed centrally in 
archived formalin-fixed paraffin-embedded (FFPE) tumor tissue. Baseline assessments before trial 
treatment include clinical examination and blood testing for safety parameters and tumor marker. 
The trial therapy consists in daily aspirin (100 mg) or placebo per os.  
The schedule of assessments during trial treatment and in the follow-up phase is in line with the 
guidelines from the Swiss Association for Gastroenterology (SGG/SSG) and the European Society 
of Medical Oncology (ESMO) for the follow-up of patients with colon cancer. Clinical examinations 
and carcinoembryonic antigen (CEA) measurements are to be performed every 3 months during the 
first 2 years following surgery, thereafter every 6 months until year 5. Bleeding-related adverse 
events potentially related to trial medication are to be recorded throughout trial treatment. 
Colonoscopy will be performed at year 1 and 4 following surgery, whereas computer tomography 
(CT) of the chest and abdomen are to be performed once a year. From year 6 to 10, disease and 


SAKK 41/13-Aspirin                                        Version 4.0, 11.11.2021                                                        Page 13 of 59 
survival status will be collected yearly. After recurrence, only survival status will be recorded for up 
to 10 years from surgery. 
 
 
STATISTICAL CONSIDERATIONS 
The sample size is based on the primary endpoint disease-free survival (DFS). Using a type I error 
of 5%, a power of 80% and a randomization ratio of 2:1, 43 events will be needed to show superiority 
of the aspirin arm under the alternative hypothesis that the hazard ratio (HR) is 0.456 (corresponding 
to a 3-year DFS of 70% in the placebo arm and 85% in the aspirin arm assuming constant hazards). 
The sample size needed is 185 patients (123 in the aspirin arm, 62 in placebo arm); the number 
needed to screen is estimated to be 1850 patients. All efficacy endpoints will be analyzed based on 
the full analysis population. The treatment effect will be assessed using Cox regression models with 
the treatment arm as independent variable and the stratification factors as strata. 
GCP STATEMENT 
This study will be conducted in compliance with the protocol, the current version of the Declaration 
of Helsinki, the ICH/GCP as well as Swiss and European legal and regulatory requirements. 
 


Adjuvant aspirin for colon cancer 
 
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2 
INTRODUCTION AND BACKGROUND 
2.1 
Disease background 
Colorectal cancer is the third most common malignancy for both women and men and is responsible 
for almost 10% of all cancer deaths [1]. Each year an estimated one million patients are diagnosed 
worldwide with colorectal cancer and about half will eventually die of it [2]. Particularly, the dramatic 
rise in the incidence of colorectal cancer in the 3rd, 4th and 5th decade is concerning [3]. Hence, 
colorectal cancer represents a tremendous public health problem. 
2.2 
Therapy background 
Patients with stage II and III colorectal cancer usually undergo an oncologic resection including en 
bloc lymphadenectomy. Stage III patients (node-positive) generally receive adjuvant chemotherapy. 
Stage II (node-negative) colorectal cancer patients may receive adjuvant chemotherapy if high risk 
features are present (e. g. poor differentiation, lymphovascular invasion, perineural invasion, T4 
tumor stage, ileus).  
Despite complete removal and use of adjuvant chemotherapy, up to 25% of stage II patients [4] and 
up to 50% of stage III will suffer from recurrences [5, 6], which is associated with poor prognosis. 
This remains an unsettling problem for surgical and medical oncologists. Tremendous efforts have 
been undertaken to improve the prognosis of completely resected colon cancer patients. Indeed, 
several randomized controlled trials were performed adding irinotecan [7], vascular endothelial 
growth factor (VEGF)-A antibodies [8, 9] or epidermal growth factor receptor (EGFR) antibodies [10] 
to standard chemotherapy. However, all these efforts failed. Hence, there is a strong need for novel 
strategies to decrease the high recurrence rate in stage II and III colon cancer patients. 
2.3 
Rationale for performing the trial 
Previous trials 
Many observational and even randomized studies have provided evidence for a protective effect of 
aspirin on colorectal cancer. In a randomized, double-blinded trial 635 patients with previous 
colorectal cancer were allocated to aspirin 325 mg daily versus placebo. After a median follow-up of 
12.8 months, one or more adenomas were found in 17% of patients in the aspirin group versus 27% 
in patients taking placebo (p=0.004) [11]. In the Nurses’ Health Study, a prospective US cohort study, 
27`077 patients were analyzed. After risk-adjusting in multivariable analyses, patients taking regular 
aspirin had a significantly lower risk of developing colorectal adenomas. Moreover, there was a clear 
association between higher daily aspirin doses and lower risk of colorectal adenomas [12].  
In October 2012, a retrospective analysis based on 2 prospective cohort studies was published in 
the New England Journal of Medicine [13], which evaluated the effect of aspirin after diagnosis of 
colorectal cancer in relation to phosphatidylinositol-4,5-biphosphonate 3-kinase (PIK3CA)-
mutational status. Patients with PIK3CA-mutated colorectal cancer taking aspirin had a large 
beneficial effect on both cancer-specific (hazard ratio (HR): 0.18; 95% confidence interval (CI) [0.05 
- 0.60], p<0.001) and overall survival (HR: 0.57; 95% CI [0.33 - 0.94], p=0.01). The improvements of 
cancer-specific and overall survival were both statistically significant as well as clinically relevant. 
Conversely, no effect whatsoever was observed in patients with PIK3CA wild type. 
In a recently published retrospective study based on prospective data [14] 896 patients after 
resection of colorectal cancer were analyzed for PIK3CA mutations. Patients with PIK3CA mutation 
taking regular low-dose aspirin were found to have a significantly lower risk of colorectal cancer 
recurrence (HR 0.11; 95% CI 0.001 - 0.832; p=0.027) compared to those not taking aspirin. Similarly 
to the publication by Liao et al. [13], no difference in recurrence-free survival was observed between 
patients who did and did not take aspirin in the PIK3CA wild type subset (HR: 0.92; 95% CI 0.60 - 
1.42, p=0.71) 
It is hypothesized that the inhibition of cyclooxygenase-2 (COX-2) through aspirin down regulates 
the PIK3CA signaling activity resulting in an inhibition of tumor cell proliferation [15]. COX-2 is an 
important mediator of prostaglandin E2 (PGE2) production, which has been demonstrated to 


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enhance tumor cell survival, angiogenesis and proliferation and reduce apoptosis [16]. Hence, the 
inhibition of COX-2 activity has a cytotoxic effect on gastric cancer cells, both in vivo and in vitro [16, 
17].  
Current trials 
There are currently no randomized trials evaluating aspirin as an adjuvant treatment after resection 
of exclusively PIK3CA mutated colorectal cancer (website www.clinicaltrials.gov, last accessed on 
March 7th, 2015). One ongoing trial is currently randomizing stage II and III colorectal cancer patients 
to daily aspirin versus no aspirin (NCT00565708), but without selecting patients with exon 9 or 20 
for PIK3CA mutations. In sharp contrast to this trial, which enrolls any patients with colorectal cancer, 
we plan to exclusively include colon cancer patients with a PIK3CA mutation and therefore 
prospectively address the question of a possible benefit of adjuvant aspirin for this patients group.  
This trial 
Although both studies mentioned above [13, 14] provide strong suggestive evidence for a very large 
protective effect of aspirin in PIK3CA mutated colorectal cancer patients, a potential selection bias 
in these retrospective analyses cannot be excluded with certainty. Therefore, these extremely 
interesting and intriguing findings need to be confirmed in a prospective trial to potentially change 
clinical practice. This trial was planned accordingly and prospectively investigates the role of aspirin 
in patients with confirmed PIK3CA mutation.  
2.4 
Choice of aspirin dosage 
Patients will be treated with a daily dose of 100 mg of adjuvant aspirin or placebo in the frame of this 
trial.  
Although there is suggestive evidence that the primary prevention of colorectal adenomas is more 
efficacious with higher dosages and longer durations of aspirin intake [12], the current state of 
knowledge suggests that low-dose, i.e. 100 mg of daily aspirin is equally efficient as 325 mg for the 
secondary prevention of the disease. The publication by Liao and colleagues suggesting a beneficial 
effect of aspirin to decrease recurrence rate in patients with colorectal cancer used 325 mg of aspirin 
daily [13], whereas patients received low-dose aspirin (≤100 mg/day) in the study by Domingo et al. 
[14]. Both studies presented a similarly low and statistically significant hazard ratio regarding 
disease-free and cancer-specific survival (HR of 0.11 and 0.18. respectively).  
In a 3-arm randomized trial with 1`121 patients with prior colorectal adenomas, there was a lower 
rate of developing adenomas in patients taking low-dose aspirin (81 mg/day) compared to those 
taking 325 mg [18]. Furthermore, in a cohort of patients diagnosed with colorectal cancer selected 
from the Eindhoven Cancer registry, patients taking low-dose aspirin had a significantly reduced risk 
of overall- and cancer-specific survival [19]. 
The excellent side effect profile of aspirin has been extensively demonstrated. A meta-analysis of 
24 randomized studies including almost 66`000 patients taking aspirin long-term showed that 
gastrointestinal hemorrhage occurred in 2.47% of patients taking long-term aspirin compared with 
1.42% taking placebo [20]. In the ATT (antithrombotic trialists`) meta-analysis with over 110`000 
patients, major gastrointestinal and extra-cranial bleeds occurred in 0.10% versus 0.07% per year 
[21]. As adverse events are dose dependent, we expect improved adherence to and reduced drop-
out rate with the administration of 100 mg aspirin. 
2.5 
Choice of design and comparator 
This is a randomized, placebo controlled, double-blinded, multicenter, phase III trial. 
As aspirin is an easily available drug, the placebo-controlled, randomized trial design is of cardinal 
importance, as there might be a relevant contamination (e. g. patients in the control group switching 
to aspirin) if the trial were open-labeled. 
Furthermore, since patients with PIK3CA mutation taking regular aspirin were found to have a 
significantly lower risk of colorectal cancer recurrence compared to those not taking aspirin in the 
two recently published retrospective studies [13, 14], the randomization ratio 2:1 was chosen to 
subject fewer patients to placebo.  


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This prospective randomized, double-blinded design will allow the immediate implementation of a 
new clinical practice, should the trial demonstrate the expected benefit of adjuvant aspirin for disease 
control. 
2.6 
Choice of study population 
We will include stage II (pT3/T4 N0 cM0) and stage III (pTx pN+ cM0) PIK3CA mutated colon cancer 
patients after complete resection of the primary tumor. It must be emphasized that the aspirin intake 
– if the patient is randomized to the intervention arm – is independent of adjuvant chemotherapy and 
will not impact the indication to give (or not) adjuvant chemotherapy.  
Rectal cancer patients will be excluded for the following two reasons: first, it is well known that the 
rate of PIK3CA mutation is relevantly lower in rectal cancer (approximately 8%) compared to colon 
cancer patients [22]. Therefore, the number needed to screen can be lowered by excluding rectal 
cancer patients. Second, rectal cancer patients are treated differently to colon cancer patients (e. g. 
neo-adjuvant radiation/chemo-radiation). Hence, including colon cancer patients only will result in a 
trial with a more homogeneous patient cohort. 
 
In summary, this randomized controlled phase III multicenter trial investigates an interesting, novel 
and relevant research question in one of the most prevalent malignancies. The trial is ethical and 
feasible as the use of daily aspirin represents a simple and safe intervention. 
If the trial confirms the protective effect of aspirin on PIK3CA mutated colorectal cancer patients, it 
would be a breakthrough in treating one of the most prevalent malignancies, result in a change of 
current clinical practice and lead to a huge benefit for our patients.  
 


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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objective 
The objective of the trial is to demonstrate a statistically significant and clinically relevant disease-
free survival benefit in stage II and III PIK3CA mutated colon cancer patients taking daily adjuvant 
aspirin for a maximum of 3 years. 
3.2 
Endpoints  
For definition of endpoints see section 13. 
3.2.1 
Primary endpoint  
The primary endpoint of the trial is: 
 
Disease-free survival (DFS) 
3.2.2 
Secondary endpoints  
Secondary endpoints of the trial are: 
 
Time to recurrence (TTR) 
 
Overall survival (OS) 
 
Cancer-specific survival (CSS) 
 
Adverse events (AEs)  
3.3 
Additional research questions  
The patient’s tumor samples will be investigated for the identification of predictive (e.g. COX-2 
overexpression, human leukocyte antigen (HLA) class I antigen expression, germline genetics) and 
prognostic (including BRAF V600E mutations, tumoral microsatellite instability status (MSI)) factors 
for the response to adjuvant therapy with aspirin and for the assessment of the biology of aspirin-
mediated response. 
4 
TRIAL DESIGN 
This is an international, multicenter, randomized, double-blinded, placebo-controlled, phase III trial.  
 
Stage II or stage III colon cancer 
PIK3CA testing 
mutated PIK3CA 
RANDOMIZATION 
2:1 
Aspirin 100 mg 
daily for maximum 3 years 
Standard chemo if indicated 
Placebo 
daily for maximum 3 years 
Standard chemo if indicated 
Follow up 
at least 3 up to 10 years from the date of surgery 


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Initial design was that following complete resection of their primary tumor, potentially eligible stage 
II or stage III colon cancer patients will undergo central PIK3CA testing. Patients with somatic 
mutations will be 2:1 randomized to daily aspirin 100 mg versus placebo for a maximum of 3 years 
or until disease recurrence, patient death or withdrawal of consent, whichever occurs first. Patients 
will be followed up for at least 3 years from the date of surgery. However, the trial was prematurely 
closed for accrual and treatment, as described in chapter 5. 
The intake of aspirin or placebo is independent of adjuvant chemotherapy, and does not impact on 
the indication to give (or not to give) adjuvant chemotherapy. 
4.1 
Methods of minimizing bias 
4.1.1 
Randomization and stratification 
Patients are randomized in a 2:1 ratio to the aspirin or placebo arm using the minimization method 
with 80% allocation probability according to the stratification factors: 
 
Stage II versus stage III colon cancer 
 
Left versus right hemicolon 
 
PIK3CA mutation in exon 9 versus 20 
 
Country 
A total of 185 patients (123 in the aspirin arm and 62 in the placebo group) were planned to be 
randomized. 
Due to the premature closure for accrual of the trial, 113 patients were randomized. 
4.1.2 
Blinding  
Patient randomization into the two treatment arms is double-blind. Neither the patient nor any of the 
investigators and other site personnel who are involved in the conduct of the trial or the analysis of 
the trial data have knowledge of the assigned treatment arm. This level of unblinding is maintained 
throughout the conduct of the trial unless there are compelling medical or safety reasons to alleviate 
the unblinding.  
At SAKK CC, Clinical Research Associates (CRAs) performing source data verification and a 
designated Clinical Data Manager (CDM) remain blinded for the entire duration of the trial. 
Blinding is performed by the authorized pre-wholesaler upon randomization of the patient (refer to 
section 7 for randomization/blinding procedures). 
At the time point the trial treatment was prematurely stopped by the sponsor (see section 5), the site 
personnel was unblinded in order to inform the randomized patients about the treatment they had 
received. That allowed the patients to decide together with their treating investigator whether or not 
to continue aspirin treatment outside of the trial. 
4.1.3 
Other methods of minimizing bias 
Patient compliance to trial treatment will be checked with the use of a patient diary. This diary will 
document the intake of the trial medication and the occasional intake of other medicinal products 
potentially interfering with COX-2 pathways, such as over-the-counter (OTC) acetylsalicylic acid 
containing products, NSAIDs or COX-2 inhibitors. 
Measures to prevent contamination will include thorough information to the patient by means of the 
patient information sheet and the patient diary. Patients will be asked to consent in written to try to 
renounce to auto-medicate with OTC acetylsalicylic acid and other NSAIDs or COX-2 inhibitors 
during trial treatment, and preferentially use the permitted analgesics (paracetamol or metamizole).  
5 
TRIAL DURATION AND TERMINATION 
The inclusion of patients has started in Q2 2016 and was planned to stop after the inclusion of 185 
patients, which was initially expected in Q2 2019. Assuming a PIK3CA mutation rate of 17% based 


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on previous reports [13, 22], and some patients not being randomized into the trial due to patient’s 
wish and eligibility criteria, the planned number of patients to be screened was 1850.  
The trial may have been stopped prematurely based on the results of two interim efficacy analyses 
(see section 15, Statistical Considerations). In addition, accrual may have been interrupted and/or 
the trial may be stopped early if new scientific data become available which substantially change the 
benefit/risk ratio.  
End of trial treatment was expected for Q2 2022. 
In Q4 2020, the sponsor decided (due to financial reasons) to prematurely stop the accrual of the 
trial and the trial treatment at the next planned visit of each patient. Last patient, last treatment took 
place in Q2 2021, with the minority of accrued patients having reached the 3 years of treatment.  
All patients randomized in Swiss sites will be followed-up for at least 3 years from the date of surgery 
until the last patient reaches the 3 years. The follow-up of patients randomized in foreign sites was 
stopped in Q2 2021 (after last patient, last treatment). Trial termination (last patient, last visit) was 
initially foreseen for Q2 2029, but is now foreseen in Q4 2023.  
 
 
 


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6 
SELECTION OF PATIENTS 
For timelines see chapter 12. 
6.1 
Inclusion criteria 
To be eligible to enter this trial, patients must fulfill the following criteria. 
6.1.1 
Written informed consent according to ICH/GCP regulations before inclusion and prior to 
any trial-related investigations. 
6.1.2 
Histologically confirmed diagnosis of adenocarcinoma of the colon. 
6.1.3 
Stage II (pT3/T4 N0 cM0) or stage III (pTx pN+ cM0) colon cancer. 
6.1.4 
Availability of cancer tissue for central molecular testing.  
6.1.5 
Presence of predefined, activating PIK3CA mutation in exons 9 or 20 (centrally assessed, 
see section 17).  
6.1.6 
Complete resection of the primary tumor (R0) within 14 weeks maximum before registration. 
6.1.7 
WHO performance status 0-2 (see Appendix 3). 
6.1.8 
Age ≥ 18 years. 
6.1.9 
Adequate hematological values: hemoglobin ≥ 80 g/L, platelets ≥ 50 x 109/L. 
6.1.10 
Adequate hepatic function: total bilirubin ≤1.5xULN, AST ≤2.5xULN, ALT ≤2.5xULN, AP 
≤2.5xULN. 
6.1.11 
Calculated creatinine clearance > 30 mL/min, according to the formula of Cockcroft-Gault 
(see Appendix 2). 
6.1.12 
Women with child-bearing potential are using effective contraception (see 9.6), are not 
pregnant or lactating and agree not to become pregnant during trial treatment. A negative 
pregnancy test before inclusion (within 7 days) into the trial is required for all women with 
child-bearing potential. 
6.2 
Exclusion criteria  
Any potential patient who meets any of the following criteria has to be excluded from entering the 
trial. 
6.2.1 
Previous or concomitant malignancy within 3 years of registration, except for adequately 
treated cervical carcinoma in situ or localized non-melanoma skin cancer.  
6.2.2 
Multiple adenocarcinomas of the colon. 
6.2.3 
Rectal cancer (defined as distance from anal verge to proximal/oral tumor edge ≤15 cm). 
6.2.4 
Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV (see 
Appendix 4), unstable angina pectoris, history of myocardial infarction) within three months 
prior to registration. 
6.2.5 
Systemic rheumatic diseases or degenerative disorders affecting the musculoskeletal 
system with a relevant risk of requiring treatment with NSAIDs in the future. 
6.2.6 
Comorbidities that require regular (i.e. more than 3x per month, any dose) intake of 
acetylsalicylic acid or other NSAIDs or COX-2 inhibitors. 
6.2.7 
Clinically relevant upper gastrointestinal bleeding within 12 months prior to registration. 
6.2.8 
Presence of any bleeding disorder that is an absolute contraindication to the use of aspirin. 
6.2.9 
General tendency to hypersensitivity and history of asthma triggered by salicylates or 
substances with a similar mechanism of action, and non-steroidal anti-inflammatory drugs 
in particular. 
6.2.10 
Any serious underlying medical condition, at the judgment of the investigator, which could 
impair the ability of the patient to participate in the trial (e.g. uncontrolled infection, active 
autoimmune disease, uncontrolled diabetes).  


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6.2.11 
Concurrent treatment with other experimental drugs or treatment in an interventional clinical 
trial within 30 days prior to trial entry. Concomitant use of adjuvant chemotherapy for stage 
III and high risk stage II colon cancer according to international treatment guidelines is 
allowed (chemotherapy regimens include intravenous 5-fluorouracil or oral capecitabine 
either alone or in combination with intravenous oxaliplatin). 
6.2.12 
Psychiatric disorder precluding understanding of trial information, giving informed consent 
or interfering with compliance for oral drug intake. 
6.2.13 
Any familial, sociological or geographical condition potentially hampering proper staging 
and compliance with the trial protocol. 
6.2.14 
Known or suspected hypersensitivity to any component of the trial drug/placebo or any 
agent given in association with this trial.  
6.2.15 
Known galactose-1-phosphate uridyl transferase deficiency, UDP galactose 4 epimerase 
deficiency, galactokinase deficiency, Fanconi-Bickel syndrome, congenital lactase 
deficiency, or glucose-galactose malabsorption (due to the lactose-containing placebo).    
6.2.16 
Any concomitant drugs contraindicated for use with the trial drug according to the approved 
product information. 


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7 
REGISTRATION AND RANDOMIZATION  
7.1 
Pre-registration procedure (PIK3CA mutation screening) 
Prior to registration, the following steps have to be performed: 
 
Fill in the patient screening and enrollment list. 
 
Check the eligibility criteria. 
 
Obtain written informed consent from the patient for PIK3CA mutation testing. A separate 
information and consent form is designed for that purpose. 
 
Paraffin block of tumor tissue must be sent to Central Pathology for PIK3CA mutation analysis 
with enough time to allow registration within 14 weeks following surgery, together with a coded 
copy of the local pathology report and the “PIK3CA testing cover letter”. Ensure to use the pre-
defined screening number in your correspondence (refer to the screening and enrollment list). 
See section 17.1 for details. 
7.2 
At registration and randomization 
 
Check the mutation status of PIK3CA centrally assessed. 
 
Obtain written informed consent from the patient for participation in the trial. 
 
When applicable: obtain written informed consent from the patient for translational research 
and banking of biological samples (on the corresponding trial-specific information and consent 
form).  
Registration and randomization is done via Internet (www.sakk.ch/edc) or - only if this is not possible 
due to technical problems (e.g. unavailability of the EDC system) - by faxing the completed, dated 
and signed paper version of the eligibility CRF to the SAKK CC (Opening hours: Monday to Friday 
8:00 a.m. to 5:00 p.m.). 
SAKK Coordinating Center  
Effingerstrasse 33 
CH – 3008 Bern 
Tel. +41 31 389 91 91 
 
In order to receive authorization for online registration and data entry, sites must send a copy of the 
completed staff list (available on the SAKK portal) to the SAKK CC. Login details for the EDC system 
will be sent to authorized persons within 2 working days.  
 
The SAKK CC will be closed on the following days: 
 
1st January 
1st August (National holiday)* 
 
2nd January 
4th Monday of November, from 3:00 pm 
 
Good Friday (Friday before Easter)* 
24th December (from 12:00 noon) 
 
Easter Monday 
25th December  
 
Ascension Thursday* 
26th December  
 
Whit Monday (Pentecost) 
31st December (from 12:00 noon) 
 
* The SAKK CC will close at 4:00 pm on weekdays before these holidays. 
Randomization  
Patient randomization is double-blind and is done by the site personnel during the online registration 
of the patient (on the same day as registration). 


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Upon randomization, a treatment arm is attributed by the system to each patient. The site and SAKK 
CC will receive a confirmation of randomization (without information on the ascribed treatment arm) 
by email. For patients enrolled in non-Swiss sites, the confirmation of randomization will also be sent 
to the relevant Cooperative Group or Clinical Research Organization responsible for local site 
management. 
7.3 
Blinding procedure and allocation of a drug code number (DCN) 
Upon receipt of the automatic confirmation of randomization, SAKK CC informs the responsible pre-
wholesaler of the UPN and the attributed treatment arm. Within 2 working days from randomization, 
the pre-wholesaler allocates one DCN to the corresponding patient and communicates this DCN to 
the site by fax or e-mail, with a copy to the SAKK CC. Thereafter, the SAKK CC provides the site 
with an unblinding scratch off card. This card must be stored in the investigator’s file. 
Refer to section 8.2.2 for the further management of DCN and the dispensing of trial medication. 
Refer to section 7.5 below for unblinding procedures. 
7.4 
After randomization 
 
Report the medical history, baseline clinical and laboratory information, surgical therapy and 
tumor location, and baseline symptoms in the eCRFs.  
 
Update the screening and enrollment list. 
 
Fill in the patient identification list. 
 
Inform the central pathologist whether the patient consented to translational research/tumor 
tissue banking by completing the bottom part of the “PIK3CA screening results cover letter”. 
Send the form per fax or email.  
The certified copy of the signed Eligibility Form (printout of eCRF form ER) has to be sent to the 
responsible clinical project manager (CPM) by email or fax within one month after randomization. 
The original is kept in the investigator’s file. 
Trial therapy should be started within 14 days from randomization. 
 
Instruct the patient about the use of the patient diary. 
7.5 
Unblinding procedures 
Unblinding during the conduct of the trial should be restricted to the cases where there are compelling 
medical or safety reasons to do so.  
If unblinding is considered for non-emergency cases, the local investigator should contact the SAKK 
CC and the coordinating investigator immediately. Any reasons for unblinding – except for an 
emergency case – have to be discussed beforehand with the coordinating investigator or the Medical 
Advisor of the SAKK CC.  
For the case that emergency unblinding is necessary: 
A scratch off card is provided to the site by the SAKK CC for each patient after the initial DCN 
allocation (at the start of trial treatment). SAKK CC ensures the correct attribution of a card to each 
patient by double signatures and documentation.  
Sites are responsible to store the card in the investigator’s file. In case an investigator breaks the 
code of a patient, the SAKK CC has to be informed immediately. The investigator will be instructed 
to keep the information strictly confidential.  
Documentation of unblinding: 
Any breaking of the code (intentional and unintentional) must be reported and explained via EDC in 
the CRF “Unblinding” (UB), irrespective of the reason for its occurrence. The unblinding and reason 
for unblinding must be recorded. 
At the time when the trial treatment was prematurely stopped by the sponsor in December 2020 (see 
section 5), all participating sites received the information about the allocated treatment arm of their 


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specific patients in order to inform them about the treatment they had received. That allowed the 
patients to decide together with their treating investigator whether or not to continue aspirin treatment 
outside of the trial. Since this general unblinding process involved all patients randomized to the trial, 
with the same date and reason for all of them, it must not be documented on the CRF UB via EDC. 
 


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8 
DRUG SUPPLY AND HANDLING 
8.1 
Drugs in protocol 
8.1.1 
Investigational medicinal product (IMP) 
In this trial the IMP is aspirin (including placebo as comparator). 
Aspirin® is a medication with marketing authorization in Switzerland and EU as an analgesic, anti-
inflammatory and antipyretic drug and, at low dose, for the prevention of cardiovascular and 
cerebrovascular diseases. In this trial, low dose aspirin (i.e. 100 mg) will be used for the adjuvant 
treatment of colon cancer.   
The comparator used in this trial is placebo. Both aspirin® and placebo will be administered orally 
once daily (o.d.). 
8.2 
Drug supply and handling of aspirin and placebo 
8.2.1 
Drug supply 
Aspirin and placebo are produced and supplied by Bayer and will be provided free of charge by the 
SAKK for all participating sites. The distribution will be managed by an authorized pre-wholesaler. 
Aspirin and placebo will be supplied as film-coated tablets for oral intake in bottles of 100 tablets. 
The aspirin tablets contain 100 mg Acidum acetylsalicylicum per tablet. The placebo tablets are 
identical, but contain no active substance (verum).  
SAKK CC will order the initial stock of IMP by the pre-wholesaler upon activation of the trial at the 
site and will reorder new trial medication for each site as soon as necessary. 
8.2.2 
DCN allocation and re-allocation 
DCN allocation for newly registered patient:  
Within 2 working days from randomization, the site is informed by fax or email of the DCN allocated 
to the randomized patient (see section 7.3). The allocated IMP bottle contains 100 tablets of trial 
medication.  
DCN re-allocation at next visit  
The site is responsible to request DCN re-allocation one week prior to the next visit of the patient. 
Please fax or e-mail the duly filled “Demand of DCN re-allocation” form to the pre-wholesaler and 
SAKK CC (form is available for download from portal.sakk.ch (Trials  SAKK 41/13-Aspirin). The 
site will be informed of the re-allocated DCN per fax or e-mail within 2 working days. 
At the visits 24 and 30 months after surgery, the form “Demand of DCN reallocation after 2 years of 
trial treatment” should be used in order to get two DCNs allocated (since there will only be half-yearly 
visits during the third treatment year). In case a patient should have more frequent visits still in the 
third treatment year, it might also be continued to order only one DCN at a time by using the initial 
“Demand of DCN re-allocation” form. 
The pre-wholesaler provides the SAKK CC monthly with an up-to-date list of all DCNs including their 
identification (aspirin or placebo), recipient site, and recipient UPN. 
In case emergency unblinding is deemed necessary (only on the basis of compelling medical or 
safety reasons) the investigator breaks the code of the patient via the unblinding scratch off card 
(which is stored in the investigator’s file). Please refer to chapter 7.5 for details on unblinding 
procedures. 
8.2.3 
Labeling of aspirin and placebo  
The trial medication will be labeled in all required local languages according to annex 13 from 
Eudralex GMP. 
8.2.4 
Handling and safety of aspirin and placebo 


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Trial medication is to be stored in a secure area at room temperature (15-25°C). 
Please refer to the Swiss product information for detailed information on handling and safety of 
aspirin, available for download in English from the SAKK portal (https://portal.sakk.ch/  Trials  
SAKK 41/13-Aspirin  Documents). 
8.2.5 
Dispensing and accountability of aspirin and placebo 
Trial medication will be given to the patient at each scheduled visit, i.e.  
- every 3 months during the first 2 years of treatment ( 1 bottle of IMP),  
- every 6 months during the 3rd year of treatment ( 2 bottles of IMP).  
Trial medication must be dispensed in the original allocated IMP bottle with the label clearly visible. 
The UPN, the name and institution of the principal investigator as well as the dispensing date have 
to be written on the label of the IMP bottle before it is given to the patient.  
IMP bottle(s) covering the treatment period between two visits will be provided to the patient at once. 
During the first two years patients will receive 1 bottle at each visit. During the third year patients will 
receive 2 bottles at each visit. 
Patient diary: Patients must be instructed to note the date of IMP intake in a diary and to return 
empty, partly used or unused bottles of trial medication at each visit. 
A patient diary covering a 3-month interval (to be used during year 1 and 2 of trial treatment) and a 
patient diary covering a 6-month interval (to be used during year 3 of trial treatment) were specifically 
designed for the trial. They are available for download from the trial-specific page on the SAKK portal. 
Drug accountability: Sites must report the dispensing and return of the trial medication (including 
UPN, date, amount dispensed/returned, batch number). For that purpose, SAKK produced two drug 
inventory logs specific for this trial (aspirin/placebo inventory log; aspirin/placebo dispensing log per 
patient), which must be kept up-to-date.  
Aspirin/placebo inventory logs are available on the SAKK portal (portal.sakk.ch  Members  Trials 
 Gastrointestinal Cancer  SAKK 41/13  useful tools). 
8.2.6 
Unused aspirin and placebo 
Unused or partly unused trial medication must be checked and reconciled with the patient diary. 
In case aspirin or placebo is lost or damaged, its disposition must be documented in the source 
documents. 
Unused, partly unused or expired trial medication has to be destroyed at the site according to local 
guidelines but only after the inspection of the CRA and receipt of instructions from SAKK CC. The 
destruction must be documented in an appropriate drug destruction certificate. Sites may use the 
local certificate or the trial-specific template provided by SAKK (available on the SAKK portal). 
8.3 
Product quality complaint handling 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have an 
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from clinical trials are crucial for the protection of patients, investigators 
and the sponsor, and are mandated by regulatory agencies worldwide. 
8.3.1 
Procedures 
In case site staff identifies a potential product complaint situation, SAKK CC must be contacted 
immediately. In case a patient identifies a potential product complaint situation, the investigator must 
be contacted immediately, as outlined in the patient information and informed consent form.  
PQCs must be forwarded within 24 hours to the SAKK CC (form available on portal.sakk.ch  Trials 
 SAKK 41/13  useful tools). If the defect is combined with a SAE/SAR, the site staff must 
additionally report the event to SAKK CC according to the reporting timelines for SAEs (see chapter 


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11.5). A sample of the suspected product should be kept at the site in accordance with the storage 
instructions for further investigation if requested by SAKK CC, the pre-wholesaler or Bayer. 
8.4 
Other drugs for anticancer treatment outside protocol 
In case standard adjuvant chemotherapy is administered concomitant to trial treatment, the treating 
physician must refer to the locally approved drug information and the respective country-specific 
guidelines for the use and handling of cytostatic compound(s).  
Any potential interactions with the trial medication (aspirin or placebo) must be considered. 


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9 
TRIAL TREATMENT 
9.1 
Treatment overview 
Treatment consists of daily intake of 100 mg aspirin (experimental arm) or placebo (control arm) per 
os. Treatment duration is maximum 3 years from treatment start or until tumor recurrence, death, 
patient refusal or withdrawal by the physician, whichever occurs first. In Q4 2020, the sponsor 
decided to prematurely stop the accrual of the trial and the trial treatment at the next planned trial 
visit of each patient. Last patient, last treatment took place in Q2 2021.  
9.2 
Therapy with aspirin/placebo 
Please refer to the Swiss product information for detailed information on handling and safety of 
aspirin, available for download in English from portal.sakk.ch ( Trials  SAKK 41/13-Aspirin). 
9.2.1 
Administration and schedule 
Aspirin or placebo is to be taken orally at a dose of 100 mg once daily, if possible before a meal, 
with some liquid. A time interval of 24 hours should occur between consecutive intakes. The omitted 
doses are not replaced (also in case of vomiting after the intake). No pre-medication or supportive 
medication is required. 
No dose reduction of aspirin or placebo is allowed. Trial treatment may be temporarily discontinued 
in case of adverse events or surgery. Interruptions should be as short as possible. Please refer to 
10.5 for more details. 
9.2.2 
Warnings and precautions 
Caution should be applied in patients with asthma, allergic disease, impairment of hepatic or renal 
function (avoid if severe) and dehydration. Elderly patients may be more susceptible to potential 
adverse events of salicylates such as aspirin. Aspirin should be used with caution in patients with a 
history of peptic ulceration or coagulation abnormalities. Caution should also be used in patients with 
known glucose-6-phosphate-dehydrogenase (G6PD) deficiency as these patients may experience 
hemolytic anemia. Aspirin prolongs bleeding time, mainly by inhibiting platelet aggregation, and it 
should be discontinued several days before scheduled major surgical procedures (see also section 
10.5). 
Refer to the current Swiss product information for information on warnings and precautions, available 
for download in English from portal.sakk.ch (Trials  SAKK 41/13-Aspirin). 
9.2.3 
Assessment of compliance 
Patient compliance shall be assessed using a patient diary during trial treatment. This diary 
documents trial medication intake and deviations from the recommendations as outlined above. 
The diary should also be used for the recording of co-medications that the patient may occasionally 
take during trial treatment, in particular OTC acetylsalicylic acid, other NSAIDs and COX-2 inhibitors.  
The patient is requested to bring the diary at each visit. The completed diary has to be checked by 
the local trial staff in presence of the patient.  
9.3 
Treatments not permitted during trial treatment phase 
The following treatments are not permitted during trial treatment with aspirin or placebo:  
o Other investigational treatments 
The following treatments should be avoided during trial treatment with aspirin or placebo except if 
taken for acute reasons and as short as possible (i.e. no more than 3x per month, any dose):  
o acetylsalicylic acid (other than trial medication) 
o other NSAIDs or COX-2 inhibitors such as diclofenac, mefenamic acid, ibuprofen, celecoxib, 
etc.. 


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Preferred alternative treatments options: paracetamol or metamizole.  
In case long-term use of acetylsalicylic acid, other NSAIDs or COX-2 inhibiting drugs is absolutely 
indicated (for whatever medical reason) trial treatment must be stopped. The patient may be 
unblinded if required for safety or medical reasons.  
The patient will remain in the trial and the follow-up examinations will be performed as planned in 
this protocol (see section 12.3). If applicable, the unblinding and reason for unblinding must be 
recorded. Please refer to section 7.5 for unblinding procedures.  
Of note: Surgical procedures are allowed during trial treatment. Trial medication (i.e. aspirin or 
placebo) should be discontinued and restarted as per local guidelines for aspirin. 
9.4 
Treatment duration 
Patients will be transferred to the follow-up phase as soon as one of the following events occurs: 
o treatment was completed as per protocol 
o recurrence (must be confirmed by imaging) 
o patient refusal (see 22.4 Premature withdrawal) 
o withdrawal by the physician (see 22.4 Premature withdrawal)  
o patient becomes pregnant 
o premature trial closure by the sponsor (in Q4 2020, the sponsor decided to prematurely stop 
the accrual of the trial and the trial treatment due to financial reasons)  
 
See section 12.3 for evaluations after treatment termination. 
All patients randomized in Swiss sites will be followed-up for at least 3 years from the date of surgery. 
The follow-up of patients randomized in non-Swiss sites was prematurely stopped in Q2 2021. 
9.5 
Concomitant adjuvant chemotherapy 
Adjuvant chemotherapy is given according to international treatment guidelines [23]. The choice of 
the individual chemotherapy regimen or the decision to do without adjuvant chemotherapy is at the 
discretion of the treating investigator. 
Adjuvant chemotherapy may be started before or after trial entry. The administration of concomitant 
therapy will be recorded in the respective eCRF. Discontinuation or modification of any adjuvant 
chemotherapy given is allowed and will be recorded in the eCRF. 
9.6 
Precaution 
The following precaution is valid for women taking part in a clinical trial: 
Women with child-bearing potential who take part in this trial should use effective contraception 
during the duration of trial treatment. Effective contraceptives can be hormonal (e.g. contraceptive 
pill, injections, or implants) or mechanical (e.g. condom, intrauterine pessar, diaphragm, cervical cap 
or another device). 
  
 


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10 
ADVERSE EVENT REPORTING, DOSE 
MODIFICATIONS AND SUPPORTIVE TREATMENT 
10.1 
Definition of adverse event (AE) 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom 
or disease temporally associated with the use of a medical treatment or procedure that may or may 
not be considered related to the medical treatment or procedure. 
10.2 
Reporting of AEs 
Patients will be instructed by the investigator to report the occurrence of any AE. 
The investigator assesses and records the specified AEs, grade 3 or higher (see section 10.2.1 
below), observed during the AE reporting period (from registration until 30 days after the end of trial 
treatment). Ongoing AEs which are not resolved within 30 days after treatment termination need to 
be followed-up until resolution or sequelae. 
10.2.1 List of AEs to be reported 
The investigator must report AEs, grade ≥3, which are possibly, probably or definitively related 
to the trial medication (aspirin/placebo). Particular attention should be made to bleeding-related 
AEs, including but not limited to: 
 
Gastrointestinal hemorrhage with loss of fresh blood per rectum  
 
Intracranial hemorrhage 
AEs associated with concomitant adjuvant chemotherapy must not be reported. 
10.2.2 Reporting procedure 
AEs are coded with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0, and assigned a grade (from 1 = mild to 5 = death related to AE) as well as a 
relationship to trial treatment. The NCI CTCAE v4.0 (as pdf) as well as instructions on how to use 
the 
criteria 
can 
be 
found 
on 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Note:  
 
Report the start and end date of the event and any changes in grading observed within the 
reporting period.  
 
Baseline symptoms will be recorded on the eCRF and will continue to be followed-up during 
treatment.  
 
AEs are documented by the codes according to CTCAE v4.0. If none of the codes are applicable, 
it exists for each of the 26 system organ classes (SOCs) the term ‘others’ to describe the AE. If 
the term ‘others’ is applicable, briefly describe the AE in a comprehensive and understandable 
manner. 
 
Laboratory values will be documented as absolute values on the eCRFs. Abnormal laboratory 
values occurring outside of predefined assessment times or not specifically asked to be assessed 
by the protocol should be documented as AE if they are grade 3 or higher. 
 
Relationship of AEs to treatment is assessed using the following scale:  
1 Unrelated  The adverse event is clearly not related to the trial treatment. The AE is 
completely independent of trial treatment and/or evidence exists that the event is 
definitely related to another etiology. 
2 Unlikely  
The adverse event is doubtfully related to the trial treatment. Temporal 
association between the AE and the trial treatment and the nature of the event is 
such that the trial treatment is not likely to have had any reasonable association 
with the observed illness/event (cause and effect relationship improbable but not 
impossible). 


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3 Possibly  
The adverse event may be related to the trial treatment. Less clear temporal 
association; other etiologies also possible. 
4 Probably  
The adverse event is likely related to the trial treatment. Clear-cut temporal 
association and a potential alternative etiology are not apparent. 
5 Definitively  The adverse event is clearly related to the trial treatment. Clear-cut temporal 
association, and no other possible cause. 
10.3 
Aspirin-related adverse events 
Aspirin has a very favorable adverse event profile. Nonetheless, special care should be taken in 
case of occurrence of bleeding events.  
Please refer to the Swiss product information of aspirin for information concerning drug-related AEs 
(available for download in English from portal.sakk.ch (Trials  SAKK 41/13-Aspirin).  
10.4 
Safety parameters 
Aspirin/placebo should be used according to the published product information and in accordance 
with best clinical practice.  
The following safety assessments must be performed at the indicated times as detailed in the 
schedule of assessments (see section 12): 
 
Assess signs and symptoms of bleeding disorders, including but not limited to: 
gastrointestinal hemorrhage with loss of fresh blood per rectum, intracranial hemorrhage. 
10.5 
General remarks on dose modifications and treatment 
interruption 
No dose reduction of aspirin or placebo is allowed. 
Trial treatment with aspirin or placebo may be temporarily discontinued in case of adverse events or 
surgery. Interruptions should be as short as possible. The omitted doses are not replaced. 
- 
Trial treatment should be temporarily discontinued in case of an AE grade 3 or higher which is 
potentially related to aspirin/placebo.  
- 
In case of AE grade 1 or 2, temporary interruption of trial treatment is at the discretion of the 
treating investigator.  
- 
In case of chemotherapy-induced thrombocytopenia, aspirin/placebo should be discontinued if 
platelets are < 50 g/L and restarted when ≥ 50 g/L.  
- 
In case of surgical procedures during trial treatment, aspirin/placebo should be discontinued and 
restarted as per local guidelines for aspirin. 
The coordinating investigator must be contacted in case the treating physician has any doubts about 
trial treatment delays or discontinuation. 
 


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11 
SAFETY REPORTING  
11.1 
Definition of serious adverse event (SAE) 
SAE are any untoward medical occurrence that at any dose results in death, is life-threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity or is a congenital anomaly/birth defect. 
11.2 
Definition of serious adverse reaction (SAR) 
SARs are all SAEs considered to be possibly, probably or definitely related to the trial treatment. 
11.3 
Definition of suspected unexpected serious adverse reactions 
(SUSARs) 
SUSARs are serious adverse reactions that are assessed as unexpected on the basis of the Swiss 
specific product information, which is the Reference Safety Information (RSI) in this trial (available 
for download in English from portal.sakk.ch (Trials  SAKK 41/13-Aspirin).  
11.4 
Reporting of SAEs and pregnancy 
11.4.1 SAEs during trial treatment 
SAEs to be reported are any of the events possibly, probably or definitively related to 
aspirin/placebo or to trial-specific procedures (i.e. SARs), occurring between registration and up 
to 30 days after the end of trial treatment and additionally fulfilling the conditions listed in the following 
table: 
SAE 
Comments 
Fatal 
Events (possibly, probably or definitively related to aspirin/placebo or to trial-
specific procedures) resulting in death. 
Life-threatening 
Events (possibly, probably or definitively related to aspirin/placebo or to trial-
specific procedures) that put the patient at immediate risk of death.
It does not include an event that, had it occurred in a more serious form, might 
have caused death. 
Requires inpatient 
hospitalization 
 
Events (possibly, probably or definitively related to aspirin/placebo or to trial-
specific procedures) which require patient hospitalization for > 24 hours. 
Events not considered to be SAE are hospitalizations > 24 hours and
occurring under the following circumstances:  
- elective surgery (planned before entry into the trial) 
- part of the normal treatment or monitoring of the trial treatment 
- hospitalization for social reasons (e.g. in rehabilitation home) 
- PD 
Prolongs 
hospitalization 
Events (possibly, probably or definitively related to aspirin/placebo or to trial-
specific procedures) which extend an existing hospitalization. 
Disabling 
Events (possibly, probably or definitively related to aspirin/placebo or to trial-
specific procedures) leading to persistent or relevant disability or incapacity.  
Secondary 
malignancy 
Any new cancer other than a relapse of the current tumor. 
Congenital anomaly Birth defect in neonate/infant or stillbirth. 
Other medically 
significant condition 
Important AEs (possibly, probably or definitively related to aspirin/placebo or 
to trial-specific procedures) that are not immediately life-threatening or do not 


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result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed above. 
11.4.2 SAEs after end of trial treatment 
During the follow-up phase (starting 30 days after end of trial treatment), the following events have 
to be reported as SAE: 
SAE 
Comments 
Fatal 
Possibly, probably or definitely related to late effects of trial medication. 
 
Life-threatening 
Possibly, probably or definitely related to late effects of trial medication. 
Disabling 
Possibly, probably or definitely related to late effects of trial medication. 
Secondary 
malignancy 
Any new malignancy other than a relapse of the current tumor. 
Congenital anomaly 
Birth defect in neonate/infant or stillbirth. 
Other medically 
significant condition 
Possibly, probably or definitely related to late effects of trial medication. 
 
 
11.4.3 Pregnancy 
In the case of pregnancy occurring during trial treatment, the investigator must report it to the SAKK 
by completing the SAKK pregnancy reporting form. This form (available on the SAKK portal, Trials 
 SAKK 41/13-Aspirin  CRFs) has to be filled in immediately and faxed to the SAKK CC.  The 
investigator shall ensure that the case is followed-up to the end of the pregnancy and supply a final 
report on the outcome to the SAKK CC. In addition, the investigator has to report any fetal anomaly, 
stillbirth or any other medicinal significant event concerning the pregnancy as SAE (see above 11.4.1 
and 11.4.2). 
11.5 
Procedure for reporting individual SAEs by the investigator 
Any SAE must be reported by submitting the completed initial report section of the trial-specific 
SAE form within 24 hours of becoming aware of the event. This form can be downloaded from the 
SAKK portal (portal.sakk.ch  Trials  SAKK 41/13-Aspirin  CRFs). 
Submission is done by sending the SAE form by email to: safety@sakk.ch. 
The SAE outcome must be reported within 2 weeks after initial report by submitting the follow-up 
report (e.g. initial SAE form, updated with follow-up information) to the SAKK CC as above. In case 
the SAE is reported as ongoing after 14 days, the follow-up report has to be submitted again with 
the final outcome. 
The originals of the SAE forms (both initial and follow-up reports) are kept at the sites in the 
investigator’s file. The SAKK CC will forward each individual SAE to the coordinating investigator 
and to Bayer. 
11.6 
Reporting of individual SAEs and SUSARs by the sponsor 
The SAKK CC ensures that all reporting requirements and timelines for reporting, as defined in the 
respective applicable national and international laws, are followed. 
The SAKK CC will forward any SAE which is fatal and occurred at a Swiss site to the lead EC 
according to the Swiss HRA and its applicable ordinances.  
The SAKK CC will report every SUSAR to all principal investigators, to the involved ECs, to 
Swissmedic and/or to the competent authorities of foreign countries (unless specified otherwise in 
the contract with a foreign site or foreign contract research organization (CRO), as specified in the 
Swiss HRA and the EU Clinical Directive 2001/20/EC. SUSARs occurring within CH or the EU will 
be entered into the Eudravigilance database by SAKK Safety Office within the required timeframe. 


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Additionally, SAKK CC will report SUSARs to Bayer. 
11.7 
Reporting of safety signals 
In case the investigator receives external safety reports/letters related to the IMP, he/she must report 
to the sponsor within 7 days. The SAKK CC will forward these reports/letters to all investigators and 
to the local and lead ECs if applicable.   
11.8 
Periodic reporting on safety to principal investigators and 
regulatory authorities 
The SAKK CC ensures that the reporting requirements and timelines for reporting, as defined in the 
respective applicable laws, are followed. 
A yearly Data Safety Update Report (DSUR) will be provided to the local investigators for filing in the 
investigator’s file. The SAKK CC will submit the DSUR to the involved ECs, to Swissmedic, to the 
competent authorities of foreign countries and to Bayer. Since the trial has been closed in the foreign 
countries in Q3 2021 without further follow-up, the DSUR will be replaced by an Annual Safety Report 
(ASR) and will be submitted from 2022 onwards only to the Swiss local investigators, competent 
authorities, ECs and to Bayer. 
 


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12 
EVALUATIONS AND INVESTIGATIONS BEFORE, 
DURING AND AFTER TRIAL TREATMENT 
All assessments and investigations must be done within the defined time as indicated below. 
An adaptable Excel schedule of assessments can be downloaded from the SAKK portal 
(portal.sakk.ch   Trials  SAKK 41/13-Aspirin  Documents  schedule of assessments). 
12.1 
Pretreatment evaluations and procedures 
Informed consent for trial entry must be obtained before inclusion of the patient into the trial and prior 
to any trial-specific procedures (with the exception of the separately consented PIK3CA mutation 
analysis). Informed consent for PIK3CA mutation testing is obtained separately from and prior to the 
consent for trial entry.  
Complete resection (R0) of the primary tumor must have been performed (max. 14 weeks prior to 
trial entry).  
Stage II (pT3/T4 N0 cM0) or stage III (pTx pN+ cM0) and histologically diagnosis of adenocarcinoma 
of the colon must have been confirmed. 
12.1.1 The following investigations have to be performed within 14 weeks before 
registration: 
 
Central PIK3CA mutation analysis (see section 17.1 for details on required material and logistics) 
12.1.2 The following investigations have to be performed within 28 days before or 
on registration: 
 
Documentation of information on the patient, including ethnicity and risk factors 
 
Documentation of medical history, including baseline symptoms, surgical therapy, pre-surgery 
CEA, tumor history and location 
 
Physical examination, including assessment of WHO PS, weight and height  
 
Hematological values: hemoglobin, platelets 
 
Renal function: serum creatinine, calculated creatinine clearance (according to the formula of 
Cockcroft-Gault, see Appendix 2) 
 
Hepatic function: total bilirubin, ALT, AST, AP 
 
Pregnancy test for women with child-bearing potential (within 7 days prior randomization) 
 
Post-resection CEA level  
 
Assessment of all inclusion/exclusion criteria 
Only for patients who consented to translational research:  
 
5 ml EDTA-blood sample (see section 18.2 for details) 
12.2 
Evaluations during trial treatment  
Trial treatment must start within 14 days following randomization. 
 
OF NOTE: the time points of investigations and assessments refer to the date of surgery and not 
the date when the patient was randomized into the trial.  
As such, the schedule of evaluations during the treatment and follow-up phases of the trial is 
according to the guidelines from the Swiss Association for Gastroenterology (SGG/SSG) & European 
Society of Medical Oncology (ESMO) for the follow-up of patients with colon cancer [24, 25]. Based 
on the recommendations of ESMO, clinical examinations and CEA measurements will be performed 
every 3 months during the first 24 months of evaluation as the vast majority of recurrences occur 
during the first 2 years after removal of the primary tumor. These examinations and any additional 
investigation upon suspected recurrence are not subjected to any limitation. 


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Table 2 below illustrates the time points of assessments in reference to the date of surgery versus 
the schedule of trial treatment. 
Table 2: summary of assessments  
Trial phase 
Adjuvant aspirin/placebo daily** 
Follow-up 
Month after surgery* 
3 
6 
9 
12 
15 
18 
21 
24 
30 
36 
42 
48 
54 
60 
Clinical examination and 
CEA level 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Colonoscopy 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
CT scan chest/abdomen 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
*Starting time point is date of colon cancer resection 
**Adjuvant aspirin/placebo treatment is initiated within max. 16 weeks after colon cancer resection and is 
administered for 3 years from treatment start (or until tumor recurrence, death, patient refusal or withdrawal 
by the physician, whichever occurs first) 
12.2.1 Year 1 and 2 following surgery  
o Assessments to be done at 3*, 6, 9, 12, 15, 18, 21 and 24 months  [± 2 weeks] 
 
Clinical examination 
 
Signs and symptoms of bleeding disorders, including but not limited to: gastrointestinal 
hemorrhage with loss of fresh blood per rectum, intracranial hemorrhage 
 
Laboratory investigations (e.g. hemoglobin, platelets) only if clinically indicated  
 
CEA level  
In case of significant increase compared to baseline (post-surgery): recurrence must be 
confirmed by colonoscopy or CT scan or other imaging technique 
 
AEs (only while patient is under trial treatment) 
Only report AEs grade ≥ 3 potentially related to trial medication 
 
Verify patient diary (i.e. patient’s compliance to the protocol treatment & patient’s intake of 
acetylsalicylic acid or other NSAIDs or COX-2 inhibitors beside trial treatment) 
 
Collect information on concomitant anti-tumor adjuvant chemotherapy (e.g. regimen (doublet 
or monotherapy) versus no adjuvant chemotherapy, start/end date, etc.) 
*) Note: If a patient is included into the trial later than three months after surgery, the visit at 3 months 
is omitted (and the first trial visit during treatment will take place 6 months after surgery). 
o Assessments to be done at 12 and 24 months  [± 2 weeks] 
 
CT scan chest/abdomen (oral and i.v. contrast strongly recommended) 
o Assessments to be done at 12 months  [± 2 weeks] 
 
Colonoscopy 
12.2.2 Year 3 following surgery  
o Assessments to be done at 30 and 36* months  [± 1 month] 
 
Clinical examination 
 
Signs and symptoms of bleeding disorders, including but not limited to: gastrointestinal 
hemorrhage with loss of fresh blood per rectum, intracranial hemorrhage 
 
Laboratory investigations (e.g. hemoglobin, platelets) only if clinically indicated 
 
CEA level 
In case of significant increase compared to baseline (post-surgery): recurrence must be 
confirmed by colonoscopy or CT scan or other imaging technique 
 
AEs (only while patient is under trial treatment) 
Only report AEs grade ≥ 3 potentially related to trial medication 


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 
Verify patient diary (i.e. patient’s compliance to the protocol treatment & patient’s intake of 
acetylsalicylic acid or other NSAIDs or COX-2 inhibitors beside trial treatment)* 
*) Note: If a patient is still under trial treatment at month 36, the last patient diary verification 
will have to be done during the first follow-up visit at month 42. 
o Assessments to be done at 36 months  [± 1 month] 
 
CT scan chest/abdomen (oral and i.v. contrast strongly recommended) 
12.3 
Evaluations in the follow-up phase   
All patients randomized in Swiss sites will be followed-up for at least 3 years from the date of surgery 
(or until death, whichever occurs first), until the last patient completes the 3 years of follow-up from 
the date of surgery, which is expected in Q3 2024. The follow-up of patients randomized in non-
Swiss sites was prematurely stopped in Q2 2021. 
Evaluations in the follow-up phase will be different for disease-free patients and patients who 
experienced recurrence. 
After a patient experienced recurrence, further treatment and investigation is up to the treating 
physician. 
12.3.1 Patients without recurrence 
Patients who completed trial treatment as per protocol (i.e. 3 years of treatment; for patients 
who stopped trial treatment earlier because of closure by the sponsor, please follow the instructions 
below under “Patients without recurrence who were transferred to the follow-up phase before 
completion of trial treatment”): 
o Bi-yearly assessments at 42*, 48, 54, and 60 months after surgery  [± 1 month] 
*) Note: If a patient is still under trial treatment at month 36, the last patient diary verification will 
have to be done during the first follow-up visit at month 42 (see section 12.2.2). 
 
Clinical examination 
 
CEA level 
In case of significant increase compared to baseline (post-surgery): recurrence must be 
confirmed by colonoscopy or CT scan or other imaging technique 
 
Patient’s intake of acetylsalicylic acid or other NSAIDs or COX-2 inhibitors  
o Yearly assessments at 48 and 60 months after surgery  [± 1 month] 
 
CT scan chest/abdomen (oral and i.v. contrast strongly recommended) 
o At 48 months only  [± 1 month] 
 
Colonoscopy 
o From year 6 to 10 after surgery (yearly assessments at months 72, 84, 96, 108 and 120 after 
surgery [± 2 months]) 
 
Disease and survival status  
 
Patient’s intake of acetylsalicylic acid or other NSAIDs or COX-2 inhibitors 
This is performed with a phone call to the primary care physician. 
Patients without recurrence who were transferred to the follow-up phase before completion 
of trial treatment (i.e. before 3 years of aspirin or placebo administration): 
o Until and including year 3 (i.e. until 36 months after surgery)  
 
Patients will be evaluated according to the schedule of assessments as described in section 
12.2, with the exception of AEs and signs or symptoms of bleeding disorders (which do not 
need to be assessed) 
o Bi-yearly assessments at 42, 48, 54, and 60 months after surgery  [± 1 month] 
 
Assessments as defined above  


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o From year 6 to 10 after surgery (yearly assessments at months 72, 84, 96, 108 and 120 after 
surgery [± 2 months]) 
 
Disease and survival status  
 
Patient’s intake of acetylsalicylic acid or other NSAIDs or COX-2 inhibitors 
This is performed with a phone call to the primary care physician. 
12.3.2 Patients after recurrence 
o Every year for at least 3 years from the date of surgery 
 
Survival status 
This is performed with a phone call to the primary care physician.  


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13 
CRITERIA OF EVALUATION AND DEFINITION OF 
ENDPOINTS 
13.1 
Criteria of evaluation 
The populations used for analysis will include the following: 
 
Full analysis population: the full analysis population is defined as all randomized patients who 
received at least one dose of aspirin/placebo excluding patients with major eligibility violations. 
Following the intention-to-treat principle, patients in this population will be analyzed according to 
the treatment they were randomized to.  
 
Per protocol (PP) population: the PP population is based on the full analysis population excluding 
patients with major protocol violations. All decisions to exclude patients from the PP population 
must be made by the coordinating investigator together with the trial team prior to the analysis, 
blinded to the treatment arm and without looking at any efficacy data. Patients in this population 
will be analyzed according to the actual treatment they received. 
 
Safety population: the safety population is defined as all patients who received any dose of 
aspirin/placebo. Patients will be analyzed according to the actual treatment they received.  
13.2 
Definition of Endpoints 
13.2.1 Primary endpoint 
The primary endpoint of this trial is DFS, defined as time from surgery until one of the following 
events, whichever comes first: 
 
recurrence  
 
second cancer 
 
death due to any reason 
Patients not experiencing an event will be censored at the date of the last available tumor 
assessment. 
13.2.2 Secondary endpoints  
Time to recurrence  
TTR will be calculated from surgery until recurrence or death due to colon cancer. Patients not 
experiencing an event or patients who died due to other reasons before experiencing an event will 
be censored at the date of the last available tumor assessment.  
Overall survival 
OS will be calculated from surgery until death from any cause. Patients not experiencing an event 
will be censored at the last date they were known to be alive. 
Cancer-specific survival 
CSS will be calculated from surgery until death due to colon cancer, whether due to the original 
tumor or to a second primary same cancer. Patients who died due to other reasons will be censored 
at the time of death. All other patients will be censored at the last date they were known to be alive. 
Adverse events 
AEs will be assessed according to NCI CTCAE v4.0.  


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14 
DOCUMENTATION 
14.1 
CRFs and reports 
CRFs specifically created for this trial are used for documentation. It is very important to adhere to 
the schedule of visits prescribed in the protocol for all patients.  
The CRFs have to be completed online (www.sakk.ch/edc) in a timely manner. The data should be 
entered into the electronic eCRFs within a month from the visit or medical examination. All eCRFs 
needed for the corresponding visit will be displayed automatically in the web-based electronic data 
capture (EDC) system for the SAKK 41/13-Aspirin trial. 
Sites must use a patient identification list in order to allow identification of a patient. This list must be 
kept at the site in the investigator’s file. 
14.2 
Notes for special handling of CRFs 
Eligibility CRF: 
 
The completed form ER in the web-based EDC system has to be printed and signed by the 
investigator. A certified copy of the signed form has to be sent to the responsible CPM by 
mail or fax within one month after the patient’s inclusion. The original signed form is kept at 
the site in the investigator’s file.  
 
If it is not possible to enter the eligibility form online for technical reasons, complete the paper 
version of the eligibility CRF and fax it in due time to the SAKK CC, which will perform the 
registration/randomization of the patient (see also section 7.2).  
SAE and pregnancy report forms: 
 
Trial-specific SAE report forms and trial-specific pregnancy report forms have to be submitted by 
email to the SAKK safety office within 24 hours of becoming aware of the SAE or pregnancy (see 
also section 11 for SAE reporting and pregnancy reporting). Originals of SAE and pregnancy 
reports are kept at the site in the investigator’s file. 
14.3 
Source data 
Additionally to other source data, the following data entered directly onto trial documents are 
considered to be source data:  
 
patient screening and enrollment list 
 
patient identification list  
 
drug inventory logs 
 
patient diary 
 
PIK3CA screening results cover letter 
 
The source of original records and all data considered to be source data are defined in the SDL form 
(source data location form). 
 


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15 
STATISTICAL CONSIDERATIONS  
15.1 
Sample size estimation  
 
Software package: East 6.2 
 
Number of treatment arms: 2 
 
Type of design: parallel design 
 
Trial intention: superiority 
 
Statistical test: One-sided log-rank test 
 
Null hypothesis: hazard ratio (HR) 1.0 
 
Alternative hypothesis: HR 0.456 (corresponding to a 3-year DFS of 70% in the placebo arm 
and 85% in the aspirin arm assuming constant hazards). This hazard ratio is based on the 
two published retrospective studies: The hazard ratio for cancer-specific survival in the study 
by Liao et al. [13] was 0.18, the hazard ratio in the study by Domingo et al. [14] for recurrence 
was 0.11. Therefore, the assumed hazard ratio of 0.456 in this trial represents a conservative 
estimate. The assumption of a 3-year DFS of 70% in the placebo arm was based on several 
studies 
[4, 
13, 
14, 
26] 
as 
well 
as 
analyses 
of 
the 
SEER 
data 
base 
(http://seer.cancer.gov/data/) and analyses performed on data of the Cantonal Hospital St. 
Gallen. 
 
Type I error: 5%  
 
Power: 80% 
 
Randomization ratio: 2:1 
 
Number of interim analyses for the primary endpoint: Two 
 
Timing of interim analyses: after 25% (11) and 50% (22) of the events, the first is expected 
after approximately 2.4 years of accrual and the second after approximately 0.5 years of 
follow-up. 
 
Stopping boundary for benefit/futility: Lan-DeMets error spending function in spirit of the 
O’Brien & Fleming boundary [27, 28]. 
 
Expected accrual rate: 60 patients per year 
 
Expected accrual time: 3 years 
 
Expected follow-up time until primary analysis: 3 years  
 
Expected proportion of lost to follow-up: 20%. This is based on various studies assessing 
aspirin intake [29-31]. 
 
Required number of events: 43 
 
Sample size: 185 (123 in the aspirin group, 62 in placebo group) 
 
Number needed to screen: 1850 assuming 17% PIK3CA mutations in colorectal cancer 
patients; estimate of 17% is based on New England Journal of Medicine publication [13]. 
PIK3CA mutations in colorectal cancer patients are described between 15% and 20% in the 
literature. The rate of PIK3CA mutation is relevantly lower in rectal cancer (approximately 
8%, [22]) compared to colon cancer. Therefore, by excluding rectal cancer patients, the 
estimate of a PIK3CA mutation rate of 17% is conservative. However, as not all the mutated 
patients will be included in the trial due to patient’s wish, ineligibility discovered after PIK3CA 
screening, etc., it is assumed that 10% of all screened patients will be finally randomized in 
the trial. 
Note: These calculations are based on the formula for the log-rank test. Due to the asymptotic 
equivalence of the test statistic of the Cox regression model without covariates and the log-rank test 
statistics under the assumed model, the sample size calculation holds also true for the unadjusted 
Cox regression model. It can be expected that inclusion of the stratification factors in the analysis 
will further increase the power as compared to the above calculations that are based on the Cox 
regression model without covariates. 


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15.2 
Interim efficacy analyses  
Two interim efficacy analyses are planned, the first after 25% (11) of the events expected after 
approximately 2.4 years of accrual and the second after and 50% (22) of the events, expected after 
approximately 0.5 years of follow-up. The accrual will not be suspended while waiting for the interim 
results. In case of a higher accrual rate than expected, the time point and number of events for the 
interim analysis may be adapted accordingly. The critical values for early stopping will be obtained 
using the Lan-DeMets error spending function in spirit of the O’Brien & Fleming boundary. 
The two interim analyses were planned to allow the trial to stop early if the beneficial effect of aspirin 
is higher than the HR of 0.45 that was assumed for the sample size calculations and is a conservative 
estimate compared to the results from the two published retrospective studies (HR 0.11 in Domingo 
et al [14] and HR 0.18 in Liao et al [13]).  
At the first interim analysis stopping for efficacy would be possible with a HR of 0.11 or lower and at 
the second interim analysis with a HR of 0.34 or lower. The proportion of patients lost to follow-up 
without reaching the primary endpoint will be assessed at the first interim analysis and if it is higher 
than 20% the sample size may be re-estimated in order to reach the required number of events in a 
reasonable time. 
The unblinded results of the interim efficacy analysis will be presented to an independent data 
monitoring committee (IDMC) appointed by the SAKK board. The SAKK board will decide on the 
continuation/modification/early stopping of the trial based on the recommendations of the IDMC.  
15.3 
Statistical analyses 
The primary analysis will take place once the 43rd DFS event has taken place or at the latest after 
3 years from the date of surgery of the last included patient. 
All efficacy endpoints will be analyzed based on the full analysis population. Supportive analyses 
based on the PP population will be performed. All safety endpoints will be analyzed based on the 
safety population. Subgroup analyses for all stratification factors except country are planned for the 
primary endpoint. All time-to-event endpoints shall have the median value of each treatment group 
estimated using the Kaplan-Meier method, along with a 95% confidence interval. The number of 
events of each endpoint shall be presented descriptively by frequency and percentage by treatment 
arm. The treatment effect will be assessed using Cox regression models with the treatment arm as 
independent variable and the stratification factors as strata. Cox regression models will also be used 
to investigate the potential effects of other factors (e.g. chemotherapy given and concomitant 
therapy) on selected endpoints. Subgroup analyses may be performed for these factors. For the 
primary analysis, patients who were unblinded before experiencing an event will be censored at the 
date of the last available tumor assessment before unblinding. A supportive analysis will be 
performed in which the unblinding will not be considered. 
Categorical variables will be summarized with frequency and percentage and may be compared 
between arms by chi-square tests or Fisher’s exact tests. Continuous variables will be summarized 
using median and range and may be compared between arms by t-tests or Wilcoxon rank sum tests. 
Laboratory values will be expressed as the absolute values and as grading according to NCI CTCAE 
v4.0 by treatment arm. AE grading shall be presented by type, grade, and relation showing frequency 
and percentage of the within-patient worst grades by treatment arms. In addition, grade ≥ 3 AEs and 
AEs with relation to treatment ≥ 3 will be summarized separately. 
Full analysis details will be outlined in the statistical analysis plan (SAP). 
15.4 
Handling of missing data and drop-outs 
No imputation of missing data will be performed. A row denoted “Missing” will be included in count 
tabulations if necessary to account for drop-outs and missing values. Patients lost to follow-up before 
reaching the primary endpoint will not be replaced. 


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16 
QUALITY OF LIFE  
Not applicable 
17 
PATHOLOGY 
PIK3CA mutation testing will be performed centrally at the Institute of Pathology, Kantonsspital St. 
Gallen, Switzerland, in order to guarantee uniformity of the analysis methodology and to allow for a 
standardized examination of cancer tissues. Results will be available within 7 working days from 
receipt of the tumor block (see section 17.2 below for details). 
17.1 
Local pathology 
17.1.1 Task of the local investigator 
The local investigator at each participating site is responsible to inform the local pathologist about 
the protocol, the trial-specific investigations and the sample handling for central PIK3CA mutation 
testing and translational research/sample banking.  
It is the task of the local investigator to determine the disease stage according to the TNM 
classification (7th edition, October 2009, see Appendix 1) and to order tumor blocks at the local 
pathology. The investigator must ensure that informed consent for PIK3CA mutation analysis 
was obtained from the patient before ordering the pathology sample. 
17.1.2 Task of the local pathologist 
The diagnosis of adenocarcinoma of the colon is performed locally. TNM classification has to be 
done according to the 7th edition, October 2009 (see Appendix 1). 
Paraffin blocks with colon cancer tissues will be ordered by the local investigator from the local 
pathologist. The local pathologist should send the blocks to Central Pathology with enough time to 
allow registration within 14 weeks following surgery.  
Patho/PIK3CA screening number:  
The local pathologist (or investigator) must ensure to assign a pre-defined Patho/PIK3CA screening 
number to every patient undergoing central PIK3CA mutation analysis, based on the screening and 
enrollment list provided by SAKK CC (available for download from portal.sakk.ch  Trials  SAKK 
41/13-Aspirin).  
The Patho/PIK3CA screening number includes a site code which is specific for each participating 
site. The site code will be communicated to the site by SAKK CC prior to activation and can also be 
found on the SAKK webpage.  
17.1.3 Required material for PIK3CA testing and translational research 
The following material is required: 
Tumor tissue: 
 
Paraffin block of the resection specimen with tumor tissue  
Documents:  
 
A copy of the local pathology report (patient information such as name and date of birth must be 
erased), coded with the pre-defined Patho/PIK3CA screening number 
 
The completed “PIK3CA testing cover letter” provided on the SAKK portal (portal.sakk.ch  
Trials  SAKK 41/13-Aspirin  useful tools) 
Reconciliation listings: 
The local pathologist (or investigator) will be requested to provide SAKK CC with the completed 
patient screening and enrollment list at regular intervals - in general, twice yearly - for the 
reconciliation of sample shipment to Central Pathology. Timing of reconciliation will be determined 
by the SAKK CC and communicated to the sites during trial conduct. 
 


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17.1.4 Labeling and handling 
All material has to be clearly labeled with: 
- 
SAKK 41/13 
- 
Patho/PIK3CA screening number (since a UPN is not yet available)  
- 
Sample ID of local pathology institute 
- 
Site 
- 
Sampling date 
17.1.5 Shipment 
Samples have to be sent to:  
Prof. Dr. Wolfram Jochum 
 
Trial SAKK 41/13 
 
Institute of Pathology 
 
Kantonsspital St.Gallen 
 
Rorschacher Strasse 95 
 
CH – 9007 St. Gallen 
 
Switzerland 
The samples, including the associated documents, are to be sent by priority postal mail (e.g. A-
Post/Courrier A/Posta A in Switzerland or equivalent postal delivery in EU).  
17.2 
Central PIK3CA mutation analysis 
PIK3CA mutation screening is conducted centrally at the Institute of Pathology, Kantonsspital St. 
Gallen, using a validated assay. Testing includes PIK3CA exons 9/20 containing the somatic PIK3CA 
hotspot mutations of colon cancer (amino acid positions E542, E545, Q546, D549 and H1047) and 
any infrequent somatic mutation within both exons. The central pathologist will inform the referring 
site of the patient’s PIK3CA mutation status within 7 working days from receipt of the tumor block, 
by faxing or emailing the completed “PIK3CA screening results cover letter” to the site and to the 
SAKK CC.  
 
The central pathologist will be requested to send at regular intervals (in general twice yearly) a list 
of all analyzed samples to SAKK CC for information and reconciliation. Timing for the reconciliation 
will be determined by the SAKK CC and communicated to Central Pathology during trial conduct. 
17.3 
Pathology samples banking 
In case the patient consented to the storage of the tumor material in the trial-associated Biobank, 
the paraffin blocks will be kept at the Institute of Pathology, Kantonsspital St.Gallen, for a maximum 
of 20 years, according to the trial-specific Biobank Regulation (see section 18.3 for further 
considerations and procedures with respect to sample banking).  
Any diagnostic sample not used for translational research or banking will be destroyed by Central 
Pathology (unless the local pathologist requests the sample back). 
 
 
 
 
 


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18 
TRANSLATIONAL RESEARCH  
In Q4 2020, the sponsor decided to prematurely stop the accrual of the trial and the trial treatment 
due to financial reasons. As a consequence, it was decided not to continue with the translational 
research subproject with blood samples. All collected blood samples are to be destroyed. However, 
the biobank and translational research subproject of the tumor tissue samples will be continued. 
 
The consent of the study patients for translational research with their clinical data and biological 
material, including the subprojects described in this section, will be obtained prior to patient’s 
inclusion into the trial with the use of a separate information and consent form.  
Participation in the translational aspects of the protocol is not mandatory. Patient refusal to 
participate in these ancillary substudies will not exclude them from participation in trial SAKK 41/13-
Aspirin. 
Any research question not included in the protocol has to be formulated in an amendment. This 
amendment has to consider the funding of the research and must be submitted to the SAKK Board 
and to the relevant Ethics Committees and regulatory authorities for authorization.  
Participation in translational research is open to all patients in Switzerland and EU. 
18.1 
Rationale and aims  
18.1.1 Tumoral expression of COX-2  
Many observational and even randomized studies have provided evidence of a protective effect of 
aspirin on colorectal cancer [11, 12]. It is hypothesized that the inhibition of COX-2 – particularly 
prostaglandin E2 (PGE2) – by aspirin results in down-regulation of phosphoinositide-3-kinase (PI3K) 
activity in PIK3CA mutant cancers through activation of Tcf/Lef signaling [16, 32]. COX-2, the 
inducible isoform of cyclooxygenase, is overexpressed in human colorectal adenomas and 
adenocarcinomas [33]. COX-2 is the rate-limiting enzyme in the conversion of arachidonic acid into 
prostaglandin H2 (PGH2), which is then converted into prostaglandin E2 (PGE2) by prostaglandin E 
synthases. Microsomal prostaglandin E synthase 1 (mPGES-1) is the major isoform involved in 
promoting PGE2 production in inflammatory sites [34]. The COX-2/mPGES-1/PGE2 pathway is 
critical in potentiating colon carcinogenesis, and selective COX-2 inhibitors have been approved as 
adjunctive therapy for patients with familial polyposis [35]. COX-2 expression has also been studied 
in human colon cancer tissues, and it has been found that COX-2 expression is significantly more 
prevalent in left-sided colon cancers as compared to right-sided colon cancers (67% versus 33%, 
p=0.05) [36]. Most importantly, COX-2 overexpression was found to be an independent predictor of 
poor prognosis in 662 colon cancer patients stage I-IV from two independent prospective cohorts 
(the Nurses' Health Study and the Health Professionals Follow-up Study [37]). In this study, COX-2 
overexpression as measured by immunohistochemistry was found in 83% of all tumors. 
18.1.2 PI3K downstream signaling 
In addition to inhibiting PGE2, aspirin has been shown to inhibit the serine/threonine kinase 
mechanistic target of rapamycin (mTOR), a downstream effector of the PI3K pathway by activation 
of adenosine monophosphate–activated protein kinase (AMPK) in colorectal cancer cells [38]. 
Signaling via mTOR controls cell survival and regulation of metabolism [39]. mTOR forms the 
catalytic core of 2 distinct complexes, mTORC1 and mTORC2, both containing mLST8 and DEPTOR 
proteins. In addition, mTORC1 consists of raptor and PRAS40, whereas mTORC2 includes rictor, 
mSIN1, and protor. mTORC1 integrates growth factor and nutrient signals to influence protein 
synthesis, growth, autophagy, and ribosomal biogenesis. The role of mTORC2 is less well defined, 
involving cell survival and cytoskeleton regulation. Furthermore, mTORC1 regulates mTORC2 
through rictor phosphorylation by S6 kinase 1 (S6K1), adding further complexity to mTOR regulation 
[40]. Substantial evidence implicates dysregulated PI3K/mTOR signaling in cancer development, 
particularly colorectal cancer [41]. Mutations in PI3K signaling genes occur in up to 40% of colorectal 
carcinomas. Raptor, rictor, and mTOR itself are overexpressed in colorectal carcinomas [42]. The 
role of mTOR in cancer biology is strengthened by evidence that negative regulators of mTOR are 
tumor suppressors. Phosphatase and tensin homolog (PTEN), which down-regulates mTOR, is 


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inactivated in 30%–40% of colorectal carcinomas [43]. Unconstrained mTOR signaling, via effectors 
S6K1 and 4E-BP1, promotes tumor growth by enhancing translation and protein synthesis. 
Activation of the AMPK, a critical cellular energy sensor, leads to mTOR suppression. AMPK is 
activated by liver kinase B1 (LKB1), a tumor-suppressor gene inactivated by germline mutations in 
Peutz–Jeghers syndrome, a colorectal cancer susceptibility disorder [44].  
18.1.3 
Tumoral expression of HLA class I antigen 
The metastatic potential of cancer cells that are shed into the bloodstream can be modified by 
environmental conditions, including platelets and bone marrow–derived cells in the vasculature [45]. 
Platelets are thought to protect disseminating tumor cells from natural killer cells, which preferentially 
recognize and eliminate cells with low or absent expression of HLA class I antigen. Therefore, the 
survival benefit associated with the use of low-dose aspirin after the diagnosis of colon cancer may 
be associated with tumors that exhibit altered expression of the HLA class I antigen. Reimers and 
colleagues studied tumor blocks from 999 patients with colon cancer surgically resected between 
2002 and 2008 and receiving low-dose aspirin, and found that the overall survival benefit associated 
with aspirin was limited to tumors expressing HLA class I antigen (adjusted hazard ratio 0.65; 95% 
CI, 0.50-0.84; P = .001) [46]. Accordingly, any study exploring the effect of PIK3CA mutations on the 
survival benefit associated with the use of adjuvant aspirin in colon cancer patients should correct 
for tumor HLA class I expression. 
18.1.4 
Tumoral BRAF V600E mutations and microsatellite instability 
In patients with stage III colon cancer, KRAS mutations are found in approximately 35% of patients, 
BRAF V600E mutations in 14% of patients, and mutations of KRAS and BRAF are nearly mutually 
exclusive [47]. KRAS mutations are more likely to be present in patients without a family history of 
colon cancer and never smokers. Tumors with KRAS mutations are less likely to have defective 
mismatch repair (dMMR) genes (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; 
P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001), but are more often 
right-sided [47]. Tumors with BRAF V600E mutations are more frequently found in patients who are 
aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers 
(OR = 1.64; 95% CI = 1.26 to 2.14; P < .001), but less likely in non-whites and men. In the patient 
cohort form the PETACC-3 study, an adjuvant trial with 3,278 patients with stage II to III colon cancer, 
BRAF mutation was significantly associated with female sex (P = .017), and highly significantly 
associated with right-sided tumors, older age, high grade, and microsatellite instability (MSI)-high 
tumors (all P < 10-4) [48]. Ogino and colleagues studied BRAF V600E mutations in 506 stage III 
colon cancer patients enrolled in the CALGB 89803 adjuvant study [49]. BRAF V600E mutational 
status was associated with inferior survival in stage III colon cancer. Compared with 431 BRAF wild-
type patients, 75 BRAF-mutated patients experienced significantly worse overall survival (log-rank 
P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63). By assessing the combined status of BRAF 
mutational status and microsatellite instability, BRAF-mutated microsatellite stable (MSS) tumors 
had an unfavorable prognosis, whereas BRAF wild-type MSI-high tumor had a favorable prognosis, 
and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor had an intermediate prognosis 
[49]. BRAF mutational status as well as MSI are hence important prognostic factors in stage II/III 
colon cancer and should be assessed in studies such as SAKK 41/13.  
18.1.5 Germline genetics 
Genetics in (fluoro)pyrimidine and folate metabolism have intensively been studied as potential 
predictors of the activity of 5FU-based chemotherapy in gastrointestinal malignancies. Key enzymes 
of the (fluoro)pyrimidine and folate metabolism are thymidylate synthase (TYMS) and methylene-
tetrahydrofolate-reductase (MTHFR), respectively. Germline polymorphisms of both TYMS and 
MTHFR are potential predictive but also prognostic markers in patients with stage II-III colon cancer. 
Three polymorphisms in the TS untranslated regions (UTRs) have been identified. TS promoter–
enhancer region (TSER) polymorphism (TS 2R/3R repeat) is a tandem repeat one, upstream of the 
TS translational start site, containing either double (2R) or triple (3R) repeats of 28-bp sequences. 
These tandem repeats have been found to be associated with the autoregulation of TS transcription 
and translation [50, 51]. More recently, additional functional variants within the 50-UTR region of the 
TS gene have been identified, and the TS 2R/3R repeat is now studied together with a G to C single 
nucleotide polymorphism within the second repeat of the 3R allele (TSER 3R G/C) [50]. In fact, the 


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TSER 3RC/3RC genotype caused a lower transcriptional activity of TS, comparable with the TS 
2R/2R genotype. Another functional TS polymorphism is a 6-bp deletion/insertion within the 30-UTR 
region of the TS gene [52]. TS 1494del6 bp has been shown to decrease RNA stability, and thereby 
to influence TS mRNA and TS protein expression in vitro. Lurje and colleagues found the high-
expression TYMS genotypes to be associated with an increased risk of tumor recurrence in 197 
patients with stage II-III colon cancer [53]. Mutations in MTHFR were found to be prognostic in stage 
II-III colon cancer patients receiving adjuvant chemotherapy [54]. Various germline genetic 
polymorphisms have been found to potentially influence the response to aspirin treatment in cancer 
patients, including but not limited to polymorphisms within the interleukin (IL)-10 gene [55], variants 
within the COX genes, GPIIb/IIIA platelet receptors, collagen or ADP receptors [56] and polymorphic 
variants within the Catechol-O-Methyltransferase (COMPT) gene [57]. Germline genetics may play 
an important role as independent predictive and/or prognostic factors in patients with colon cancer 
receiving adjuvant chemotherapy and/or aspirin. 
18.1.6 
Objectives 
The objective of the ancillary substudies of SAKK 41/13 is to explore individual patient’s tumor tissue 
for important predictive (COX-2 overexpression by immunohistochemistry (IHC), HLA class I antigen 
expression, germline genetics) and prognostic (BRAF V600E mutations, tumoral MSI status) factors. 
This will allow to gain a comprehensive understanding of the therapeutic impact of low-dose aspirin 
in this group of patients.  
Biobanks for tumor tissue will be implemented to permit future research on colon cancer.  
18.2 
Samples and schedule of sampling 
 
Archival diagnostic tumor samples of consented patients, which were sent to Central 
Pathology for PIK3CA mutation analysis, will be used for research projects (refer to section 17.1 
for the logistics of tumor sample handling and shipment).  
 
In addition, peripheral blood (5 ml EDTA blood) was collected by venipuncture within 4 weeks 
prior to patient’s inclusion into the trial.  
No tube or shipping material will be provided by the SAKK CC. All sites have to use their own 
disposables. 
18.2.1 Handling and labeling 
Blood samples had to be clearly labeled with: 
- 
SAKK 41/13 
- 
Patient UPN 
- 
Site  
- 
Sampling date 
and had to be stored at -20°C (alternatively, -80°C) at the site until shipment without prior 
centrifugation. 
18.2.2 Shipment 
Blood samples were supposed to be shipped IN BATCHES to: 
 
 
 
PD. Dr. Dr. Markus Jörger 
 
Trial SAKK 41/13 
 
Medical Oncology, KSSG 
 
Rorschacherstr. 95 
 
CH – 9007 St. Gallen 
  
Switzerland 
In general, shipment will be made at the end of the accrual phase (unless otherwise specified in trial-
specific agreements). Nevertheless, due to the premature stop of the trial, it was decided not to 
continue with the translational research subproject with blood samples. All collected blood samples 
are to be destroyed. 
 


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18.3 
Sample biobanking 
In case the patient agreed to the banking of tumor tissue, any residual histological sample or tumor 
tissue in excess will be stored for a maximum of 20 years at the Pathology Institute located at the 
Cantonal Hospital, St. Gallen, for future investigations in connection with colon cancer.  
The banking of material must conform to the HRA and its corresponding ordinance HFV/ORH, and 
to the recommendations from the Swiss Ethics Committees on research involving humans. It is 
regulated by corresponding trial-specific Biobank Regulations. The patient will have no commercial 
rights to the data, information, discoveries, or derivative materials gained or produced from the 
samples. 
The patient retains the right to have their stored material irreversibly anonymized at any time by 
contacting the principal investigator according to the HRA and its applicable ordinances. The SAKK 
will be responsible for the anonymization of the sample(s) at the request of the patient. However, 
data which is already obtained from this material can be used for the intended analysis.  
The SAKK will be responsible for the destruction of the sample(s) at the end of the storage period. 
The investigator will provide the sponsor with the required trial code and patient identification (UPN) 
so that any remaining sample can be located and destroyed. 
Any new research on these samples that is not planned in this protocol must first be approved by 
the SAKK board and by the relevant Ethics committee. 
Any diagnostic sample will be returned to the site in case of need for diagnostic purposes. 
 
19 
DIAGNOSTIC SUBSTUDY  
Not applicable 
20 
ECONOMIC EVALUATION  
Not applicable 
21 
INDEPENDENT RESPONSE REVIEW  
Not applicable 
  


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22 
ETHICAL CONSIDERATIONS 
This protocol was written and the trial will be carried out in accordance with the principles enunciated 
in the current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) 
issued by ICH, the applicable Swiss HRA and its associated ordinances KlinV/Oclin and HFV/ORH 
and the requirements from the Swiss and European regulatory bodies [58-63].  
The protocol, the patient information and consent form, as well as all other trial-related documents 
shall be submitted to all involved ECs and to the competent authorities in agreement with local legal 
requirements for formal authorization. Any amendment to the protocol or patient information and 
consent form will be submitted for authorization to these institutions. 
The decision of the ECs and competent authorities with regard to the conduct of the trial will be made 
in written to the sponsor prior to trial initiation. Patient recruitment at a participating site can only take 
place after the site has been approved by the responsible regulatory bodies and has been officially 
opened for accrual by the SAKK CC. 
Any substantial amendment to the protocol (except for safety reasons) can only be implemented at 
a site after obtaining written authorization by the corresponding regulatory bodies.  
Sites in Switzerland have to adhere to the Swiss HRA and all applicable local regulatory guidelines. 
Sites in foreign countries have to adhere to their national law and locally applicable regulatory 
guidelines.  
22.1 
Risks/benefits 
This trial investigates the use of adjuvant aspirin in patients with colon cancer following primary site 
surgery in a potentially curative setting. This treatment proposal is based on retrospective analyses 
which suggested a clinically relevant effect of using low-dose aspirin in patients carrying activating 
mutations of the PIK3CA gene in exons 9 and 20. On the one hand, aspirin is a very well-known 
drug, with minimal risk of adverse events at a daily dose of 100 mg. On the other site, the potential 
clinical benefit is very substantial, with a reduction of the risk of dying from colon cancer of roughly 
70-80%. Therefore, the risk-benefit ratio is suggested to be very favorable in this group of patients. 
22.2 
Trial categorization 
Clinical trial with IMP (including placebo as comparator). 
Aspirin is a medication with marketing authorization in Switzerland and EU as an analgesic, anti-
inflammatory and antipyretic drug and, at low dose, for the prevention of cardiovascular and 
cerebrovascular diseases. In this trial, low dose aspirin (i.e. 100 mg) will be used daily during a 
maximum of 3 years for the adjuvant treatment of colon cancer. According to the Swiss HRA and its 
corresponding ordinance KlinV/Oclin on clinical trials, this trial is classified as category B. 
22.3 
Patient information and informed consent 
The informed consent procedure must conform to the Swiss law and the guidelines on GCP issued 
by ICH.  
All patients will be informed of the aims and procedures of the trial, the possible AEs, how to react 
in case an AE occurs, and possible hazards to which they will be exposed. They will be informed as 
to the strict confidentiality of their patient data, but they need to know that their medical records may 
be reviewed for trial purposes by authorized individuals other than their treating physician. 
The investigator must provide the patient with sufficient opportunity to consider whether or not to 
participate and minimize the possibility of coercion or undue influence. The information provided 
shall be in a language intelligible to the patient and may not include any content that appears to 
waive any of the patient’s legal rights, or appears to release the investigator, the sponsor, or the 
institution from liability for negligence. 
It will be emphasized that participation is voluntary and that the patient is allowed to refuse further 
participation in the trial whenever he/she wants. This will not prejudice the patient's subsequent care. 
Informed consent will be obtained twice: 


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For the pre-registration investigation of PIK3CA mutation status  
- at screening and before any protocol-specific procedures for PIK3CA mutation analysis of the 
patient tumor material,  
Only for patients with mutated PIK3CA  
- before registration and prior to any protocol-specific procedures (except for the separately 
consented PIK3CA mutation analysis). 
Informed consent shall be obtained on a written form approved by the local EC and signed and 
personally dated by the patient and the investigator. The patient information as well as a copy or 
original of the signed and dated informed consent will be handed to the patient. No inclusion of legally 
incompetent patients is permitted in this trial. 
In case new results become available that shift the risk/benefit ratio, the patient should re-consent. 
Patients refusing to accept non-mandatory translational projects can nevertheless participate in the 
trial. 
22.4 
Premature withdrawal 
Patients have the right to refuse further trial treatment for any reason and at any time. In that case, 
they will be transferred to the follow-up phase. Patients who decide to withdraw from the trial (i.e. 
refuse further data collection) will be informed that all data collected until the time point of their 
withdrawal will be used. For the patient’s security, a last examination should be performed.  
Patients who withdraw from the trial have the right to know which treatment they received. However, 
every effort should be made to keep the patients who refuse further trial treatment without evidence 
of compelling medical or safety reason and accept further follow-up assessments and data collection 
(according to the protocol) blinded to the received treatment.  
Patients may be withdrawn at any time from trial treatment at the discretion of the treating investigator 
due to an SAE or based on any other relevant medical condition. The investigator may unblind the 
patient in the case where there are compelling medical or safety reasons to do so. The patient will 
be transferred to the follow-up phase. 
22.5 
Patient information at trial unblinding 
Upon trial unblinding each trial participant will be informed about the administered treatment. 
 
 
 


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23 
ADMINISTRATIVE CONSIDERATIONS 
23.1 
Insurance 
The SAKK will indemnify patients for damages they have suffered as participants in the trial. For this 
purpose, SAKK has taken out a special insurance for clinical trials with Chubb Insurance Company 
of Europe SE, Zollikerstrasse 141, 8034 Zürich, Switzerland.  
23.2 
Monitoring and auditing 
All source data must be accessible for auditing and monitoring. CRAs and auditors will maintain 
patient confidentiality. 
23.2.1 Monitoring strategy 
This trial will be monitored. The SAKK is performing risk-adapted monitoring according to the concept 
developed by the ADAMON group. Based on the risk analysis, low monitoring strategy has been 
chosen. The different monitoring activities as well as the frequency of the visits are described in a 
trial-specific monitoring plan. 
23.2.2 Auditing/inspecting 
Authorities have the right to perform inspections, and the SAKK has the right to perform on-site 
auditing during working hours upon reasonable prior notice.  
23.3 
Quality control and quality assurance 
Several procedures ensure the quality of the trial in compliance with applicable regulatory 
requirements, GCP and the protocol: 
 
Written standard operating procedures are implemented 
 
Personnel involved in conducting the trial is qualified by education, training and experience  
 
An updated staff list must be kept at the site 
 
Validation of database and statistical analysis 
 
Quality control principles are implemented (randomization and blinding procedures require 
double signatures and are documented) 
 
On-site and central monitoring evaluates protocol compliance (SDV, verification of informed 
consent etc.) by personnel designated by the SAKK 
 
Data captured online is validated in real-time, yielding errors (for inacceptable data) and warnings 
(for possibly inconsistent data - these warnings may be overruled by the user) 
 
Audit trail of changes 
 
Medical data review is performed by the coordinating investigator or a delegated person (all 
CRFs will be reviewed and checked on medical content)  
 
Central management of deviations and implementation of corrective and preventive measures 
 
Independent data monitoring committee 
 
Central PIK3CA mutation screening 
 
Safety monitoring 
 
Accountability of IMP (aspirin or placebo) and patient diary 
 
Internal audit procedures 
 
 
 


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23.4 
Trial activation procedure 
The procedure for trial activation at a site is described in the final protocol letter, which is sent to the 
investigators who committed to participate in the trial. All participating investigators must follow the 
instructions given in this letter for the preparation of site documents.  
Upon receipt of the site documents, the SAKK CC - or the Cooperative Group or appointed CRO in 
EU (in agreement with the specificities defined in the contract with foreign sites and the Cooperative 
Group/appointed CRO) - will proceed with the submission to the relevant ECs and competent 
authorities. 
Any site which is interested to participate in the trial but has not committed yet, is requested to contact 
the SAKK CC. The SAKK CC will evaluate the feasibility of the site participation and initiate the trial 
activation steps for the site if applicable. 
The investigator is only allowed to screen and register patients into the trial after the involved 
ECs, Swissmedic or the responsible competent authorities in EU countries authorized the 
trial at the site and the SAKK CC opened the site for accrual. 
23.5 
Local trial records 
23.5.1 Investigator’s file 
All trial-related correspondence should be filed in the investigator’s file. A suggested table of contents 
(according to ICH E6, chapter 8) is provided on the SAKK portal (portal.sakk.ch  Trials  SAKK 
41/13-Aspirin  useful tools). 
23.5.2 Useful tools  
CRFs, drug order forms and accountability logs, documents required for EC approval, a schedule of 
assessments etc. can be downloaded from the SAKK portal (portal.sakk.ch  Trials  SAKK 41/13-
Aspirin). 
23.5.3 Record retention 
The site will retain all essential documents according to ICH/GCP. This includes copies of the patient 
trial records, which are considered as source data, patient informed consent statement, laboratory 
printouts, drug inventory and destruction logs, and all other information collected during the trial. 
These documents will be stored for at least 10 years in Switzerland (at least 15 years in EU countries) 
after the termination of the trial. The start and the end of this retention period will be communicated 
to the sites by the SAKK CC. 
For the patient trial records, which are entered into the EDC system, the sponsor guarantees the 
access and availability of the data at any time for at least 10 years (respectively, 15 years in EU) 
after the termination of the trial. The data of patients who consented to the banking of their clinical 
data and their biological material may be used for additional investigations in the field of cancer. The 
banking of data must conform to the HRA and its corresponding ordinances, and to the 
recommendations from the Swiss Ethics Committees on research involving humans. The SAKK will 
be the exclusive owner of any data, discoveries, or derivative materials from the banked data. The 
patient will have no commercial rights to the data, information, discoveries, or derivative materials 
gained or produced from the banked data. 
The patient retains the right to have their recorded clinical data irreversibly anonymized at any time 
by contacting the principal investigator according to the HRA and its applicable ordinances. The 
SAKK will be responsible for the anonymization of the data at the request of the patient. However, 
data which is already obtained from this material can be used for the intended analysis 
In the event that the principal investigator retires or changes employment, custody of the records 
may be transferred to another competent person who will accept responsibility for those records. 
Written notice of such transfer will be given to the SAKK CC. The SAKK will notify the concerned 
regulatory authorities. 
 


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23.6 
Trial registration 
The SAKK will register the trial at www.clinicaltrials.gov and on the SNCTP at www.kofam.ch. With 
the participation of sites in the EU it will also be registered with the EudraCT database 
(https://eudract.emea.europa.eu) of clinical trials. 
23.7 
Participation of local and foreign sites 
A list of sites and investigators that have agreed to participate in the trial are given in a separate 
document which can be downloaded from portal.sakk.ch ( Trials  SAKK 41/13-Aspirin).  
Separate trial-specific agreements will be issued for participating sites outside of Switzerland. 
23.8 
Modifications of the protocol 
23.8.1 Substantial amendment 
Any amendment which may have an impact on the conduct of the trial, the potential benefit of the 
trial, or may affect patient safety, including changes of trial objectives, trial design, patient population, 
sample sizes, trial procedures, or significant administrative aspects. Such an amendment must be 
accepted by the SAKK Board and must have the authorization of the respective EC and competent 
authority (if applicable) prior to implementation. 
23.8.2 Safety amendment  
A safety amendment is a special kind of substantial amendment which is released when it is 
necessary to eliminate immediate hazards to trial participants. A safety amendment requires 
immediate implementation at local sites and is submitted in parallel for authorization to the ECs and 
the competent authority (if applicable).  
23.8.3 Non substantial amendment 
Non-substantial amendments such as minor corrections and/or clarifications that have no effect on 
the way the trial is conducted have to be submitted to the ECs once a year, together with the 
submission of the annual DSUR. Non-substantial amendments which affect the evaluation of the 
competent authority have to be submitted to the CA as soon as possible. 
23.9 
Trial termination 
The SAKK CC is responsible for submitting the information about trial termination to the national 
authorities according to local legislation (e.g. Switzerland, according to HRA).  
 
 
 
 


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24 
PUBLICATION 
The results of the trial will be published according to the current version of the SAKK publication 
guidelines (available on the SAKK portal). The SAKK publication guideline guarantees the freedom 
of reporting of the participating physicians.  
 
25 
CONFIDENTIALITY 
25.1 
Copyright 
The information contained in this protocol is copyright protected by the SAKK (Swiss Group for 
Clinical Cancer Research). This information is given for the needs of the trial and must not be 
disclosed to persons outside of the SAKK without prior written consent of the SAKK CC. 
25.2 
Confidentiality 
Trial-related data of the patient will be provided in a coded manner to the SAKK CC. The names of 
the patients will not be disclosed to the SAKK CC. A unique patient number (UPN) will be attributed 
to each patient registered into the trial.  
Identification of patients must be guaranteed at the site. For this purpose, sites are requested to use 
the patient screening and enrollment and the patient identification lists specifically produced for the 
trial (available on the SAKK portal). In order to avoid identification errors, the year of birth and the 
UPN have to be provided on the CRFs. Patient confidentiality will be maintained according to the 
locally applicable legislation. Patients must be informed of, and agree to, data and material transfer 
and handling, in accordance with the Swiss data protection law. 
All information concerning the IMP supplied by Bayer in connection with this trial and not previously 
published is considered confidential and proprietary information.  
 


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27 
APPENDICES 
Appendix 1 
TNM Classification 
According to UICC 2009 [64].  
T - Primary tumor  
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ: intraepithelial or invasion of lamina propria 
T1 
Tumor invades submucosa 
T2 
Tumor invades muscularis propria 
T3 
Tumor invades through the muscularis propria into the pericolorectal tissues 
T4a 
Tumor penetrates to the surface of the visceral peritoneum 
T4b 
Tumor directly invades or is adherent to other organs or structures 
N - Regional lymph nodes  
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in 1-3 regional lymph nodes 
N1a 
Metastasis in 1 regional lymph node 
N1b 
Metastasis in 2-3 regional lymph nodes 
N1c 
Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or 
perirectal tissues without regional nodal metastasis  
N2 
Metastasis in 4 or more lymph nodes 
N2a 
Metastasis in 4-6 regional lymph nodes 
N2b 
Metastasis in 7 or more regional lymph nodes 
M - Distant metastasis 
M0 
No distant metastasis 
M1 
Distant metastasis 
M1a 
Metastasis confined to 1 organ or site (e.g., liver, lung, ovary, non-regional node) 
M1b 
Metastases in more than 1 organ/site or the peritoneum 
 
Stage 
T 
N 
M 
0 
Tis 
N0 
M0 
I 
T1, T2 
N0 
M0 
II 
T3, T4 
N0 
M0 
IIA 
T3 
N0 
M0 
IIB 
T4a 
N0 
M0 
IIC 
T4b 
N0 
M0 
III 
Any T 
N1, N2 
M0 
IIIA 
T1, T2 
N1 
M0 
T1 
N2a 
M0 
IIIB 
T3-T4a 
N1 
M0 
T2-T3 
N2a 
M0 
T1-T2 
N2b 
M0 
IIIC 
T4a 
N2a 
M0 
 
T3, T4a 
N2b 
M0 
T4b 
N1, N2 
M0 
IVA 
Any T 
Any N 
M1a 


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IVB 
Any T 
Any N 
M1b 
 
Histopathological Grading 
GX: The tumor grade cannot be identified. 
G1: The cells look more like normal tissue cells (well differentiated). 
G2: The cells are somewhat different (moderately differentiated). 
G3: The cells look very unlike normal cells (poorly differentiated). 
G4: The cells barely resemble normal cells (undifferentiated). 
 
 
Appendix 2 
Calculation of creatinine clearance 
Creatinine clearance should be calculated according to the formula of Cockcroft-Gault [65]. 
Cockcroft-Gault formula: 
 
Constant is 1.04 for females and 1.23 for males  
 
 
Appendix 3 
WHO performance status  
Performance status should be calculated according to the ECOG/WHO definition [66].  
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 
Appendix 4 
New York Heart Association (NYHA) classification 
according to the Criteria Committee of the New York Heart Association [67]. 
Class I 
Patients have cardiac disease but without significant limitations of physical activity. 
Ordinary activity does not cause undue fatigue, palpitations, dyspnea (shortness of 
breath), or anginal pain. 
Class II 
Patients have slight limitations of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain. 
Class III 
Patients have marked limitations of physical activity. They are comfortable at rest, 
however less than ordinary physical activity results in fatigue, palpitations, dyspnea 
or anginal pain. 
Class IV 
Patients are unable to carry out any physical activity without symptoms referred to 
above. Some Class IV patients may have symptoms at rest. 
 
= 
Creatinine clearance (ml/min) 
(140 - age) x weight (in kg) x constant 
serum creatinine (in µmol/L)