Conditions: Breast Cancer
Keywords: Primary Breast Cancer Celecoxib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2639
Healthy volunteers: no

Brief summary:
It has been found that the chemical changes that take place in a patient's body during the development of inflammation may provide an environment which stimulates cancer cells. One step in the development of inflammation is the production of certain chemical substances which are important in the formation and spread of tumours. These are called prostaglandins. Cyclo-oxygenase II (COX-2) is an enzyme (a substance that speeds up chemical changes in the body) involved in the production of these prostaglandins and although it is not usually present in most tissues it is made at the sites of inflammation. Celecoxib is a selective Non-Steroidal Anti Inflammatory Drug (NSAID) which works by blocking the action of the COX-2 enzyme, leading to a decrease in the production of prostaglandins and a reduction in inflammation.

The purpose of this study is therefore to find out if celecoxib can be used after breast cancer treatment (chemotherapy and/ or radiotherapy) to reduce inflammation and thus reduce the ability of new tumours to grow and survive.

2590 women with primary breast cancer will be recruited in this study from several locations in the United Kingdom and Germany. Eligible patients will be randomly allocated a treatment group, which can be celecoxib or placebo. Both treatments are taken orally (celecoxib 400mg daily, placebo 2 tablets daily) for a total of 2 years. In addition, hormone receptor positive patients will receive endocrine treatment as per local practice. Patients will prematurely discontinue treatment with celecoxib/placebo if disease progression is confirmed or if patients experience unacceptable toxicity.

Patients will be seen every 6 months for the first 3 years and then off treatment follow-up is carried out annually. Participating patients will also be given the option to take part in the pathology sub-study by donating a sample of the tumour tissue collected at the time of the primary surgery.

Detailed description:
It has long been recognised that there is an association between chronic immune activation and cancer but the mechanisms behind this observation are not fully understood. The inflammatory process may provide an environment for development of malignant disease, with mediators of inflammatory response such as the cyclo-oxygenases playing an important role and providing a target for therapeutic intervention.

Prostaglandins (PGs) are synthesised from phospholipids by the action of phospholipase A2 and cyclo-oxygenases. Cyclo-oxygenase (COX) -1 differs from COX-2 in that the latter is inducible and its expression is induced by a large range of oncogenes and growth factors. Celecoxib is a selective COX-2 inhibitor that does not cause the effects of COX-1 inhibition, namely gastrointestinal ulceration.

The key regulatory step in this process is the enzymatic conversion of fatty acids to PGG2 and PGH2 by COX. PGH2 is subsequently converted to one of several structurally related PGs including PGE2, PGD2, PGF2, and thromboxane A2 (TxA2), by the activity of specific PG synthases. PGs have important functions in every organ system and regulate a variety of physiological functions such as immunity, maintenance of vascular integrity and bone metabolism. COX-2 is not normally expressed in most tissues, but is induced by a wide spectrum of growth factors and pro-inflammatory cytokines in specific pathophysiological conditions. The expression of COX-2 is highly induced in cells transformed with the oncogene v-src or treated with phorbol esters.

Several studies have suggested an association between non-steroidal anti-inflammatory drug (NSAID) consumption and decreased breast cancer risk.

Elevated COX expression in breast cancer was suggested some time ago by the finding of elevated PG production in breast tumours.

There is pharmacological and genetic evidence to indicate that a significant component of the anticancer property of NSAIDs is due to their ability to inhibit the COX-2 enzyme.

This phase III randomised study assesses the impact on disease free survival and overall survival of the Cox-2 inhibitor Celecoxib as maintenance therapy following surgery and chemotherapy in the treatment of primary breast cancer.

2590 women with primary breast cancer will be recruited in this study from several locations in the United Kingdom and Germany.

Prior to randomization all patients should have completed at least 4 cycles of (neo) adjuvant chemotherapy. Patients who satisfy all the eligibility criteria for the study will be informed and consented to join the study. The Local Investigator will then contact the ICCG randomization centre to randomize the patient by fax or by telephone.

1. Assessments required pre-randomisation

   * Complete history and physical examination (within 4 weeks before randomisation)
   * Haematology (Hb, WBC or ANC, platelets) \& Biochemistry \[serum bilirubin, creatinine, alkaline phosphatase\] (within 4 weeks before randomisation)
   * Mammogram, Chest X-ray, liver ultrasound, bone scan (at a maximum 00 months prior to diagnosis of breast cancer). In case of clinical symptoms metastatic disease has to be excluded before randomisation by the appropriate investigations
   * Collection of tissue blocks for the central tumour banks at Glasgow Royal Infirmary (for sites managed by ICCG) land Studienzentrale in Frankfurt (for sites managed by GBG)
2. Treatment

   Treatment must begin within 14 working days after randomisation and within 12 weeks of day 1 of the last cycle of adjuvant chemotherapy. Radiotherapy should be given according to local policy (concomitant trial treatment and radiotherapy is permitted). Patients will be randomised 2: 1 (in favour of celecoxib) to receive:

   Two Placebo capsules twice daily with food or Two Celecoxib 200mg capsules twice daily (800mg per day) with food The duration of celecoxib/placebo treatment is 2 years. In addition all postmenopausal ER + and/or PgR+ postmenopausal patients will receive exemestane (25mg daily) for 5 years. The start of the treatment will be at same time as starting celecoxib or placebo.
3. Routine Follow up Visits During the course of the trial all patients will be followed up every 3 months in the first year, every 6 months in !years 2 and 3 and annually from year 4 onwards.

   Follow up Assessments
   * Clinical examination and history
   * Haematology \& biochemistry
   * Metastatic screen -additional tests/investigations (eg. Bone/liver scan etc) are at the investigators discretion if clinically indicated.
   * Serious Adverse Events
4. Follow up upon relapse Any relapse requires treatment to be stopped and patients should have the minimum tests carried out as described in section (c) above.

Relapse is categorized as ipsilateral breast or axillary nodal relapse \[loco regional\] distant relapse (including supraclavicular nodes) \[distant\] and contralateral breast disease (malignant) \[2nd primary\]. In the event of tumor recurrence the relevant recurrence form should be completed and the trials office notified within 4 weeks.

All patients will be followed up long term irrespective o whether they have been withdrawn from treatment prematurely.

Arms:
arm 1: Patients in this arm will receive 400mg of celecoxib once daily. In addition, Hormone Receptor (+) patients will receive endocrine treatment according to local practice. arm 2: Patients in this arm will receive 2 tablets once daily. In addition Hormone Receptor (+) patients will receive endocrine treatment according to local practice.

Interventions: intervention 1: Celecoxib intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will receive 400mg of Celecoxib once daily for two years or until disease progression (if before the two years limit) or until development of unacceptable toxicities. In addition ER(+) patients will receive endocrine treatment according to local practice. intervention 2: Two capsules once daily with food

Protocol document:
Prot_000.pdf: 
REACT Protocol, Version 39, dated 01.11.2016 
 
Page 1 of 48 
 
 
 
 
A PHASE III MULTICENTRE DOUBLE BLIND RANDOMISED TRIAL OF 
CELECOXIB VERSUS PLACEBO IN PRIMARY BREAST CANCER PATIENTS 
(REACT – RANDOMISED EUROPEAN CELECOXIB TRIAL) 
 
ICCG C/20/01, GBG 27, BIG 1- 03, ISRCTN NO: 48254013, EUDRACT NO: 2004-00004939 
 
 
COORDINATING GROUPS: 
INTERNATIONAL COLLABORATIVE CANCER GROUP 
 
GERMAN BREAST GROUP 
SPONSOR: 
IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND 
MEDICINE, EXHIBITION ROAD, LONDON SW7 2AZ, U.K 
 
 
AN INTER COOPERATIVE GROUP STUDY 
PROTOCOL – VERSION 39, 01.11.2016 
 
 
 
 
 
 
Cancer Research UK Imperial Centre: Clinical  
Trials Section  
Department of Surgery and Cancer 
Imperial College London 
3rd Floor Radiotherapy Building  
Hammersmith Hospital Campus,  
Du Cane Road, 
London,  
W12 0NN 
UK 
REACT@imperial.ac.uk 
Tel +44 (0) 20 3311 7046 
Fax +44 (0) 20 3311 7443 
German Breast Group 
GBG Forschungs GmbH 
Martin-Behaim-Straße 12 
63263 NEU-ISENBURG 
Germany 
www.germanbreastgroup.de 
REACT@germanbreastgroup.de  
Tel   +49 (0) 6102 7480 0 
Fax  +49 (0) 6102 7480440 
 
 
 
CONFIDENTIAL:  Information and data included in this protocol contain privileged or confidential information which is 
the property of ICCG and GBG Forschungs GmbH. No person is authorised to make this public without the written 
permission of ICCG and GBG Forschungs GmbH. These restrictions on disclosure will apply equally to all future 
information supplied to you which is indicated as privileged or confidential. This material may be disclosed to and used 
by your staff and associates as may be necessary to conduct the clinical study. 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 2 of 48 
INTERNATIONAL COLLABORATIVE CANCER GROUP (United Kingdom) 
Protocol development group: 
Member 
Hospital/Institution 
City 
Phone 
Fax 
Dr L. Beex 
University Hospital Nijmegen 
Nijmegen 
+31 24 3615215 
+31 24 3540788 
Prof J. Bliss 
Institute of Cancer Research 
Sutton 
+44(0)2087224297 +44(0)20 8770 7876 
Dr P. Conte 
University Hospital 
Modena 
+39 059 4223299 
+39 059 4224429 
Prof R.C.Coombes 
ICCG Data Centre, Imperial College 
London 
London 
+44(0) 207 59 
42791 
+44(0)2033117443 
Dr M. Espie 
Hôpital St Louis 
Paris 
+331 42 49 92 93 
+331 42 49 44 73 
Dr E. Hall 
Institute of Cancer Research 
Sutton 
+44(0)2087224292 +44(0)20 8770 7876 
Dr P. Hupperets 
University Hospital Maastricht 
Maastricht 
+31 43 3877025 
+31 43 3875006 
Prof M. Marty  
L'Institut Gustave-Roussy 
Paris 
+ 331 42 11 46 72 
+331 42 11 53 22 
Dr F. Morvan 
Centre Hospitalier René Dubos 
Pontoise 
+331 30 75 42 82 
+331 30 75 42 84 
Dr J. Wils 
St Laurentius Ziekenhuis 
Roermond 
+31 475 38 24 66 
+31 475 38 24 36 
Dr P. Vassilopoulos 
Saint-Savvas Anticancer Hospital 
Athens 
+302 10 6430811 
+ 302 10 6420146  
The Protocol board were initially involved with the initiation and design of the study, they are no longer operating in the 
same capacity and have since dissolved.  Any amendments made to the study Protocol are overseen by the Trial 
Management Group and Trial Steering Committee. 
Chief Investigator: 
Prof R.C. Coombes 
ICCG Data Centre, Imperial College 
London  
London 
+44(0) 207 59 
42791 
+44(0)2083835830 
Co Investigator: 
Dr P. Hupperets 
University Hospital Maastricht 
Maastricht 
+31 43 3877025 
+31 43 3875006 
Data Management / Monitoring and Address for Reports on Serious Adverse Events: 
REACT ICCG Data 
Centre  
(Open 9.00am –
4.30pm) 
Dept of Surgery & Cancer, 
Imperial College London,  
3rd Floor Radiotherapy Building, 
Hammersmith Hospital Campus, Du 
Cane Road, London, W12 0NN, UK 
London 
+44(0)2033117046 +44(0)2033117743 
Database Management: 
Institute of Cancer 
Research 
Clinical Trials and Statistics Unit , 
Institute of Cancer Research 
Sutton 
+44(0)2087224472 +44(0)2087224368 
Randomisation: 
REACT Trial Team 
ICCG Data Centre, Imperial College 
London , 
London 
+44(0)2033117046 +44(0)2087410731 
Statistics 
Prof J. Bliss  
Clinical Trials and Statistics Unit 
Institute of Cancer Research 
Sutton  
+44(0)2087224297 +44(0)2087707876 
 
Date: 01.11.2016 
 
Chief Investigator:  R.C.Coombes 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 3 of 48 
International Collaborative Cancer Group 
 
INVESTIGATOR’S AGREEMENT 
 
I have read the following protocol by the International Collaborative Cancer Group: 
 
A PHASE III MULTICENTRE DOUBLE BLIND RANDOMISED TRIAL OF CELECOXIB VERSUS 
PLACEBO IN PRIMARY BREAST CANCER PATIENTS 
 
and agree to conduct the trial in compliance with the study protocol and to ensure that all data are recorded, 
reported and maintained in accordance with the protocol. I agree to provide all research personnel involved 
with the study with copies of the protocol and medication information. 
 
. 
 
 
 
Chief Investigator / ICCG: 
Date: 
01.11.2016 
Name: 
Prof R.C. Coombes 
 
 
Signature: 
 
 
Principal Investigator at Centre: 
Date: 
 
Name: 
 
 
 
Signature: 
 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 4 of 48 
GERMANY 
Protocoldevelopment group: 
Member 
Hospital / Organisation 
City 
Phone 
Fax 
 Prof. Dr. C. Denkert 
Charité Campus Mitte 
10117 Berlin 
030 / 450536047 
030 / 450536900 
 Dr. H. Eidtmann 
Universitätsfrauenklinik 
24105 Kiel 
0431 / 5972040 
0431 / 5972146 
 Prof. Dr. W. Eiermann Frauenklinik vom Roten 
Kreuz 
80637 München 
089 / 15706620 
089 / 15706623 
 Prof. Dr. J. Huober 
Universitätsfrauenklinik 
89075 Ulm 
0731/50058526 
0731/50058512 
 Prof. Dr. G. von  
 Minckwitz 
GBG Forschungs GmbH 
63263 Neu-Isenburg 
06102 / 7480 429 
06102  7480 440 
 PD Dr. T. Reimer 
 Universitätsklinikum Südstadt 18057 Rostock 
0381 / 44016170 
0381 / 44016188 
Dr. B. Conrad 
Elisabeth Krankenhaus 
34117 Kassel 
0561 / 7201154 
0561 / 7201162 
Prof. Dr. C. Jackisch 
Klinikum Offenbach 
63069 Offenbach 
069 / 84053850 
069 / 84054456 
Prof. Dr. S. Loibl 
GBG Forschungs GmbH 
63263 Neu-Isenburg 
06102 / 7480 418 
06102  7480 440 
Dr. F. Marmé 
Universitätsklinikum 
69120 Heidelberg 
06221 / 567856 
06221 / 561393 
Prof. Dr. V. Möbus 
Klinikum Frankfurt Höchst 
65929 Frankfurt 
069 / 31062339 
069 / 31062555 
Prof. Dr. E. Stickeler 
Universitätsklinikum 
79106 Freiburg 
07612 / 7031480 
07612 / 7031690 
Prof. Dr. M. Untch 
HELIOS Klinikum Berlin Buch 13125 Berlin 
030 / 940113395 
030 / 940153319 
Prof. Dr. C. Thomssen 
Universitätsklinik Gynäkologie 06120 Halle 
03455 / 571847 
03455 / 5715-01 
Coordinating Investigator 
Prof. Dr. G. von 
Minckwitz 
 GBG Forschungs GmbH  
63263 Neu-Isenburg 
06102 / 7480 429  
 06102 / 7480 440 
Randomisation and Address for Reports on Serious Adverse Events 
Project Manager 
GBG Forschungs GmbH  
63263 Neu-Isenburg 
06102 / 7480 203 06102 / 7480440 
Biometrics 
Dr. V. Nekljudova 
GBG Forschungs GmbH 
63263 Neu-Isenburg 
06102 /7480 467 
06102 / 7987440 
Monitoring 
German Breast Group 
GBG Forschungs GmbH  
63263 Neu-Isenburg 
06102 / 7480 0 
06102 / 7987440 
Data Management 
German Breast Group 
GBG Forschungs GmbH  
63263 Neu-Isenburg 
06102 / 7480 0 
06102 / 7987440 
 
Coordinating Investigator: 
 
 
 
 
 
Biostatistician: 
 
01.11.2016 
 
 
 
 
 
                                 01.11.2016 
_________________________________  
 
 _______________________________ 
  Date 
 
 Prof. Dr. G. von Minckwitz                   Date 
 
 
Dr. V. Nekljudova 
 
 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 5 of 48 
GERMANY 
INVESTIGATOR'S AGREEMENT 
 
 
Ich habe den folgenden Prüfplan der German Breast Group gelesen: 
 
 
EINE MULTIZENTRISCHE, DOPPELBLINDE, RANDOMISIERTE STUDIE 
DER PHASE III ZUM VERGLEICH VON CELECOXIB VERSUS PLACEBO 
BEI PATIENTINNEN MIT PRIMÄREM MAMMAKARZINOM 
(REACT – Randomised EuropeAn Celecoxib Trial) 
Prüfplan - Amendment 4 (Version 38, 29/09/2015) 
 
 
und versichere, dass er alle notwendigen Angaben zur Durchführung der Studie enthält. Ich werde die 
Studie wie hierin vorgesehen durchführen. Ich werde allen an der Durchführung der Studie beteiligten Ärzten 
Kopien des Prüfplans und Arzneimittelinformationen zur Verfügung stellen. Ich versichere, dass eine 
ordnungsgemäße Dokumentation aller mit der Studie in Zusammenhang stehenden Daten erfolgt. 
 
 
Leitender Klinischer Prüfarzt: 
 
Datum: 
 
01.11.2016 
 
  
 
Unterschrift:    _______________________ 
 
 
 
 
 
 
 
 
 
 
Prof. Dr. G. von Minckwitz 
 
Prüfärztin / Prüfarzt: 
 
Datum: 
___________________  
Unterschrift:           _______________________ 
 
Stempel oder Name in Blockschrift 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 6 of 48 
Table of Contents 
1 
Abbreviations _______________________________________________________________ 9 
2 
TRIAL SUMMARY ___________________________________________________________ 10 
3 
BACKGROUND AND INTRODUCTION ____________________________________________ 12 
3.1 
Celecoxib as adjuvant therapy for primary breast cancer _______________________________ 12 
3.2 
Dosage and Duration of Celecoxib _________________________________________________ 13 
3.3 
Pharmacokinetics of Celecoxib ____________________________________________________ 15 
3.4 
Rationale for the use of Celecoxib _________________________________________________ 15 
3.5 
Risk Benefit Assessement ________________________________________________________ 16 
4 
STUDY OBJECTIVES __________________________________________________________ 17 
4.1 
Primary Objective ______________________________________________________________ 17 
4.2 
Secondary Objectives ___________________________________________________________ 17 
4.3 
Tertiary Objectives _____________________________________________________________ 17 
5 
TRIAL ORGANISATION _______________________________________________________ 17 
6 
TRIAL DESIGN ______________________________________________________________ 19 
7 
PATIENT SELECTION _________________________________________________________ 20 
7.1 
Chemotherapy Treatment for Primary Disease _______________________________________ 20 
7.2 
Participation in Other Studies _____________________________________________________ 20 
7.3 
Inclusion Criteria _______________________________________________________________ 20 
7.4 
Exclusion Criteria _______________________________________________________________ 21 
7.5 
Entry Procedure ________________________________________________________________ 22 
7.6 
Randomisation ________________________________________________________________ 23 
8 
TREATMENT _______________________________________________________________ 24 
8.1 
Source of Drug _________________________________________________________________ 24 
8.2 
Celecoxib / placebo Packaging and Labels ___________________________________________ 24 
8.3 
Drug Distribution _______________________________________________________________ 25 
8.4 
Drug Dispensing ________________________________________________________________ 25 
8.5 
Storage _______________________________________________________________________ 25 
8.6 
Code Breaking _________________________________________________________________ 26 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 7 of 48 
8.7 
Drug Interactions/Precautions ____________________________________________________ 26 
8.8 
Drug Accountability _____________________________________________________________ 27 
9 
FOLLOW UP SCHEDULE _______________________________________________________ 27 
9.1 
Routine follow-up visits _________________________________________________________ 27 
9.2 
On-treatment assessments _______________________________________________________ 27 
9.3 
UK Off-treatment Follow-up assessments ___________________________________________ 28 
9.4 
Germany Off-treatment follow up _________________________________________________ 29 
9.5 
Schedule of Assessments ________________________________________________________ 30 
9.6 
Follow-up upon relapse__________________________________________________________ 30 
9.7 
Premature discontinuation of treatment ____________________________________________ 30 
9.8 
Treatment Breaks ______________________________________________________________ 31 
9.9 
End of Trial ____________________________________________________________________ 31 
10 
ADVERSE EVENT REPORTING ________________________________________________ 31 
10.1 
Definition of an Adverse Event (AE) ______________________________________________ 31 
10.2 
Procedure for collecting Adverse Events __________________________________________ 31 
11 
SERIOUS ADVERSE EVENTS AND SERIOUS ADVERSE REACTIONS ____________________ 32 
11.1 
Definition of a Serious Adverse Event (SAE) ________________________________________ 32 
11.2 
Procedures for reporting SAEs __________________________________________________ 32 
11.3 
Definition of a Serious Adverse Reaction (SAR) _____________________________________ 32 
11.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) __________________________ 33 
12 
STUDY ENDPOINTS ________________________________________________________ 33 
12.1 
Primary end-points ___________________________________________________________ 33 
12.2 
Secondary end-points _________________________________________________________ 33 
12.3 
Definition of disease related events ______________________________________________ 33 
12.4 
Safety Evaluation _____________________________________________________________ 34 
13 
STATISTICAL ISSUES ________________________________________________________ 34 
13.1 
Stratification ________________________________________________________________ 34 
13.2 
Sample Size _________________________________________________________________ 34 
13.3 
Analysis ____________________________________________________________________ 34 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 8 of 48 
13.3.1 
Efficacy Analysis _____________________________________________________________________ 34 
13.3.2 
Safety Analysis _______________________________________________________________________ 35 
14 
STUDY LOGISTICS __________________________________________________________ 36 
14.1 
Role of Independent Data Monitoring Committee (IDMC) ____________________________ 36 
14.2 
Analyses for Publication _______________________________________________________ 37 
14.3 
Publishing policy _____________________________________________________________ 37 
15 
SUB PROTOCOLS __________________________________________________________ 37 
16 
TRIAL ADMINISTRATION AND DATA MANAGEMENT _____________________________ 37 
16.1 
Case Report Forms (CRFs) ______________________________________________________ 38 
16.2 
Liability/Indemnity/Insurance __________________________________________________ 38 
16.3 
Patient Confidentiality_________________________________________________________ 38 
16.4 
Ethics Issues _________________________________________________________________ 39 
16.5 
Monitoring Strategy __________________________________________________________ 39 
17 
REFERENCES ______________________________________________________________ 40 
APPENDIX I: Study Contacts ______________________________________________________ 43 
APPENDIX II: Acceptable Chemotherapy Regimes _____________________________________ 44 
APPENDIX III: Drug Interactions/ Precautions ________________________________________ 46 
APPENDIX IV – Protocol Amendment History ________________________________________ 47 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 9 of 48 
1  Abbreviations 
ACE 
Angiotensin Converting Enzyme 
ADAPT 
Alzheimer’s Disease Anti-Inflammatory Prevention Trial 
ALP 
Alkaline Phosphatase 
ANC 
Absolute Neutrophil Count 
APC 
Adenoma Prevention with Celecoxib 
AUC 
Area Under Curve 
CDC 
Coordinating Data Centre 
COX 
Cyclo-oxygenase 
CRF 
Case Report Form 
DCIS 
Ductal Carcinoma In Situ 
DFS 
Disease free Survival 
ECG 
Electrocardiogram 
ER 
Oestrogen receptor 
FISH 
Fluorescent In Situ Hybridisation 
GBG 
German Breast Group 
GnRH 
Gonadotropin-releasing hormone 
Hb 
Haemoglobin 
HER2 
Human Epidermal growth factor Receptor 
HR 
Hormone Receptor 
ICCG 
International Collaborative Cancer group 
ICR-CTSU 
Instiute of Cancer Research Clinical Trials and Statistics Unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Institution Ethics Committee 
IES 
Intergroup Exemestane Study 
IRB 
Institution Review Board 
NADH 
Nicotinamide Adenine Dinucleotide Phosphate Hydrogen 
NADPH 
Nicotinamide Adenine Dinucleotide Phosphate 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PG 
Prostaglandin 
PgR 
Progesterone receptor 
PreSAP 
Prevention of Spontaneous Adenomatous Polyps 
QD 
Once Daily 
QOD 
Every other day 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Event 
TMG 
Trial Management Group 
TX 
Thromboxane 
WBC 
White Blood Cells 
 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 10 of 48 
2 
TRIAL SUMMARY 
Title 
A phase III, multicentre, double blind, randomised trial of celecoxib versus 
placebo in primary breast cancer patients. 
Study Objectives 
The primary aim is to assess the disease free survival (DFS) benefit of two years 
adjuvant therapy with the COX-2 inhibitor celecoxib compared with placebo in 
primary breast cancer patients.  
Study Design 
A multicentre, phase III, randomised, double-blind, placebo-controlled trial. 
Patients are randomised between two years celecoxib and placebo in a 2:1 ratio 
in favour of celecoxib. 
Sample Size 
2590 patients  
Main Eligibility Criteria 
Completely resected breast cancer. Entry into the study must be within 4 months 
of day 1 of the last cycle of adjuvant chemotherapy or within 3 months of the end 
of surgery, or within 6 weeks of the end of radiotherapy. Patients can have 
radiotherapy concurrently with study drug.  
Node negative, T1, Grade 1 patients are excluded.  
Her 2 +++ or FISH positive patients are excluded. 
All HR negative patients MUST have received chemotherapy. 
Treatment 
400mg celecoxib/placebo once daily for a total of 2 years. 
HR positive patients will also receive endocrine therapy according to local 
practice. 
Follow up in UK 
Year 1              Baseline and months 3, 6 and 12 
Year 2 & 3        6 monthly (months 18, 24, 30 & 36) 
Year 4 & 5        annually (months 48 & 60) 
Year 6 – 10*    annual follow up  
 
Follow up in Germany  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Endpoint 
On-treatment  follow up: 
Year 1              Baseline and months 3, 6 and 12 
Year 2              6 monthly (months 18, 24) 
 
Off-treatment follow up:   
Year 3 – 10* 
Information on the health status and late side-effects of the patient will be 
collected at least annually using a self-reporting system via a patient 
questionnaire, chart reviews at the sites or based on information deriving from 
the GBG registry of previous study participants 
* Should cost effective, reliable systems be in place, for example electronic 
methods of routine data collection, and at the discretion of the Trial Steering 
Committee, off-treatment follow up may continue beyond 10 years 
 
 
Disease free survival 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 11 of 48 
Secondary Endpoints 
• Overall survival. 
• Toxicity associated with long term use of celecoxib in primary breast cancer 
patients. 
• Cardiovascular mortality. 
• Incidence of second primaries. 
• Subgroup analysis based on HR status (HR+ve, HR-ve) will be performed 
using the same endpoints as in the analysis of all patients. 
 
 
 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 12 of 48 
3 BACKGROUND AND INTRODUCTION 
3.1  Celecoxib as adjuvant therapy for primary breast cancer 
It has long been recognised that there is an association between chronic immune activation and cancer but 
the mechanisms behind this observation are not fully understood (O’Byrne and Dalgleish, 2001). The 
inflammatory process may provide an environment for development of malignant disease, with mediators of 
inflammatory response such as the cyclo-oxygenases playing an important role and providing a target for 
therapeutic intervention. 
 
Prostaglandins (PGs) are synthesised from phospholipids by the action of phospholipase A2 and cyclo-
oxygenases. Cyclo-oxygenase (COX) -1 differs from COX-2 in that the latter is inducible and its expression is 
induced by a large range of oncogenes and growth factors. Celecoxib is a selective COX-2 inhibitor that 
does not cause the effects of COX-1 inhibition, namely gastrointestinal ulceration (Emery et al, 1999; 
Waddell and Loughry, 1983). Celecoxib is currently available for clinical use in Europe and the US for the 
treatment of chronic arthritic conditions. 
 
The key regulatory step in this process is the enzymatic conversion of fatty acids to PGG2 and PGH2 by 
COX. PGH2 is subsequently converted to one of several structurally related PGs including PGE2, PGD2, 
PGF2, and thromboxane A2 (TxA2), by the activity of specific PG synthases. PGs have important functions 
in every organ system and regulate a variety of physiological functions such as immunity, maintenance of 
vascular integrity and bone metabolism. COX-2 is not normally expressed in most tissues, but is induced by 
a wide spectrum of growth factors and pro-inflammatory cytokines in specific pathophysiological conditions. 
(Smith et al, 2000; Smith et al, 1996). The expression of COX-2 is highly induced in cells transformed with 
the oncogene v-src (Xie et al, 1991) or treated with phorbol esters. (Kujubu et al, 1991). 
 
Several studies have suggested an association between non-steroidal anti-inflammatory drug (NSAID) 
consumption and decreased breast cancer risk. These include the studies of Friedman and Ury (1980) and 
Harris et al (1996), the latter showing a reduction to 66% in women who were treated with NSAIDs for more 
than one year. A further two studies also showed a reduction in incidence (Schreinemachers and Everson, 
1994; Sharpe et al, 2000). There are a number of potential mechanisms that can be evoked to explain these 
findings, including the inhibition of procarcinogen activation and formation, tumour cell invasion and 
metastasis, induction of apoptosis, inhibition of angiogenesis and endothelial tube formation (Elder et al, 
1996; Sheng et al, 1997). 
 
Elevated COX expression in breast cancer was suggested some time ago by the finding of elevated PG 
production in breast tumours (Bennett et al, 1977); PGs are also known to be involved in invasion (Liu and 
Rose, 1996). COX-2 is expressed in breast cancers (Parrett et al, 1997) and can be detected by 
immunohistochemistry (Soslow et al, 2000). COX-2 overexpression in mice resulted in mammary tumour 
development in 85% of mice (Liu et al, 2001). COX-2 expression seems associated with c-erbB2 expression 
(Subbaramaiah et al, 1999) and with aromatase content (Brueggemeier et al, 1999). These observations 
suggest that COX-2 inhibition could have a role to play in enhancing treatment directed at either of these 
molecular targets. 
 


REACT Protocol, Version 39, dated 01.11.2016 
 
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Colorectal polyps may disappear in patients taking NSAIDs for pain relief (Waddell and Loughry, 1983; 
Giovanucci et al, 1994; Giovanucci et al, 1995; Thun et al, 1991; Labayle et al, 1991; Nugent et al, 1993; 
Giardiello et al, 1993). These studies used NSAIDs that inhibit both COX-1 and COX-2; encouraging results 
have also been obtained with the selective COX-2 inhibitor, celecoxib (Steinbach; 2000). There is 
pharmacological and genetic evidence to indicate that a significant component of the anticancer property of 
NSAIDs is due to their ability to inhibit the COX-2 enzyme. The role for COX-2 in promoting tumour–
associated angiogenesis has been clarified by Dormond and co-workers (Dormond et al, 2001). 
 
COX-2 inhibition plays a role in the prevention of a number of cancer types, in addition to breast, and may 
also have a role in treatment. Studies using twice daily celecoxib include: 
• 
Phase III Neoadjuvant trial of pre-operative exemestane or letrozole +/- celecoxib in the treatment of 
ER positive postmenopausal early breast cancer [Neo-Excel] (A UK study, currently being initiated 
by P. Canney) 
• 
NCI/MSKCC phase 2 study of celecoxib and herceptin in women with HER2+ metastatic breast 
cancer refractory to herceptin. Treatment continues until disease progression/toxicity. 
• 
NCI phase 1 randomised study of 6 weeks neoadjuvant celecoxib for localised prostate cancer 
• 
RTOG phase 1/2 study of external beam radiotherapy and brachytherapy, celecoxib,  
• 
NCI/UCSF randomised phase 2 study of two years celecoxib for prevention of basal cell carcinoma 
in patients with basal cell naevus syndrome. 
 
NSAIDs and specific COX-2 inhibitors can inhibit solid tumour cell proliferation both in vitro and in vivo. Two 
separate animal studies have shown that selective COX-2 inhibitors can prevent mammary tumour 
formation, reducing the incidence by up to 85% (Harris et al, 2000; Nakatsugi et al, 2000). Recently these 
results have been confirmed by Rozic et al (2001) who also observed the anti-angiogenic activity of COX-2 
antagonists. COX-2 inhibition can reverse resistance to apoptosis (Tsujii et al, 1995) and has been 
implicated in growth factor production which stimulates angiogenesis (Tsujii et al, 1998). 
 
A principal attraction of selective COX-2 antagonists is the lower incidence of side effects compared with 
other NSAIDs. Thus, in a study published in 2000 with more than 8000 patients with osteoarthrosis who 
received celecoxib 400mg twice daily for a period of 6 months , the incidence of gastrointestinal side-effects, 
including gastrointestinal bleeding and dyspepsia, was reduced (Silverstein et al, 2000). 
 
3.2 Dosage and Duration of Celecoxib 
Since COX-2 inhibitors do not inhibit COX-1, it is expected that they will not interfere with homeostatic 
prostanoid-dependent processes such as upper gastrointestinal tract mucosal protection and platelet 
aggregation. A recent randomised study (Simon et al, 1999) compares side effects of celecoxib in patients 
randomised to 100mg, 200mg or 400 mg (twice daily) with naproxen, 500mg (twice daily), in 1149 patients 
with rheumatoid arthritis. The overall incidence of gastrointestinal tract adverse effects was 19% for placebo, 
28%, 25% and 26% for celecoxib at 200mg, 400mg, and 800mg/day respectively, compared with 31% for 
naproxen. 
 
The long term use of celecoxib has recently been evaluated in two trials comparing celecoxib to placebo in 
subjects at risk for spontaneous adenomatous polyposis.In the Adenoma Prevention with Celecoxib (APC) 


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study, participants were randomly assigned to take either 200mg of celecoxib twice a day, 400mg of 
celecoxib twice a day, or placebo for 3 years. At the time of analysis 77% of the 2035 patients had completed 
the study and all of the remaining surviving patients had completed at least 2.8 years of follow up. A 
composite cardiovascular endpoint of death from cardiovascular causes, myocardial infarction, stroke or 
heart failure was reached in 7 of 679 patients in the placebo group (1%) as compared with 16 of 685 patients 
receiving 200mg of celecoxib twice daily (2.3%; hazard ratio, 2.3; 95% CI, 0.9 to 5.5 and with 23 of 671 
patients receiving 400mg of celecoxib twice daily (3.4%; hazard ratio, 3.4; 95% CI, 1.4 to 7.8 (Soloman et al, 
2005). 
 
In contrast, preliminary results from the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial 
showed no apparent increase in cardiovascular risk. Preliminary data released in December 2004 stated a 
1.8% incidence (11 events) of cardiovascular events in the placebo group (n=628) in comparison to 1.7% 
incidence (16 events) of cardiovascular events in those taking celecoxib 400mg daily (n=933). The analysis 
performed on the findings in this trial and in the APC trial, which demonstrated an increased risk of events 
with celecoxib, were identical, having been performed by the same independent cardiovascular safety review 
committee. In the PreSAP trial, however, the review committee determined that those patients on celecoxib 
demonstrated no increased risk in cardiovascular events compared to those taking placebo. The difference 
in the dosing regimens between these two trials – twice daily in the APC study as compared with once daily 
in the PreSAP study supports the hypothesis that sustained inhibition of prostacyclin may contribute to the 
increase in cardiovascular risk. However other potential differences in the trials, including geographic 
differences, differences in the patient population, and differences in use of concomitant medications, may 
also have contriibuted to the disparity in the preliminary findings. 
 
Another trial whose findings contrast with the APC study was the Alzheimer's Disease Anti-Inflammatory 
Prevention Trial (ADAPT), a study designed to assess the efficacy of celecoxib in the prevention of 
Alzheimer's disease. The study involved 750 patients of >70 years old, who were treated for up to 3 years 
with naproxen 220mg twice daily, celecoxib twice daily or placebo. Preliminary results from this study 
showed a 50% increased risk of cardiovascular events in patients who were on the naproxen regimen 
compared to placebo but not celecoxib relative to placebo. 
 
In another study, arthritis patients were randomised to receive celecoxib 400mg twice daily, ibuprofen 800mg 
3 times daily or diclofenac 75mg twice daily. The incidences of serious cardiovascular thromobembolic 
events were not significantly different (< 1.5% in all arms) between celecoxib and NSAID comparators. 
 
In a meta-anaysis of randomised trials in patients receiving celecoxib, there was no increased cardiovascular 
risk with celecoxib relative to placebo and it demonstrated a comparable rate of cardiovascular events with 
celecoxib treatment compared with nonselective NSAIDS (White 2007). 
 
A meta-analysis has shown a significant reduction in myocardial infarction in women treated with tamoxifen 
(Braithwaite 2003). Recent evidence from an epidemiological study using the General Practice Research 
Database also suggests that tamoxifen therapy reduces the risk of myocardial infarction and angina 
(Bradbury 2005) and in results from the EBCTG Overview 2005, patients who were treated with 5 years 
tamoxifen had no excess of CV deaths overall (death rate ratio = 0.968 [SE 0.11] NS) which was consistent 
with decreased risk of cardiac events (death rate ratio = 0.79 [SE =0.11] 2P =0.06) (EBCTCG 2005). 


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As regards concurrent administration of celecoxib with the other main class of endocrine therapies, the 
Aromatase Inhibitors, a recent review and analysis of patients with metastatic or locally advanced breast 
cancer has concluded that the combination of celecoxib and an AI (in this case, exemestane) had similar 
cardiac side- effects when compared to exemestane alone (Falandry et al, Ann Oncology, 2008). A more 
recent meta-analysis of all studies comparing AIs with placebo has concluded that there may be a slight 
increase in cardiac events (<1%) in those patients receiving up-front AI, but this was not observed in patients 
pre-treated with tamoxifen (Amir E etal, 2011. JNCI). 
3.3 Pharmacokinetics of Celecoxib  
The following has been obtained from the Investigator Brochure, December 2012 . Absorption: peak plasma 
levels of celecoxib occur approximately three hours after an oral dose. Under fasting conditions, both peak 
plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200mg BID; at 
higher doses, there are less than proportional increases in Cmax and AUC. Absolute bioavailability studies 
have not been conducted. With multiple dosing, steady state conditions are reached on or before day 5. The 
pharmacokinetic parameters of celecoxib in a group of healthy subjects are as follows: Cmax 705ng/ml; 
Tmax 2.8, t½ 11.2. In healthy subjects, ~97% celecoxib is protein bound within the clinical dose range. 
Celecoxib is eliminated predominantly by hepatic metabolism with <1% unchanged drug recovered in the 
urine. At higher doses (400mg twice daily) celecoxib should be administered with food. 
 
3.4 Rationale for the use of Celecoxib 
In summary, therefore, there are multiple reasons for initiating a randomised study to examine the impact of 
COX-2 inhibition in enhancing the adjuvant treatment of breast cancer - as follows: 
• 
inhibition of angiogenesis 
• 
inhibition of cell growth 
• 
inhibition of tumour-associated inflammation 
• 
inhibition of invasion 
• 
promotion of apoptosis 
The conventional way of evaluating a novel anti-cancer compound in the adjuvant setting would be to carry 
out a formal study in patients with metastatic disease of a variety of solid tumours and then proceed to phase 
2 studies in patients with metastatic breast cancer. However, in this instance, this is not felt to be the 
appropriate way forward for two reasons: firstly, many thousands of patients have already received celecoxib 
at the proposed dose, and it is much less toxic than either conventional NSAIDs or chemotherapy, with a 
withdrawal rate of 2-4%, and no attributable deaths; secondly, there is a wealth of data to show that NSAIDs 
prevent tumour progression in animal models and carcinogenesis in humans. Furthermore, the mechanisms 
susceptible to COX-2 inhibition (see above) are likely to be operative in the micrometastatic situation, rather 
than in the context of advanced disease. For these reasons, we do not believe that the conventional route 
from metastatic to adjuvant therapy should necessarily be followed. 
 


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3.5 Risk Benefit Assessement  
From completed studies to date, the following drug related adverse events are considered to be expected 
and common following treatment wit celecoxib:  abdominal pain, diarrhea, dyspepsia, flatulence, peripheral 
edema, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection and rash.  
 
Cardiovascular Risk 
Celecoxib may cause an increased risk of serious cardiovascular thrombotic events, myocardial infraction 
and stroke, which can be fatal. All NSAIDs may have similar risk. This risk may increase with the duration of 
use. Patients with cardiocasvular disease or risk factors for cardiovascular disease are at greater risk. A 
cardiovascular assessment is carried out during screening to exclude patients at risk. Patients on study 
treatment will be monitored and will have a cardiovascular assessment at 12 months visit and at end of 
treatment (normally 24 months). 
 
Gastrointestinal Risk  
Celecoxib as other NSAIDs cause an increased risk of serious gastrointestinal adverse events including 
bleeding, ulceration, and perforation of the stomach and intestines, which can be fatal. These events can 
occur at any time during use and without warning symtoms. Elderly patients are at greateser risk of serious 
gastrointestinal events. Patiens will need to be advised to be alert and to report any symtomps of stomach 
bleed.  
 
Hepatic Effects 
Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking 
NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) 
have been reported in approximately 1% of patients in clinical trials with NSAIDs.  These laboratory 
abnormalities may progress, may remain unchanged, or may be transient with continuing therapy.  Rare 
cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic 
failure (some with fatal outcome) have been reported with NSAIDs, including Celecoxib. In controlled clinical 
trials of Celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 
times the upper limit of normal) of liver associated enzymes was 6% for Celecoxib and 5% for placebo, and 
approximately 0.2% of patients taking Celecoxib and 0.3% of patients taking placebo had notable elevations 
of ALT and AST. If clinical signs and symptoms consistent with liver disease develop, or if systemic 
manifestations occur (e.g., eosinophilia, rash, etc.), Celecoxib should be discontinued. 
 
Renal Effects 
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.  Renal 
toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the 
maintenance of renal perfusion.  In these patients, administration of an NSAID may cause a dose-dependent 
reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal 
decompensation.  Patients at greatest risk of this reaction are those with impaired renal function, heart 
failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the 
elderly.  Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical 
trials with Celecoxib have shown renal effects similar to those observed with comparator NSAIDs. No 
information is available from controlled clinical studies regarding the use of Celecoxib in patients with 


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advanced renal disease. Therefore, treatment with Celecoxib is not recommended in these patients with 
advanced renal disease.  
 
Potential Benefit  
Celecoxib has been widely used across the world and has a well-established safety profile. Studies have 
showed that COX-2 inhibition plays a role in the prevention of cancer and may also play a role in treatment 
as discussed in section 3.1.Therefore, the proposed study will assess the potential of COX-2 inhibitors as 
“maintenance therapy”, following surgery with or without chemotherapy (+ or - radiotherapy), to improve 
disease free survival of patients with primary breast cancer. 
 
Overall Risk Benefit  
Although there can be no certainty of clinical benefit to patients, studies have showed that the use of NSAIDs 
and specific COX-2 inhibitors can inhibit tumour cell proliferation both in vivo and in vitro. It has been shown 
that patients exposed to selective COX-2 antagonists have fewer incidences of GI side effects when 
compared with other NSAIDs. In addition to this, clinical data for hormone receptor positive patients showed 
that the concomitant use of celecoxib and hormone treatment is considered to be safe. Thus, the risk-benefit 
assessment for this study supports the safe oral administration of celecoxib (400 mgs daily) for patients with 
primary breast cancer according to the proposed study design. 
 
4 STUDY OBJECTIVES 
4.1 Primary Objective 
To assess the disease free survival (DFS) benefit of two years adjuvant therapy with the COX-2 inhibitor 
celecoxib compared with placebo in primary breast cancer patients. 
 
4.2 Secondary Objectives 
• 
To compare overall survival 
• 
To define the safety of adjuvant therapy with celecoxib in this patient population 
• 
To compare incidence of second primary breast cancers 
• 
To assess tolerability of celecoxib with hormone therapy. 
• 
To assess DFS benefit of two years adjuvant celecoxib compared with placebo in HR positive (i.e. 
ER positive and/or PR positive) and in HR negative (i.e. ER negative/PR negative) disease. 
4.3 Tertiary Objectives 
To investigate COX-2 level and other tumour-associated proteins in the tumour tissue and relate these 
findings to the trial outcome. 
 
5 TRIAL ORGANISATION 
This is an intergroup co-operative multicentre, randomised, double blind, placebo-controlled trial. 
 


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This trial has been developed by the Steering Committee of the International Collaborative Cancer Group 
(ICCG) and the German Breast Group (GBG) and will be run under the auspices of the Breast International 
Group (BIG). The trial will be co-ordinated jointly by the ICCG Data Centre located at the Charing Cross 
campus of Imperial College London, with support from the Institute of Cancer Research Clinical Trials and 
Statistics Unit and by the GBG Forschungsgesellschaft mbH. 
 
In this study, the two Coordinating Data Centres (CDCs) will be responsible for the overall conduct of the trial 
and the collection of data. An Independent Data Monitoring Committee (IDMC) will be appointed to review 
safety and efficacy data, in confidence, on a regular basis as they see fit, but at least annually. 
 
 
 


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6 TRIAL DESIGN 
A phase III, multicentre, double-blind, placebo controlled, randomised trial. Patients are randomised between 
two years celecoxib and placebo in a 2:1 ratio in favour of celecoxib. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Breast Cancer 
(T1N0 Grade 1 excluded, Her 2 +++ or FISH +ve excluded) 
Complete Resection 
Margins ≥1mm 
Placebo once daily for 
2 years  
Celecoxib once daily 
for 2 years 
+/- (Neo) adjuvant Chemotherapy 
+/- Radiotherapy (can be concurrent) 
HR +ve patients will receive endocrine therapy according to local practice 
 
R


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7 PATIENT SELECTION 
7.1 Chemotherapy Treatment for Primary Disease 
Prior to randomisation, patients may have received chemotherapy1. Any patients who have received 
chemotherapy should have finished their treatment at least three weeks prior to randomisation, and must 
have received at least 4 cycles. The schedule of preference is FEC 3-weekly for 6 courses, however, other 
dose schedules of FEC or FAC plus combinations that contain EC/AC followed by a taxane, or 
Epirubicin/Doxorubicin plus a taxane are permitted. CMF may be substituted for patients where Epirubicin is 
contraindicated. (See Appendix II for recommended chemotherapy regimens). All patients should have an 
electrocardiogram (ECG) and clinical cardio-vascular assessment before randomisation, at the 12 month visit 
and at the end of celecoxib/placebo therapy (normally at 24 month visit). If treatment is terminated early a 
cardiovascular assessment and ECG must be performed as soon as possible, but no further cardiac 
assessments are required by the protocol. 
 
As the trial is open to patients who may or may not have received chemotherapy, it is recommended that 
eligible patients in the UK should be identified at the hospital multidisciplinary team meetings and referred to 
the local investigator. All patients will receive further information about the study, including the patient 
information sheet prior to consent. 
7.2 Participation in Other Studies 
Patients previously entered into interventional trials, regardless of endpoint, can only be entered into the 
study provided that the Trial’s Steering Committee and/or Management Group (as applicable) approve 
participation in REACT. The treatment phase of any interventional trial should have finished before patients 
start taking celecoxib/ placebo. In addition, the REACT Trial Management Group (TMG) needs to be 
informed of this decision. Trials of neo-adjuvant chemotherapy where the primary endpoint is pathological 
tumour response are permitted with the prior consent of the REACT TMG. 
 
7.3 Inclusion Criteria  
All the following criteria must be fulfilled for study entry: 
1. Completely resected (≥1mm), histologically or cytologically proven unilateral breast cancer. 
2. Female ≥18 years of age, no upper age limit 
3. If (neo)adjuvant chemotherapy has been received, then the patient must have received at least 4 
cycles.  Patients must have completed chemotherapy prior to study entry.  
4. HR negative women must have received prior chemotherapy.   
5. Study entry must be within any of the following timelines: 
• 
3 months of the end of definitive breast surgery OR 
• 
Between 3 weeks and 4 months after day 1 of the last cycle of adjuvant chemotherapy OR 
• 
6 weeks of the end of radiotherapy. 
6. World Health Organisation (WHO) performance status 0 or 1 
7. Pre-treatment haematology and biochemistry values within acceptable local limits: 
• 
Haemoglobin (as per local ranges) 
                                                     
1 All HR negative patients MUST have received chemotherapy prior to study entry. 


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• 
WBC ≥ 3.0 × 109/l or ANC ≥ 1.5 × 109/l 
• 
Platelets ≥ 100 × 109/l 
• 
Serum bilirubin <1.5  x UNL 
• 
Alkaline phosphatase ≤ 1.5 × UNL 
• 
Serum creatinine < 1.5 × UNL 
8. Negative pregnancy test in patients of child-bearing potential. 
9. Normal baseline ECG and normal clinical cardiovascular assessment after completion of all (neo) 
adjuvant chemotherapy.  
10. No previous or current evidence for metastatic disease. 
11. Be accessible for and consent to long term follow-up. 
12. Written informed consent prior to commencement of specific protocol procedures must be obtained 
and documented according to the local regulatory requirements. 
 
A randomisation form detailing basic eligibility and identifying information must be received before the patient 
can be randomised. 
7.4 Exclusion Criteria 
Any patient with any of the following criteria will not be eligible for randomisation: 
1. Patients with node negative, T1, Grade 1 breast cancer. 
2. Unresectable, metastatic or bilateral breast cancer. 
3. Active or previous peptic ulceration or gastrointestinal bleeding in the last year. 
4. Active or previous history of inflammatory bowel disease. 
5. A past history of adverse reaction/hypersensitivity to NSAIDs, including celecoxib and salicylates, or 
sulphonamides. 
6. On current or planned chronic NSAIDs therapy (except low dose aspirin ≤ 100 mg QD or 325mg 
QOD). Chronic use of NSAIDs is defined as a frequency of 1 or more a day, for more than a total of 
6 weeks per year. 
7. Current or long-term use of oral corticosteroids.  
8. Known or suspected congestive heart failure (>NYHA I) and/or coronary heart disease, previous 
history of myocardial infarction, uncontrolled arterial hypertension (ie BP >160/90mmHg) under 
treatment with two anti-hypertensive drugs, rhythm abnormalities requiring permanent treatment. 
ECG should be considered within normal limits by a clinician prior to starting trial therapy. 
Echocardiogram although not essential can be carried out if the investigator judges it to be 
necessary.  
9. Patients with diabetes controlled by diet and oral medication are eligible for the study however 
patients with insulin dependent diabetes are excluded. 
10. Past history of stroke/TIA, symptomatic peripheral vascular disease or carotid disease. 
11. Previously entered into an adjuvant chemotherapy trial for which approval for entry into REACT has 
not been granted by the Steering Committee/Management Group of the other trial. 
12. ER receptor status unknown. 
13. HER2+++ or FISH positive, or HER 2 status unknown. 
14. HR negative and not received (neo)adjuvant chemotherapy 
15. Use of hormone replacement therapy within the last 6 weeks. 


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16. Pregnant or lactating women or women of childbearing potential unwilling or unable to use adequate 
non-hormonal contraception. No previous or concomitant malignancies except adequately treated 
squamous cell / basal cell carcinoma of the skin, in situ carcinoma of the cervix or DCIS/LCIS of the 
breast, unless there has been a disease-free interval of 10 years or more. 
17. Psychiatric or addictive disorders which could preclude obtaining informed consent. 
18. Clinical evidence of severe osteoporosis and/or history of osteoporotic fracture. 
 
Note: Use of Bisphosphonates for clinical purposes is not an exclusion criterion. 
7.5 Entry Procedure 
Assessments required pre-randomisation: 
• 
Complete history and physical examination (within 4 weeks before randomisation) 
• 
WHO Performance Status assessment 
• 
Clinical cardiovascular assessment including cardiac history, blood pressure, pulse, results for HDL 
and total cholesterol, smoking status and diabetes.  
• 
Baseline ECG (standard 12 lead ECG) within three months of entry in the study to exclude any 
cardiac condition that would preclude entry into REACT. The ECG should be performed after 
completion of all (neo) adjuvant chemotherapy. A copy of the ECG obtained at each visit should be 
sent to the designated CDC. The ECGs and reports must have the identity of the patient protected. 
Only the patient’s initials, trial ID number, date of birth, site number and date of assessment should 
be included on the report and on the ECG trace. 
Note: The baseline ECG does not have to be sent to the CDC before a patient can be randomised. 
• 
Haematology (Hb, WBC or ANC, platelets) & Biochemistry (serum bilirubin, creatinine, alkaline 
phosphatase), and cholesterol (within 4 weeks before randomisation). 
• 
Pregancy Test (patients of child-bearing potential must have had a negative pregnancy test result 
within 7 days prior to randomisation. Pregancy test can either be urine or serum based. 
• 
Mammogram at a maximum of 3 months prior to diagnosis of breast cancer. If mammography is part 
of the current practice in the participating centre or a mammographic screening program is in place, 
the program should continue and all patients participating in this program should have mammograms 
performed as scheduled. No additional mammograms (further to routine screening program) will be 
required as part of the REACT study. Imaging/Examinations, where clinically indicated metastatic 
disease should be excluded prior to randomisation using investigations according to local practice 
(i.e. Chest X-ray / CT, liver ultrasound, bone scan). However, it is recommended that in the case of 
node positive breast cancer with more than 3 positive nodes, that all three of these investigations are 
performed routinely to exclude metastatic disease.  
Also to be recorded: 
• 
Demography (date of birth & ethnic origin). 
• 
Breast cancer history (date of surgery, surgical procedure, size and grade of primary tumour nodal 
status, ER status, radiotherapy and chemotherapy). 
• 
Concomitant medication (description of classes of concomitant medication taken at the time of 
randomisation). 
• 
Menopausal status:  
a) Postmenopausal: 
 >12 months since last menstrual period at time of diagnosis OR 


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 postmenopausal gonadotrophin levels (luteinizing hormone or follicle stimulating hormone 
levels >40 IU/L) or postmenopausal estradiol levels (<5ng/dL) OR 
 prior bilateral oophorectomy OR 
 radiation menopause (at least 3 months previously). 
 NB Chemotherapy or GnRH induced amenorrhoea is not accepted 
b) Perimenopausal: 
 Women with irregular periods within 6 months or more prior to diagnosis.   
 
c) Premenopausal 
 
• 
With patient’s specific consent, pathology information relating to tissue to be donated to the central 
tumour banks.  
• 
With patient’s specific consent, hospital and/or health service number. 
7.6 Randomisation  
Each participating centre should agree its affiliation to one of the CDCs prior to participating in the study. 
Randomisation will be carried out by one of the CDCs.  
Patient randomisation will only be accepted from authorised investigators. 
Patients may be randomised within any of these timelines: 
• Within 3 months of definitive breast surgery OR 
• Within 4 months of day 1 of the last cycle of adjuvant chemotherapy. Patients should have finished 
chemotherapy prior to randomisation and there should be a gap of at least three weeks between day 
1 of the last cycle and the date of randomisation OR 
• Within 6 weeks of the end of radiotherapy. Patients can have radiotherapy concurrently with study 
medication as long as this is not part of a radiotherapy trial. 
 
No patients who have started and terminated chemotherapy before they have received 4 cycles, will 
be permitted to be randomised. 
 
Centres affiliated to the ICCG will randomise patients by FAX to the ICCG. Centres affiliated to GBG will 
randomise patients using the MedCODES®-System. All centres will be required to complete a randomisation 
request form before randomisation. 
 
Confirmation of randomisation will be provided within 24 hours on working days and all patients will be 
allocated a unique trial identification (ID) number and a box number for the first 12 months of study 
treatment. 
 
The unique trial identification number consists of eight (8) characters - two letters for the country 
abbreviation, three digits for the Centre number (i.e. hospital) and three digits for the patient number (within 
each centre). 
 
This number should be used on all Case Report Forms (CRFs) and all subsequent correspondence relating 
to that patient. 
 
The CDC will contact the site with a new box number prior to patient resupply at 12 months. Each patient will 
be assigned unique box numbers and these should be recorded on the designated part of the CRFs. 


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Separate randomisation lists will be prepared for each participating centre. The randomisation list will provide 
the link between the patient’s trial ID and the drug supply. Copies of the lists will be held by the randomising 
CDC. If a trial ID has been incorrectly allocated, no attempt should be made to rectify the error but details of 
the mistake should be recorded, including an appropriate explanation, and forwarded to the CDC 
immediately. The patient should continue with the number that has been allocated. Allocation of subsequent 
patients will continue using the first unallocated number from the randomisation list. 
 
8 TREATMENT 
Treatment must begin within 14 days after randomisation. Radiotherapy should be given according to local 
policy (concomitant trial treatment and radiotherapy is permitted provided patients are not receiving 
treatment as part of a radiotherapy trial). Patients will be randomised 2:1 (in favour of celecoxib) to receive: 
 
Placebo: Two capsules once daily with food OR 
Celecoxib: Two 200mg capsules once daily (400mg per day) with food  
 
The duration of celecoxib/placebo treatment is 2 years. 
 
Since the trial is double-blind, the patient’s specific treatment will not be indicated on the trial supplies or 
mentioned during the randomisation process. The unique box number allocated at the time of randomisation 
allows the tracing of each patient’s treatment to their allocated treatment code in the case of unblinding (see 
separate section 8.6 for information on code breaking). 
 
In addition all HR+ve patients will receive endocrine therapy according to local practice. Patients who are 
eitherHR+ve (both ER+ve/PgR-ve and ER+ve/PgR+ve) or PgR+ve (e.g. ER-ve/PgR+ve) are considered to 
be HR+ve for the purposes of this study. 
8.1 Source of Drug 
Pfizer Inc. manufactures celecoxib 200 mg capsules and matching placebo capsules. 
8.2 Celecoxib / placebo Packaging and Labels   
Pfizer Inc. will supply celecoxib or placebo in white plastic bottles. Drug will be distributed to each 
participating centre and will be used solely for the treatment of patients in the REACT trial. Each bottle will 
contain 140 celecoxib 200 mg capsules or matching placebo with a child resistant cap and tamper-evident 
seal. The box that will be assigned at dispensing will contain 6 bottles of celecoxib/placebo representing a 1 
year supply.  
 
The box will be labelled in accordance with Annex 13 and will have a two-part tear-off label, which will 
contain minimally, the protocol number, a blank for the unique trial identification number, a blank for the 
investigator name, and the box number. The bottles will also be labelled in accordance with Annex 13 and 
will contain minimally, the protocol number, a blank for the unique trial identification number, a blank for the 
investigator name, box number, storage instructions and administration instructions.All blanks on the box and 
bottle labels should be completed prior to dispensing.  


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At the time of dispensing the right side of the box tear-off label will be removed and attached to the 
dispensing records to verify correct box number as well as to provide details for unblinding (in the case of an 
emergency only). Other site personnel should not have access to this information. Celecoxib / placebo will be 
resupplied at one year following the allocation of a new box number from the CDC. It is the responsibility of 
the Principal Investigator (PI) to ensure that drug is available for the duration of treatment. 
 
It should be noted that during the course of the study each patient will be allocated one unique trial 
identification number. However, to aid drug supply, each patient will be allocated a different box number 
each time they are dispensed medication. 
 
The left side of the label that will remain on the bottle at dispensing will contain minimally, the protocol 
number, a blank for the unique trial identification number, lot number, storage instructions and administration 
instructions. The right side of the label will contain minimally, the protocol number, lot number and a blank for 
the unique trial identification number. At the time of dispensing the right side of the label will be removed and 
attached to the dispensing records. 
8.3 Drug Distribution 
Celecoxib / placebo for the duration of the study will be supplied by Pfizer Inc. and will be distributed to the 
participating centres by Almac Clinical Services. Celecoxib / placebo will be dispensed through the hospital 
pharmacy or investigator upon receipt of the unique trial identification number and box number allocated by 
the CDC. 
 
Randomisation lists for each Centre will be generated by the ICR-CTSU, with a copy sent to each CDC. An 
agreed number of allocations will be sent to the Centre pharmacy or investigator. The CDC will be 
responsible for informing ALMAC when further supplies are required. 
8.4 Drug Dispensing 
The person at the investigator Centre responsible for dispensing will dispense study medication. The unique 
trial identification number will be written on the box label. Prior to dispensing, the tear-off section of the label 
should be removed and attached to the appropriate dispensing records. For centres affiliated to the GBG, 
patients will be provided with a patient-passport where the next visit date, box number(s) and contact 
information will be noted. Celecoxib/placebo will be dispensed at baseline and at the 12 month visit.  
8.5 Storage  
The study drug must be stored at room temperature at 25°C (77°F); excursions permitted to 15-25°C (59-
77°F). The investigator will be responsible for ensuring that the study medication is stored in a secured area, 
such as a pharmacy or locked cabinet. The study product may not be used outside the context of the 
protocol. Under no circumstances should the PI or Centre personnel supply product to other investigators or 
clinics, or allow the drug supplies to be used other than as directed by this protocol without prior 
authorization of study management. 


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8.6 Code Breaking 
Unblinding is restricted to emergency situations and should only be used under circumstances where 
knowledge of the treatment is necessary for the proper clinical care of the patient. The blinded code will be 
broken on the occasion of a Serious Adverse Event (SAE) only if a relationship between the reaction and the 
double blind medication is definite, probable or possible AND the event is unexpected i.e. SUSAR. 
Unblinding can also be carried out if a study participant becomes pregnant while on treatment with 
celecoxib/placebo or within 30 days after the end of treatment. In this case the pregnancy and the baby will 
need to be followed up for a period of 18 months to assess any congenital anomaly or birth defect. If the 
pregnancy occurs after 30 days of the end of treatment, it will no longer need to be reported to the sponsor 
and no further follow up is necessary.  
If the blinded treatment code needs to be broken, the relevant code break card should be retrieved. This can 
be identified from the tear-off label attached to the dispensing records. It is the responsibility of the PI to 
ensure that code break cards are stored in a secure area and that only appropriate personnel have access to 
them.  
An ‘Unblinding Request’ must be completed and the CDC informed immediately. The reason for unblinding 
and date should be recorded on the Unblinding Request and signed by the PI. The request should be sent to 
the person or department responsible for storing the code break envelopes.   
 
An ‘End of Blinded Study Drug’ form must be sent to the CDC if treatment is discontinued prematurely for 
any reason.  
8.7 Drug Interactions/Precautions 
Celecoxib should not be given to patients who have demonstrated allergic type reactions to sulphonamides 
or who have experienced asthma, urticaria or allergic type reactions after taking aspirin or other NSAIDs. 
Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver. Co-administration of 
celecoxib with drugs that are known to inhibit 2C9 should be carried out with caution. In vitro studies indicate 
that celecoxib although not a substrate is an inhibitor of cytochrome P450 2D6. Therefore, there is a potential 
for an in vivo drug reaction with drugs that are metabolised by P450 2D6. 
 
Clinical studies have identified potentially significant interactions with fluconazole and lithium. Experience 
with nonsteroidal anti-inflammatory drugs NSAIDs also suggests the potential for interactions with 
furosemide and ACE inhibitors (see Appendix III). 
 
The following medications are not permitted while patients are receiving celecoxib/placebo: 
• 
Chronic use of other NSAIDs (chronic use is defined as a frequency of 1 or more a day, for more 
than a total of 6 weeks per year) 
• 
Oral corticosteroids 
• 
Hormonal replacement therapy 
• 
Hormonal contraception methods (birth control pill or implants). 
These medications should not be given concomitantly with celecoxib/ placebo. A treatment break of up to 
one month is allowed. If a patient requires a longer break from celecoxib/ placebo the patient should be 
withdrawn from study medication but should continue on follow-up. 
 
A more detailed list of drug interations and precautions can be found in Apendix III. 


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8.8 Drug Accountability 
Patients must be asked to bring their trial medication with them every time they attend the clinic, for purposes 
of drug accountability. Every effort should be made to encourage patients to return the unused medication 
and empty packs/bottles. The unused capsules should be collected by the investigator/study nurse and 
returned to pharmacy for destruction according to local practices. Drug accountability and destruction will be 
recorded on study specific forms. 
 
9 FOLLOW UP SCHEDULE 
9.1 Routine follow-up visits  
During the course of the trial, all patients will be followed-up as follows: 
UK: 
Year 1  
 
 
 
Baseline and months 3, 6 and 12 
Year 2 & 3 
 
 
6 monthly (months 18, 24, 30 and 36) 
Year 4 & 5         
 
Annually (months 48 & 60) 
Year 6 – 10*        
 
Annual follow up  
 
Germany: 
Year 1               
 
Baseline and months 3, 6 and 12 
Year 2               
 
6 monthly (months 18, 24) 
Year 3 – 10* 
Annual follow up via a self reporting questionnaire, chart reviews at the sites or 
based on information deriving from the GBG registry of previous study participants. 
 
 
* Should cost effective, reliable systems be in place, for example electronic methods of routine data 
collection, and at the discretion of the Trial Steering Committee, off-treatment follow up may continue beyond 
10 years 
 
9.2 On-treatment assessments 
• 
Patient and disease status 
• 
Physical examination  
• 
WHO performance score  
• 
Blood pressure 
If BP>140/90 is detected during follow-up then the patient should be referred to the GP for further 
assessment of blood pressure and treatment as per National Guidelines 
• 
Clinical cardiovascular assessment (including cardiac history, blood pressure, pulse, results for HDL 
and total cholesterol and smoking status) and ECG 12 months after randomisation and at the end of 
celecoxib/placebo therapy (normally at 24 months ). If treatment is terminated early a cardiovascular 
assessment and ECG must be performed but no further cardiac assessments are required.  A copy 
of the ECG obtained at each visit should be sent to the designated CDC  
If at 12 months and at the end of celecoxib/placebo (normally at 24 months) the ratio between Total 
and HDL cholesterol is equal or higher than 6, patients should be recommended to see their primary 


REACT Protocol, Version 39, dated 01.11.2016 
 
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care physician with a view to being offered dietary advice and/or lipid lowering therapy as per 
National Guidelines  
• 
Safety relevant concomitant medication  
• 
Endocrine treatment details – name of treatment, date of first intake, treatment compliance (if 
applicable) 
• 
Bisphosphonates (if applicable) – start and end date 
• 
Imaging/Examinations– additional tests/investigations (e.g. Bone/liver scan etc) to detect metastatic 
disease are at the investigators’ discretion if clinically indicated 
• 
Compliance of trial medication 
• 
Adverse events assessment. Only AEs assessed as CTCAE grade 2 or above should be reported on 
the relevant CRFs. All other AEs should be treated and followed-up as per normal local practice 
9.3 UK Off-treatment Follow-up assessments 
• 
Patient and disease status 
• 
Other cancer treatment details (if applicable):  
Endocrine therapy – Name of treatment  
Bisphosphonates – Start and end date  
• 
Adverse events that occurred within 30 days after discontinuation of celecoxib/placebo. Only AEs 
assessed as CTCAE grade 2 or above should be reported on the relevant CRF 
• 
In the off-treatment follow up period following the 30 days after discontinuation of celecoxib/placebo, 
only PI assessed Cardiac and GI side effects/ illnesses  assessed as CTCAE grade 2 or above 
should be reported on the relevant CRF 
• 
Serious Adverse Events (if in the opinion of the Investigator the event is related to 
celecoxib/placebo) 
• 
Imaging/Examinations – additional tests/investigations (e.g. Bone/liver scan etc) to detect 
metastatic disease are at the investigators’ discretion if clinically indicated 


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9.4 Germany Off-treatment follow up  
Post-treatment data will be collected annually using a self-reporting system via a patient questionnaire, chart 
reviews at the sites or based on information deriving from the GBG registry of previous study participants: 
• 
Patient and disease status 
• 
Other cancer treatment details (if applicable):  
Endocrine therapy – Name of treatment / Start and end date  
Bisphosphonates intake 
• 
CTCAE grade 2 or above Adverse events relating to GI surgery and Myocardial infarction 
 


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9.5 Schedule of Assessments 
Months from Randomisation 
0 (Baseline) 
3 
6 
12 
18 
24 
30 
36 
48 
60 – 
120 
Demography, breast cancer history, 
menopausal status1 
X 
 
 
 
 
 
 
 
 
 
WHO Performance 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
 
 
 
 
Blood Pressure 
X 
X 
X 
X 
X 
X 
 
 
 
 
Haematology and Biochemistry  
X 
 
 
 
 
 
 
 
 
 
Safety Relevent Concurrent  Medication  
X 
X 
X 
X 
X 
X 
 
 
 
 
Mammogram   
X  
 
 
 
 
 
 
 
 
 
Clinical Cardiovascular Assessment / ECG  
X 
 
 
X 
 
X 
 
 
 
 
Dispense Celecoxib/ placebo  
X 
 
 
X 
 
 
 
 
 
 
Patient and disease status  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment Compliance 
 
X 
X 
X 
X 
X 
 
 
 
 
 Endocrine Treatment (if applicable) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bisphosphonate Treatment  (if applicable) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events2 
 
X 
X 
X 
X 
X 
X 
 
 
 
Cardiac and GI Ilnesses and side effects  
 
 
 
 
 
 
X 
X 
X 
X 
Tumour Block Collection (optional) 
X 
 
 
 
 
 
 
 
 
 
Chest X-ray /Liver ultrasound /Bone scan  
X 
 
 
 
 
 
 
 
 
 
Imaging/examinations  
X 
 
 
 
 
 
 
 
 
 
  
9.6 Follow-up upon relapse 
Upon relapse, patients should have the appropriate clinically indicated tests as determined by local practice, 
but which must include as a minimum those described in section 9.3 and 9.4. Follow-up after relapse should 
be according to the routine follow-up schedule defined above unless otherwise indicated clinically. 
9.7 Premature discontinuation of treatment 
Patients will be withdrawn from trial treatment if, in the opinion of the investigator, it is medically necessary, 
or if it is the wish of the patient. Any patient who is found to have developed new Q-waves, indicative of 
myocardial infarction on routine ECG, will be removed from the celecoxib/placebo therapy immediately. The 
                                                     
1 As detailed in section 7.5.  
2 Adverse events (CTC grade 2 or above) that occur within 30 days after discontinuation of celecoxib/placebo (normally 
at 24 months) should be reported at the 30 MFU visit using the current AE Reporting forms. In case of premature 
discontinuation of celecoxib/placebo, AEs that occur within 30 days after discontinuation should be reported at the next 
visit. All reported AEs need to be followed-up until resolution. 


REACT Protocol, Version 39, dated 01.11.2016 
 
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development of new Q-waves on ECG should be reported as a Serious Adverse Event within the guidelines 
stated in Section 11.  
 
If a patient does not return for a scheduled visit, every effort should be made to contact the patient. In any 
circumstance, every effort should be made to document the patient outcome, if possible. If a patient requests 
withdrawal from the trial (as distinct from premature withdrawal from treatment), the patient must be asked 
whether she accepts that her clinical data will continue to be used for trial purposes (particularly details of 
disease related events and follow-up). 
 
Patients will discontinue study treatment in the case of any relapse. Patients treatment after relapse is at the 
discretion of the investigator. Other reasons for a patient to discontinue study treatment include; the 
occurrence of an SAE, which is considered to be related to treatment and unexpected and which 
necessitates a change in treatment, the withdrawal of consent, or the experience of unacceptable toxicity. 
There will be no dose modification and the patient will be discontinued from study treatment should any 
unacceptable event occur. An End of Treatment with Blinded Study Drug ‘form must be completed, and the 
CDC informed if treatment is discontinued prematurely for any reason. CDC should be notified as soon as 
possible in this instance.  
All patients will continue to be followed-up, irrespective of whether they have discontinued study treatment 
prematurely, unless, in exceptional circumstances, they withdraw their consent to be followed up. 
 
9.8 Treatment Breaks 
Treatment breaks up to one month are permitted; however, the overall treatment duration should not be 
extended past 2 years to account for such breaks. 
 
Note: There is no evidence of delays in wound healing if celecoxib/placebo is used in the perioperative 
period. 
9.9 End of Trial 
The end of trial will be last patient’s last data capture.  
 
10 ADVERSE EVENT REPORTING 
10.1 Definition of an Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient administered a drug; the event does 
not necessarily have a causal relationship with the treatment or usage. 
10.2 Procedure for collecting Adverse Events 
All adverse events assessed by the PI as NCI-CTCAE grade 2 or above will be collected from the time of the 
randomisation until 30 days after the discontinuation of celecoxib/ placebo and should be reported on the AE 
reporting Form. Whenever one or more signs and/or symptoms correspond to a disease or a well-defined 
syndrome only the main disease/syndrome should be reported. The severity of adverse events will be 


REACT Protocol, Version 39, dated 01.11.2016 
 
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graded according to the current NCI-CTCAE criteria. For each sign/symptoms, the highest grade observed 
since the last visit should be reported. 
During off treatment follow-up only Cardiac and GI side effects/ illnesses assessed as NCI-CTCAE grade 2 
and above should be reported. 
11 SERIOUS ADVERSE EVENTS AND SERIOUS ADVERSE REACTIONS 
11.1 Definition of a Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is defined as any of the following, whether or not considered related to the 
trial treatment: 
• 
Death 
• 
Life-threatening condition (i.e. immediate risk of death) 
• 
In-patient hospitalisation, excluding elective surgery, or prolongation of existing hospitalisation. 
• 
Persistent or significant disability/incapacity 
• 
Permanent impairment of function or permanent damage to body structure or if an intervention is 
required to prevent permanent impairment or damage.  
• 
Cancer* 
• 
Congenital anomaly/birth defect 
• 
Overdose (excluding asymptomatic overdose) 
• 
Development of new Q-waves on ECG 
 
 [*other than breast cancer recurrence, the patient having had breast cancer and relapse with breast cancer 
being a study end-point]. 
 
Any other adverse event that the investigator or company judges to be serious or which is defined as serious 
by the regulatory agency in the country in which the adverse event occurred. 
 
 If a serious adverse event occurs during the follow-up period, it must be reported if in the investigator’s 
judgement there is a relationship to any study medication. 
11.2 Procedures for reporting SAEs 
In the event of a SAE the investigator must: 
• 
Complete a Serious Adverse Event Report Form and fax to the designated CDC within 24 hours of 
awareness of the event. This should contain all information known at the time of the report. 
• 
The initial report should then be followed by the completed (with full information) Serious Adverse 
Event Report Form within 5 days of the event. 
• 
Follow up of patients who have experienced an SAE should continue until recovery is complete or 
the condition has stabilised. 
All SAEs will be centrally reviewed to confirm relatedness and expectedness as defined in 11.3.  
11.3 Definition of a Serious Adverse Reaction (SAR) 
A SAR is defined as a SAE (see section 11.1) that is judged by the local Investigator to have a definite, 
probable or possible causal relationship with the use of one or other of the study drugs. 


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The expectedness of a SAR should be assessed in accordance with the information in the current Celecoxib 
Investigator Brochure and/or UK/German SmPC Expected SARs should be reported as per the SAE 
reporting guidelines (section 11.2) and followed up until recovery is complete or the condition has stabilised.  
11.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are those events which  
• 
meet the criteria of ‘serious’ (see section 11.1), AND 
• 
are judged to have a definite/probable/possible causal relationship with one or other of the study 
drugs (section 11.3), AND 
• 
are NOT  consistent with the information listed in the current IB or SmPC. 
 
SUSARs should be reported to the relevant CDC as per the SAE reporting guidelines (section 11.2). In 
addition they should be reported to the appropriate Ethics Committee by the relevant CDC, according to local 
regulations. 
 
The CDCs are responsible for circulating information on SUSARs to participating centres and notifying both 
the Safety Department of Pfizer Inc. and the Health Authorities. 
 
Follow up of patients who have experienced a SUSAR should continue until recovery is complete or the 
condition has stabilised. 
12 STUDY ENDPOINTS 
12.1 Primary end-points 
The primary aim is to assess the disease-free survival (DFS) benefit of two years adjuvant therapy with the 
COX-2 inhibitor celecoxib compared with placebo in primary breast cancer patients. 
12.2 Secondary end-points 
Secondary endpoints will determine:  
• 
overall survival (OS) 
• 
the toxicity associated with long term use of celecoxib in primary breast cancer patients 
• 
cardiovascular mortality 
• 
the incidence of second primary cancers 
Subgroup analysis based on HR status (HR+ve, HR-ve) will be performed using the same endpoints as in 
the analysis of all patients.  
12.3 Definition of disease related events 
Disease free survival is defined as time from randomisation to the date of first event; with events contributing 
to the analysis defined as loco-regional and distant breast cancer recurrence, new primary breast cancer 
(ipsilateral or contralateral) and death without disease relapse (intercurrent death). 
 
First local recurrence and first distant recurrence will be recorded on separate parts of the CRF. In the event 
of local progression, all patients must be followed up for distant recurrence, second malignancy and survival. 
Similarly in the case of second malignancy, the appropriate CRF should be completed and patients should 


REACT Protocol, Version 39, dated 01.11.2016 
 
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continue to be followed for disease progression and where possible the relation of any subsequent disease 
progression and/or death due to the primary or second cancer should be established. 
 
Date of suspicion of relapse, action taken to confirm relapse and date relapse confirmed will all be recorded 
on the CRF. 
 
Any relapse requires study treatment to be stopped, and thus is included as an event. Any malignant 
contralateral breast disease will be included as a second primary, and relapse with supraclavicular disease 
will be included as local relapse according to TNM classification v6. 
 
‘Breast cancer’ deaths will be all deaths with breast cancer specified as a cause of death and deaths from 
any cause following a distant relapse. 
 
Patients may continue to receive the study treatment after a second (non-breast) primary is diagnosed; the 
final decision is at the Investigator’s discretion.  
12.4 Safety Evaluation  
A potential increase in cardiovascular rates has been suggested with selective COX-2 inhibitors (Mukherjee 
et al, 2001). Cardiovascular events will therefore be closely monitored and will be a primary safety 
consideration.  
 
13 STATISTICAL ISSUES 
13.1 Stratification 
At randomisation, patients will be stratified by centre and hormone receptor status (ER and/ or PgR positive 
versus ER/PgR negative). 
13.2 Sample Size 
In order to detect a 20% reduction in risk of recurrence in the five year DFS (e.g. from 70% to 75.2%), 2590 
patients (709 events) are required (hazard ratio=0.8). This number is based on a 2:1 randomisation 
(celecoxib vs. placebo) with 80% power and α=0.05 (two-sided). The figure of 70% DFS at five years in the 
control group is based on an estimation of more than 40% of the patients randomised being HR negative. 
Once recruitment is ongoing the IDMC may be asked to consider an increase in sample size. Formal interim 
analysis of efficacy based on log-rank comparison and an estimate of the hazard ratio will be conducted after 
¼, ½, and ¾ of the required number of events (see section 13.1). 
13.3 Analysis 
13.3.1 Efficacy Analysis 
All patients will be evaluated for endpoints in the arm to which they were randomised, irrespective of the 
treatment they actually receive. No patient will be removed from the analyses irrespective of whether she is 
found to have violated the eligibility criteria after randomisation or to have been withdrawn from trial 
medication prematurely, except in the case that she withdraws her consent to use of data already collected 
in the trial. Thus, analysis will be by intention to treat including all consenting patients randomised. 


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The principal analysis will be based on a log rank comparison of DFS. DFS is defined as time from 
randomisation to date of diagnosis of first local or distant metastases at any site or second breast primary 
confirmed by an appropriate method (see 12.3). Probabilities of DFS and OS will be presented as Kaplan-
Meier survival curves with fixed term survival estimates. Hazard ratios will also be calculated. Cox regression 
techniques will be used to adjust for important factors likely to influence prognosis or confound any treatment 
effect. These factors may include ER, menopausal and COX-2 status, and chemotherapy regimen. 
Exploratory sub group analyses will be reported by hormone status, menopausal status, nodal status, and 
previous use of chemotherapy (or not). Baseline characteristics will be described by randomised treatment 
group. All statistical tests will be two-sided and 95% confidence intervals will be used. 
 
13.3.2 Safety Analysis  
There will be a sequential monitoring of toxicity and it is likely that the first analysis will be carried out when 
the first 100 patients have completed the first 6 months of assessment. 
 
Toxicity and the frequency and nature of adverse events will be compared between the randomised groups. 
Summary measures and non-parametric tests will be used as necessary. In particular, the proportion of 
patients experiencing toxicity of CTC grade 3 or 4 and the maximum CTC toxicity grade will be compared. An 
analysis of safety endpoints by treatment received will be performed. 
 
Incidence of cardiovascular events after randomisation will be compared between the two arms and the 
absolute difference in incidence will be estimated (with associated confidence limits). 
 
Subgroup analysis based on HR status (HR+ve, HR-ve) will be performed using the same endpoints as in 
the analysis of all patients. The trial is not powered to detect differences within these subgroups thus these 
analyses will be descriptive in nature unless changes are made to the design of the trial or there is an 
increase in sample size (see 14.1 for details of this possibility). 
 
 
 


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14 STUDY LOGISTICS 
14.1 Role of Independent Data Monitoring Committee (IDMC) 
An IDMC has been formed to review safety and efficacy data, in confidence, on a regular basis as they see 
fit, but at least annually. Following each meeting, the IDMC will report their findings and recommendations to 
the TMG. Interim analysis of side-effects, tolerability, disease-free and overall survival for all randomised 
patients will be supplied in strict confidence by the trial statistician to the IDMC together with any other 
analyses that the IDMC may request. 
 
The main criterion for early release of efficacy data from the trial by the TMG upon suggestion from the IDMC 
will be that evidence from the trial and from other sources suggests a) proof beyond reasonable doubt that 
for all, or for some types of patient, one treatment regimen is clearly indicated or contra-indicated in terms of 
a net difference in DFS or OS, and b) evidence that might reasonably be expected to influence routine 
clinical practice. Criteria for the above will usually be a difference in DFS or OS at any stage significant at p < 
0.001 by overall log-rank analysis. Particular consideration will also be given to cardiovascular event rates 
and, in addition to early reporting on the basis of efficacy, a stopping rule based on excess toxicity in the 
celecoxib arm will be employed. No results on survival or recurrence will be made available to participants or 
the sponsor until the IDMC considers the results to be clinically and statistically informative. 
Once recruitment is ongoing the IDMC may be asked to consider: 
 
a) An increase in sample size. 
Factors dictating this would be:  
i) 
a review of the absolute size of detectable benefit in the light of any new emerging data (as was the 
case with the Intergroup Exemestane Study) 
ii) if the withdrawal rate from celecoxib/placebo treatment was substantial and sensitivity analyses 
indicated that the observed withdrawal rate (if it were to continue) was likely to impact on the trials 
ability to detect the hypothesised treatment effect. 
iii) consideration of endocrine subgroup specific analyses 
iv) consideration of a randomisation in HR+ patients between exemestane and non-steroidal aromatase 
inhibitor  
b) Extending the celecoxib treatment to between 3-5 years or a further randomisation at 2 years of 
treatment to stop versus continue (to a total of 3-5 years). 
 
Any of these amendments would require a full re-definition of the statistical considerations for each of the 
specific hypotheses. 
 
Should the original expected event rates used to calculate the sample size be different from those observed 
in the maturing data the IDMC may advise an alternative timing for the principal analysis of the primary 
endpoint based on maturity of follow-up, rather than after 709 events have been obtained. 
 
The TMG will make the final decision based on the recommendations of the IDMC and other factors, such as 
patient accrual. 
 
The IDMC will reserve the right to release any data on outcome or side-effects through the Chairman to the 
TMG to participants if it determines at any stage that the combined evidence from this and other studies 


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justifies it. This includes the circulation of unblinded toxicity data if the IDMC believes that this may lead to 
improvement in patient care. 
14.2 Analyses for Publication 
Unless the IDMC advises otherwise, it is expected that the first analyses for publication/presentation will be 
performed when the required number of events is reached. All trial data are owned by the TMG which will 
have representation from ICCG and GBG and investigators participating in the trial. 
14.3 Publishing policy 
All publications and presentations relating to the trial will be authorised by the trial Steering Committee. 
Authorship will be determined by the REACT TMG, but will include the Chief Investigators and statisticians. A 
writing committee may be appointed. Further authorship will be determined by centre accrual and/or TMG 
membership and/or direction of sub-studies depending on the publication policy of the chosen journal. The 
REACT TMG will have the final decision as to which individuals are the named authors in the light of the 
above considerations. The trials offices who have undertaken the data management and all participating 
centres will be acknowledged in the final manuscript according to patient accrual. 
 
Participants may only present data separately to the total data available, with the permission of the TMG, 
and not less than 6 months after publication of the main results. 
 
Pfizer Inc. has the right to review all abstracts, papers, or other research communications prior to their 
submission to journals, meetings, or conferences. Pfizer Inc. may request removal of propriety information 
and may suggest editorial changes in the papers to the TMG. The TMG has final authority over the content 
of all publications.  
 
15 SUB PROTOCOLS 
A pathology study is taking place. The consent form for the main trial will give patients the opportunity to 
participate. 
 
The aim is to investigate modulators of celecoxib response. A request for a representative formalin fixed 
paraffin embedded (FFPE) tumour block from the patient’s definitive breast cancer surgery will be sent by the 
CDC to the investigator for any patients who consent to the sub-study.  
 
16 TRIAL ADMINISTRATION AND DATA MANAGEMENT 
Each collaborative group will be responsible for the day-to-day conduct of the trial for their collaborating 
hospitals. 
 
The responsibilities will include some or all of the following: 
• 
initiation visits to selected centres (it is important that the investigator and their relevant personnel 
are available during these visits and that sufficient time is devoted to the process). 
• 
communication with/submission to local ethics committee 
• 
randomising patients 


REACT Protocol, Version 39, dated 01.11.2016 
 
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• 
receipt or collection of CRFs from the hospitals 
• 
raising and resolving queries with local investigators 
• 
performing an initial data clean 
• 
monitoring of centres  
• 
requesting drug supply, circulating SAEs and safety reports to centres 
16.1 Case Report Forms (CRFs) 
CRFs should be completed for each subject and should not be made available to third parties. 
 
CRFs will either be in the form of a booklet (if you are affiliated to the ICCG) or as an electronic document (if 
you are affiliated to GBG). 
 
CRF documents will be supplied by the CDCs. CRF booklets will contain forms in triplicate. The top two 
copies must be sent to the CDC undertaking the data management as soon as they are due. The bottom 
copy must be retained in the booklet and held by the investigator. All sections are to be completed on the 
form before sending or submitting to the CDC. If information is not known it must be clearly stated. 
 
The electronic version of the CRF is suited for online documentation through MedCODES® only. 
 
To enable evaluations and/or audit from Health Authorities the investigator must agree to keep records, 
including the identity of all participating subjects (sufficient information to link records, e.g. CRFs and hospital 
records), all original signed Consent Forms, copies of CRFs and drug dispensing.  
 
16.2 Liability/Indemnity/Insurance 
This study is an investigator-led trial designed by the ICCG at Imperial College London and the GBG. The 
study is sponsored by Imperial College London and is being supported by Pfizer Inc. Imperial College, as 
sponsor of the study, maintains a "No Fault" Compensation Scheme through its public liability insurance 
policy. If patients suffer any harmful effects as a result of participation in this study, compensation may be 
claimed through this scheme. The GBG will provide insurance for all patients recruited in Germany according 
to the requirements of German Law. 
16.3 Patient Confidentiality 
The personal data recorded on all documents will be regarded as confidential, and to preserve each 
subject's anonymity, only their initials and date of birth will be recorded on the CRF. The investigator must 
ensure the patient's confidentiality is maintained. 
 
The investigator must keep a separate log of patients' trial number, names, addresses and hospital numbers. 
The investigator must maintain in strict confidence trial documents which are to be held in the local hospital 
eg patients' written consent forms. 
 
The ICCG/GBG will maintain the confidentiality of all subject data and will not reproduce or disclose any 
information by which subjects could be identified, other than reporting of SAEs as required by law. 


REACT Protocol, Version 39, dated 01.11.2016 
 
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Representatives of the trial team will be required to have access to patient notes for quality assurance 
purposes but patients should be reassured that their confidentiality will be respected at all times. 
 
In the case of special problems and/or regulatory audit queries, it may also be necessary for authorised 
representatives of the appropriate regulatory authority to have access to the complete study records. Patient 
confidentiality will be protected at all times. 
16.4 Ethics Issues 
The study described in this protocol will be conducted in compliance with guidelines for Good Clinical 
Practice and applicable regulatory regulations. 
 
The trial will be performed in accordance with the recommendations guiding physicians in biomedical 
research involving human subjects adopted by the 18th World Medical assembly, Helsinki, Finland, 1964 and 
any later revisions.  
 
It is the responsibility of the PI to obtain approval of the trial protocol and any subsequent amendment from 
the IRB/IEC. All correspondence with the IRB/IEC should be filed by the investigator. Copies of the IRB/IEC 
approval should be forwarded to the CDC. 
 
It is the responsibility of the investigator to give each patient, prior to inclusion in the trial, full and adequate 
verbal and written information regarding the objective and procedures of the trial and the possible risks 
involved. The patients must be informed about their right to withdraw from the trial and the possible risk 
involved. The patient information sheet is written according to national guidelines and must be given to each 
patient before enrolment. It is the responsibility of the investigator to obtain signed informed consent from all 
patients prior to inclusion in the trial. 
 
All amendments and translations to the patient information sheet must be agreed prior to trial 
commencement. The trial sites may be subject to inspection by appropriate regulatory authorities. 
 
Patient identification data will be required at randomisation to assist with long term follow-up.  
16.5 Monitoring Strategy 
This study will take a Risk-Based, ‘fit for purpose’ approach to the initiation and monitoring of this study 
consistent with the principles of GCP.  Monitoring procedures and requirements will be documented in a 
Monitoring Plan. The appropriate level and nature of monitoring required for the trial will be assessed by 
undertaking a formal risk assessment of the study. 


REACT Protocol, Version 39, dated 01.11.2016 
 
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American Journal of Cancer 


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APPENDIX I: Study Contacts 
1. 
International Collaborative Cancer Group (ICCG) 
 
 
Prof R C Coombes 
Director of ICCG Data Centre 
ICCG Data Centre 
Department of Surgery and Cancer 
Imperial College London 
3rd Floor Radiotherapy Building 
Hammersmith Hospital Campus,  
Du Cane Road, London, W12 0NN, 
UKTel: +44 (0) 207 59 42792 Fax: +44 
(0) 20 3311 7743 
E: c.coombes@imperial.ac.uk  
Clinical Trials Manager 
ICCG Data Centre 
Department of Surgery and 
Cancer 
Imperial College London 
3rd Floor Radiotherapy 
Building, 
Hammersmith Hospital Campus, 
Du Cane Road, London, W12 
0NN, UK 
Tel: +44 (0) 20 3311 7046 
Fax: +44(0) 20 3311 7743 
E: REACT@imperial.ac.uk 
Prof J M Bliss (Statistician) 
Clinical Trials and Statistics Unit 
The Institute of Cancer Research 
15 Cotswold Road 
Sutton.  
Surrey, SM2 5NG 
UK 
Tel: +44 (0) 20 8722 4297 
Fax: +44(0) 20 8770 7876 
E: judith.bliss@icr.ac.uk 
 
 
  
 
 
2. 
German Breast Group (GBG) 
 
 
Prof. Dr. Gunter von Minckwitz 
GBG Forschungs GmbH (CEO) 
Coordinating investigator 
Martin-Behaim-Straße 12 
63263 Neu-Isenburg  
Germany 
 
Tel.: +49 (0) 6102 7480 429 
Fax: +49 (0) 6102 7987440 
E:minckwitz@germanbreastgroup.de  
Prof. Dr. Bernd Gerber /  
Dr. Toralf Reimer 
Members of the GBG Subboard 
Universitätsfrauenklinik Rostock 
Südring 81 
18059 Rostock  
Germany 
Tel.: +49 (0) 38144014500 
Fax: +49 (0) 38144014599 
E: bernd.gerber@med.uni-
rostock.de 
E: toralf.reimer@med.uni-
rostock.de 
Dr. Julia Kaiser  
REACT Project ManagerGBG 
Forschungs GmbH 
Martin-Behaim-Straße 12 63263 
Neu-Isenburg  
Germany 
Tel.: +49 (0) 6102 7480 203 
Fax: +49 (0) 6102 7480 440 
E: react@germanbreastgroup.de  
 
Dr. Valentina Nekljudova (Statistician) 
GBG Forschungs GmbH 
Martin-Behaim-Straße 12 
63263 Neu-Isenburg  
Germany 
Tel.: +49 (0) 6102 7480 467 
Fax: +49 (0) 6102 7480 440 
E:nekljudova@germanbreastgroup.de 
 
 
REACT Data Management 
GBG Forschungs GmbH 
Martin-Behaim-Straße 12  
63263 Neu-Isenburg  
Germany 
Tel.: +49 (0) 6102 798740 
Fax: +49 (0) 6102 7987440 
 
 
 
3. 
Pfizer Inc. 
 
 
 
Craig Eagle 
Medical Director, Celecoxib 
Pfizer Inc., 
235 East 42nd Street 
New York, NY 10017 
USA  
Tel: +1 212 733 2323 
E: Craig.eagle@pfizer.com 
REACT Clinical Study Manager 
Worldwide Medical Oncology 
Pfizer Global Pharmaceuticals  
235 East 42nd St. 
New York, NY 10017 
USA 
 
 
 


REACT Protocol, Version 39, dated 01.11.2016 
 
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APPENDIX II: Acceptable Chemotherapy Regimes 
Completion of a minimum of 4 cycles of a chemotherapy is required for eligibility.  
The recommended regimen is FEC. 
In all cases, the maximum cumulative allowable dose of epirubicin is 720mg/m². 
 
All preferred dosages correspond to the first starting dose. Dose reductions due to toxicity in the following 
cycles do not compromise eligibility of the patient. 
 
Epirubicin in combination with Cyclophosphamide +/- 5-Fluorouracil (FEC or CEF or EC) 
The minimum dose for Epirubicin is 50 mg/m² given on days 1 and 8 q day 28 or 75 mg/m² given on day 1 q 
day 21 or 60 mg/m² given on day 1 q day 21 for at least 5 cycles. 5-Fluorouracil and Cyclophosphamide 
should be given both at a dosage of at least 500 mg/m². 
If Epirubicin is given in combination only with Cyclophosphamide the minimal dose should be 90 mg/m² 
every 3 weeks. 
 
Epirubicin given in combination with a taxane (+/- Cyclophosphamide) 
The minimal allowable dose for Epirubicin is 75 mg/m². Paclitaxel should be given at a minimal dose of 175 
mg/m² and Docetaxel at a minimal dose of 75 mg/m². The dose of Cyclophosphamide should not be less 
than 500 mg/m². The regimen should be given every 14 to 21 days. Bevacizumab is allowed with EC for 
patients on the Gepar-5 trial. 
 
Epirubicin given in sequence with a taxane 
The minimum dose of Epirubicin is 90 mg/m² given alone or in combination with Cyclophosphamide 
(minimum dose 600 mg/m²) every 2 to 3 weeks. The dosage of Docetaxel should be 100 mg/m² every three 
weeks or 75mg/m² every two weeks or 80mg/m² every week. The dosage ofPaclitaxel should be 175 mg/m² 
over 3 hours or 80 mg/m² weekly for 12 cycles, RAD001 is allowed with Paclitaxel for patients on the Gepar-
5 trial. 
 
E-CMF (or Epi-CMF) 
The minimum dose of Epirubicin is 100mg/m2 i.v. given on day 1 and repeated every 21 days for 4 cycles, 
followed by 4 cycles (28 days) Classical / Bonadonna CMF: 
The minimum dose of cyclophosphamide is 100mg/m² if given orally on days 1-14 and 600mg/m² if given 
intravenously on day 1 and 8. The recommended dose of methotrexate is 40mg/m² and of 5-Fluorouracil is 
600mg/m² given on day 1 and 8. The cycle should be repeated on day 29. 
 
Doxorubicin in combination with Cyclophosphamide +/- 5-Fluorouracil (FAC or CAF or AC) 
The minimum dose for Doxorubicin is 50 mg/m² intravenously given on day 1 q day 21 or 30mg/m2 days 1 
and 8 q day 28 for at least 6 cycles. Cyclophosphamide should be given 500mg/m2 on day 1 and 8 or 
100mg/m2 day 1-14 respectively and 5-Fluorouracil should be given at a dosage of at least 500 mg/m² i.v.  
If doxorubicin is given in combination only with cyclophosphamide the doses should be doxorubicin 45-60 
mg/m² i.v. and cyclophosphamide 400-600 mg/m2 i.v. every 3 weeks for at least 4 cycles. 
 
Doxorubicin given in combination with a taxane (+/- Cyclophosphamide)The minimal allowable dose for 
doxorubicin is 50mg/m². Paclitaxel should be given at a minimal dose of 175 mg/m² and docetaxel at a dose 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 45 of 48 
of 75 mg/m². The dose of Cyclophosphamide should not be less than 500 mg/m². The regimen should be 
given every 21 days. 
 
Doxorubicin given in sequence with a taxane 
The minimum dose of doxorubicin is 60mg/m² given alone or in combination with Cyclophosphamide 
(minimum dose 600 mg/m²) every 3 weeks for 4 cycles. This should be followed by 100 mg/m² docetaxel be 
for 4 cycles. 
 
A-CMF (or Adria-CMF) 
The minimum dose of doxorubicin is 75mg/m2 i.v. given on day 1 and repeated every 21 days for 4 cycles, 
followed by 8 cycles (28 days) Classical / Bonadonna CMF. The minimum dose of Cyclophosphamide is 
100mg/m² if given orally on days 1-14 and 600mg/m² if given intravenously on day 1 and 8. The 
recommended dose of Methotrexate is 40mg/m² and of 5-Fluorouracil is 600mg/m² given on day 1 and 8. 
The cycle should be repeated on day 29.  
CMF 
The use of the CMF regimen alone is only allowed in patients where Epirubicin and doxorubicin are 
contraindicated, e.g. in cases where there is abnormal cardiac function (see above). The minimum dose of 
Cyclophosphamide is 100mg/m² if given orally on days 1-14 and 600mg/m² if given intravenously on day 1 
and 8. Patients on the ICE2 trial will receive only 500 mg/m² of Cyclophosphamide. The recommended dose 
of Methotrexate is 40mg/m² and of 5-Fluorouracil is 600mg/m² given on day 1 and 8. The cycle should be 
repeated on day 29.  
Docetaxel given in combination with Cyclophosphamide  
The combination of Docetaxel 75 mg/m2 and Cyclophosphamide 600 mg/m2 intravenously every three 
weeks for 4-6 cycles. i.e. anthracycline free 
 
5-Fluorouracil, Epirubicin and Cyclophosphamide followed by Docetaxel (FEC – T) and Docetaxel 
followed by 5-Fluorouracil, Epirubicin and Cyclophosphamide +/- Bevacizumab (4 cycles only) 
The minimum dose of Epirubicin should be 60 mg/m². 5-Fluorouracil and Cyclophosphamide should be given 
both at a dosage of at least 500 mg/m². Each should be given on day 1 and this should be repeated every 
three weeks up to a total of 3 or 4 cycles. Docetaxel should be given at a minimum dose of 75mg/m² on day 
1 every three weeks up to a maximum of 8 cycles in total. This sequence can be reversed so that Docetaxel 
is given prior to FEC. Bevacizumab may be given in combination with Docetaxel for patients participating in 
the ARTEMIS trial. 
 
Weekly nab-paclitaxel in combination with capecitabine (ICE II trial).Nab-Paclitaxel (100mg / m²) on 
days 1, 8 and 15 repeated every three weeks with no infusion every six weeks plus Capecitabine (2000mg / 
m²) on days 1 to 14 repaeted every three weeks to a total of 6 cycles. 
 
Some of the above regimens are only applicable in the context of chemotherapy trials. 
 
Other regimens are only allowed after acceptance by the Trial Management Group.  
 


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APPENDIX III: Drug Interactions/ Precautions 
Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver. Co administration of 
celecoxib with drugs that are known to inhibit 2C9 should be administered with caution. In vitro studies 
indicate that celecoxib, although not a substrate is an inhibitor of CYP2D6. Therefore, there is a potential for 
an in vivo interaction with drugs that inhibit CYP2D6. 
 
Clinical studies have identified potentially significant interactions with fluconazole and lithium. Experience 
with nonsteroidal anti inflammatory drugs NSAIDs suggests the potential for interactions with furosemide and 
ACE inhibitors. 
 
Angiotensin-converting enzyme (ACE) inhibitors - concurrent use with celecoxib may decrease the 
antihypertensive effects of ACE inhibitors; also, risk of renal failure is increased in patients taking these 
medications. 
 
Antacids, aluminum- or magnesium-containing - the administration of celecoxib with an aluminum– or 
magnesium–containing antacid has been reported to result in a 37% decrease in the peak plasma 
concentration and a 10% decrease in the area under the plasma concentration–time curve [AUC] of 
celecoxib  
 
Diuretics, thiazide or Furosemide - nonsteroidal anti-inflammatory drugs may decrease the natriuretic 
effects of diuretics, possibly by inhibiting renal prostaglandin synthesis; also, risk of renal failure is increased 
in patients taking these medications  
 
Fluconazole - in clinical trials, concurrent administration of fluconazole 200 mg daily resulted in a two-fold 
increase in plasma concentration of celecoxib; the increase in plasma concentration of celecoxib was due to 
the inhibition of celecoxib metabolism via P450 2C9 by fluconazole; therefore, if celecoxib is coadministered 
with fluconazole, it is recommended that the dose of celecoxib should be initiated at the lowest 
recommended dose,. As it is not possible to adjust the dose of celecoxib in this study we do not recommend 
the concurrent administration of fluconazole and celecoxib in this trial. 
 
Lithium - a 17% increase in the plasma concentration of lithium has been reported in patients receiving 
lithium 450 mg twice a day with celecoxib 200 mg twice a day compared with patients receiving lithium alone; 
therefore, monitoring of lithium concentrations is recommended when treatment is initiated and when 
treatment with celecoxib is discontinued. 
 
Anticoagulants – Anticoagulant activity should be monitored particularly in the first few days of initiating 
celebrex activity in patients receiving warfarin or other similar agents, since these agents are at increased 
risk of bleeding complications. 
 
Bevacizumab - Common toxicities associated with bevacizumab include hypertension, bleeding episodes 
and thrombotic events, however at the current time there is limited information concerning drug interactions 
with bevacizumab and other medication. Until such information is available the concurrent use of celecoxib 
and bevacizumab is not recommended in this trial. 
 
Precautions  
Celecoxib should not be given to patients who have demonstrated allergic type reactions to sulphonamides 
or who have experienced asthma, urticaria or allergic type reactions after taking aspirin or other NSAIDs. 
 


REACT Protocol, Version 39, dated 01.11.2016 
 
Page 47 of 48 
APPENDIX IV – Protocol Amendment History 
 
Protocol Version 30.0, December 2003 amended to Version 31.0, 29 July 2005  
Substantial amendment 
Amended to allow trial to re-start and incorporate additional patient safety checks  
 
Protocol Version 31.0, 29 July 2005 amended to Version 32.0, 24 May 2006 
Substantial amendment 
Incorporationg additional patient safety checks 
 
Protocol Version 32.0, 24 May 2006 amended to Version 32.1, 19 July 2007 
Non-substantial amendment  
Administrative changes 
 
Protocol Version 32.1, 19 July 2007 amended to Version 33.0, 14 December 2007 
Substantial amendment 
Extension of endocrine therapy treatment to include AIs 
 
Protocol Version 33.0, 14 December 2007 amended to Version 34.0, 28 September 2009 
Substantial amendment 
Change to inclusion criteria to include perimenopausal women  
 
Protocol Version 34.0, 28 September 2009 to version 35.0 23 March 2011 
Substantial amendment 
Change to inclusion / exclusion citeria to exclude all patients with node negative, T1, grade 1 tumours. 
Removal of reference to St. Gallen criteria 
Removal of menopausal status from eligibility criteria 
Administrative changes 
 
Protocol Version 35.0, 23 March 2011 to Version 36.0, 31 August 2012 
Substantial Amendment 
Removal of Exemestane as an IMP and clarification that HR+ve patients should receive endocrine therapy 
according to local practice 
Change to inclusion criteria to specify that all patients of child-bearing potential must have a negative 
pregnancy test in order to be eligible. Previously this was specified for premenopausal patients only 
Clarification that patients should not take other NSAIDs, corticosteroids or HRT while on study treatment 
Follow-up assessments have been divided into on-treatment follow-up assessments and off-treatment 
follow-up assessments and the schedule of assessments has been updated 
Updated SAE definition to exclude hospitalisation due to symptoms of breast cancer recurrence/progression  
Change to end of trial definition 
Administrative changes 


REACT Protocol, Version 39, dated 01.11.2016 
 
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Protocol Version 36.0, 31 August 2012 to Version 37.0, 30 January 2014 
Substantial Amendment 
Clarification on Advserse Events (AE) reporting procedures 
Guindance for Investigators on how to manage High levels of Cholesterol and BP during patient follow up 
Removal of the expected Adverse Reactions (ARs) summary table. Investigators should refer to the current 
celecoxib Investigators Brochure for assessing ARs 
Clarification of study assessements at study entry and during follow-up  
Adminstrative changes 
 
Protocol Version 37.0, 30 January 2014 to Version 38.0, 29 September 2015 
Substantial Amendment 
Clarification on REACT Post treatment follow-up procedures in Germany  
Change to ICCG address 
Clarification regarding unblinding and reporting of pregnancies  
Administrative Changes  
 
Protocol Version 38.0, 29 September 2015 to Version 39.0, 01 November 2016 
Subtantial Amendment  
Replacement of inadvertent deletion of text in section 11.1 
 

SAP_001.pdf: 
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GBG
GERMAN
BREAST
GROUP
A PHASE III MULTICENTRE DOUBLE BLIND
RANDOMISED TRIAL OF CELECOXIB VERSUS PLACEBO
IN PRIMARY BREAST CANCER PATIENTS
(REACT - Randomised EuropeAn Celecoxib Trial)
Statistical Analysis Plan
Version 1.0
1210312014
STUDY NO: ICCG Cl20/01,GBG27, BIG 1- 03, ISRCTN No: 48254013
COORDINATING GROUPS: INTERNATIONAL COLLABORATIVE CANCER GROUP
GERMAN BREAST GROUP
SPONSOR: IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE,
EXHIBITION ROAD. LONDON SW7 2AZ. U.K
AN INTER COOPERATIVE GROUP STUDY


This statistical analysis plan has been approved by the following personnel. All versions of this
document and any subsequent approved amendments will be stored in the statistical section of the
Trial Master File.
This statistical analysis plan is a framework guide to analysis and may be supplemented by
additional analyses. Trial statisticians reserve the right to amend analysis methods as appropriate
after discussion with the ICR-CTSU scientific Lead,
Trial Statlstician: Lucy Kilburn (Holly Toveypames Morden providing cover during matemity
leave)
Signed:#
\J
Date: l!/oG/zo l+
ICR-CTSU Scientific l-€adr Judith Bliss
Signed:
Date:'lllgf ao i5
Chief hvestlgator: Profe6, Charles Coombes
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Document history
Version
Date
Changes made


Contents


REACT Statistical Analysis Plan - Version 1.0
1.0 Introduction
1.1 Trial deslgn
REACT is a ohase III multicentre double blind randomised trial of celecoxib versus placebo in
primary breast cancer patients. The primary aim is to assess the disease free survival (DFS)
benefit of two years adjuvant therapy with the COX-2 inhibitor celecoxib compared with placebo in
primary breast cancer patients. Patients are randomised between two years celecoxib and placebo
in a 2:1 ratio in favour of celecoxib. Additionally ER+ and/or PgR+ patients will receive endocrine
therapy according to local practice. It is planned to accrue a total of 2590 patients.
Homone receptor (ER and PgR) negative patients will not receive endocrine treatment.
1.2 Study population
This study is for resected node positive or high risk node negative breast cancer. All HR negative
patients MUST have received chemotherapy. Entry into the study is within between 3 weeks and 4
LULI "rbLt' "
5
Disease-free primary breast crncer
patients who hav€ completed surgery,
with or without (neo) adjuvant
chemotherapy ( ! radiotherapy)
Plscebo (once
daily for 2
years)
Celecoxib 4fi)mg
(once daily for
2 years)
If ER+ and/or PgR +
Endocrine therapy according to local practice.


REACT Statistical Analysis Plan - Version 1.0
month'ofdaylofthe|astcyc|eofadjuvantchemotherapy,Within3monthsoftheendof
definitive breast surgery, or within 6 weeks of the end of radiotherapy' Patients can have
radiotherapy concurrently with study drug.
More detailed inclusion and exclusion criteria are:
All the following criteria must be fulfilled for study entry:
1. Completely resected (>lmm), histologically or cytologically proven unilateral breast cancer.
2. Female >18 years of age, no upper age limit
3. If neo-adjuvant chemotherapy has been received, then the patient must have received at
least 4 cycles and entry must be within 3 months of definitive breast surgery
4. Within 3 months of the end of definitive breast surgery (if no chemotherapy is to be given)
5, If adjuvant chemotherapy has been received* then the treatment must be finished and the
patient must have received at least 4 cycles. Entry into the study must be within between 3
weeks and 4 months of day 1 of the last cycle.
6. Within 6 weeks of the end of radiotherapy
7. WHO Performance status 0 or 1
8. Pre-treatment haematology and biochemistry values within acceptable local limits:
Haemoglobin
WBC > 3.0 ' 109/l or ANC > 1.5 x 109/l
Platelets>100'109/
Serum bilirubin < 1.5 UNL
Alkaline phosphatase < 1.5 x UNL
Serum creatinine < 1.5 x UNL
9. Negative pregnancy test in premenopausal patients.
10. Normal baseline ECG and normal clinical cardiovascular assessment after completion of all
(neo) adjuvant chemotherapy
11. No previous or current evidence for metastatic disease
12. Be accessible for and consent to long term follow-up
13. Wriften informed consent prior to commencement of specific protocol procedures must be
obtained and documented according to the local regulatory requirements
* ER negative women must have received prior chemotherapy.


REACT Statistical Analysis Plan - Version 1.0
A randomisation form detailing basic eligibility and identirying information must be received before
the patient can be randomised.
Any patient with any of the following criteria will not be eligible for randomisation:
1. Patients with node negative, T1, Grade 1 breast cancer.
2. Unresectable, metastatic or bilateral breast cancer
3. Active or previous peptic ulceration or gastrointestinal bleeding in the last year
4. Active or previous history of inflammatory bowel disease
5. A past history of adverse reaction/hypersensitivity to NSAIDS, celecoxib, salicylates or
sulphonamides
6. On current or planned chronic NSAIDs therapy (except low dose aspirin <100 mg QD or 325m9
QOD). Chronic use of NSAIDs is defined as a frequency of I or more a day, for more than a
total of 6 weeks per year.
7. Current or long-term use of oral corticosteroids
8. Known or suspected congestive heart failure (>NYHA I) and/or coronary heaft disease, previous
history of myocardial infarction, uncontrolled afterial hypertension (i.e. BP >160/90mmHg)
under treatment with two anti-hypetensive drugs, rhythm abnormalities requiring permanent
treatment. ECG should be considered within normal limits by a clinician prior to stafting trial
therapy. Echocardiogram although not essential can be carried out if the investigator judges it
to be necessary.
9. Patients with diabetes controlled by diet and oral medication are eligible for the study however
patients with insulin dependent diabetes are excluded.
10. Past history of strokefnA, symptomatic peripheral vascular disease or carotid disease
11. Previously entered into an adjuvant chemotherapy trial for which approval for entry into
REACT has not been granted by the Steering Committee/Management Group of the other trial.
12. ER receptor status unknown
13. HER2+++ or FISH positive or HER 2 status unknown.
14. Hormone receptor negative and not received (neo) adjuvant chemotherapy
15. Use of hormone replacement therapy within the last 6 weeks
16. Pregnant or lactating women or women of childbearing potential unwilling or unable to use
adequate non-hormonal contraception.
17. No previous or concomitant malignancies except adequately treated squamous cell / basal cell
carcinoma of the skin, in situ carcinoma of the cervix or DCIS/LCIS of the breast, unless there
has been a disease-free interval of 10 years or more.
18. Psychiatric or addictive disorders which could preclude obtaining informed consent.


REACT Statistical Analvsis Plan - Version 1.0
19. Clinical evidence of severe osteoporosis and/or history of osteoporotic fracture.
Note: use of Bisphosphonates for clinical purposes is not an exclusion criterion.
2.0 Trial objectives
There are several reasons for initiating a randomised study to examine the impact of COX-2
inhibition in enhancing the adjuvant treatment of breast cancer - COX-2 inhibition may result in
inhibition of angiogenesis, inhibition of cell growth, inhibition of tumour-associated inflammation,
inhibition of invasion and promotion of apoptosis.
2.1 Primary objectives
. To assess the disease free survival (DFS) benefit of two years adjuvant therapy with the
coX-2 inhibitor celecoxib compared with placebo in primary breast cancer patients.
2. 2 Secondary objectives
. To compare overall survival.
. To define the safety of adjuvant therapy with celecoxib in this patient population.
. To compare incidence of second primary breast cancers.
o To assess the tolerability of celecoxib with hormone therapy'
. To assess acute and late toxicities after radiotherapy for each treatment group'
2.3 Tertia ry objectives
To investigate COX2 level and other tumour-associated proteins in the tumour tissue and relate
these findings to trial outcome.
3.0 Sample size and power
In order to detect a 20olo reduction in risk of recurrence in the five year DFS (e.9. from 70olo to
75.2o/o),2590 patients (709 events) are required (hazard ratio=0.8). This number is based on a
2:1 randomisation (celecoxib vs. placebo) with 80o/o power and ct=0.05 (two-sided). The figure of
70o/o DFS at five years in the control group is based on an estimation of more than 40olo of the
patients randomised being HR negative.
Once recruitment is on-going the Independent Data Monitoring Committee (IDMC) may be asked
to consider an increase in sample size. Formal interim analysis of efficary based on log-rank


REACT Statistical Analysis Plan - Version 1.0
comparison and an estimate of the hazard ratio will be conducted after approximately 1/+,1/2, and
3/+ of the reouired number of events.
4.O Randomisation prccedures
Patients confirmed as being eligible for the trial are randomised to receive either celecoxib or
placebo in a 2:1 ratio in favour of celecoxib. The first patient was recruited on L910U2007,
randomisation is performed using computer generated permuted blocks. Patients are stratified
according to their treatment centre and hormone receptor status. Patients are randomised:
. Within 3 months of definitive breast surgery, (if no chemotherapy is to be given or already
received neo-adjuvant chemotherapy). The patient can be given radiotherapy concurrently
with the study medication.
. If adjuvant chemotherapy has been received then the treatment must be finished and the
patient must have received at least 4 cycles, Entry into the study must be within between
3 weeks and 4 months of day 1 of the last cycle.
. Within 6 weeks of the end of radiotherapy.
No patients who have started and terminated chemotherapy before they have received 4 cycles, is
permitted to be randomised.
Each patient is allocated a unique trial number which is used to identify the patient on all
subsequent case repoft forms.
5.0 Endpoints
5,1 Primary
The primary aim is to assess the disease-free survival (DFS) benefit of two years adjuvant therapy
with the COX-2 inhibitor celecoxib compared with placebo in primary breast cancer patients'
5.2 Secondary
. Overall survival (OS);
. the toxicity associated with long term use of celecoxib in primary breast cancer patients;
. cardiovascularmortality;
. the incidence of second primary cancers.
Subgroup analysis based on HR status (HR+, HR, will be performed using the same endpoints as
Lucy Kilburn
12/0J/2011


REACT Statistical Analysis Plan - Version 1.0
in ft analysis of all patients. These analyses will be exploratory in nature as the trial is not
oowered to detect differential treatment effecG within these subgroups.
6.0 Analysis methods
6.1 Efficacy Analysis
All patients will be evaluated for endpoints in the treatment group to which they were randomised,
irrespective of the treatment they actually receive. No patient will be removed from the analyses
irrespective of whether she is found to have violated the eligibility criteria after randomisation or to
have been withdrawn from trial medication prematurely, except in the case that she withdraws her
consent to use of data already collected in the trial. Thus, analysis will be by intention to treat
including all patients randomised.
The principal analysis will be based on a log rank comparison of DFS (as defined below).
probabilities of DFS and OS will be presented as Kaplan-Meier survival curves with fixed term
survival estimates. Hazard ratios will also be calculated, Cox regression techniques will be used to
adjust for impotant factors likely to influence prognosis or confound any treatment effect. These
factors may include ER, menopausal, COX-2 status and chemotherapy regimen' Exploratory sub
group analyses will be reported via Forest plots by hormone status, menopausal status, nodal
status, and previous use of chemotherapy (or not). Baseline characteristics will be described by
randomised treatment group. All statistical tests will be two-sided and 95Vo confidence intervals
will be used.
6.2 Safety Analysis
A ootengal increase in cardiovascular rates has been suggested with selective COX-2 inhibitors
(Mukherjee et al, 2001). Cardiovascular events will therefore be closely monitored and will be a
primary safety consideration. There will be a sequential monitoring of toxicity and it is likely that
the first analysis will be carried out when the first 100 patients have completed the first 6 months
of assessment.
Toxicity and the frequency and nature of adverse events will be compared between the
randomised groups. Summary measures and non-parametric tests will be used as necessary. In
particular, the proportion of patients experiencing toxicity of CTC grade 3 or 4 and the maximum
CTC toxicity grade will be compared. An analysis of safety endpoints by treatment received will be
peformed. "Other" toxicities specified by text will be coded according to the latest version of
MedDM available. The Chief Investigator may wish to group MedDM codes further into more
clinically meaningful groups for analysis and interpretation.
10


REACT Statistical Analysis Plan - Version 1,0
Incidence of cardiovascular events after randomisation will be compared between the two
treatment groups and the absolute difference in incidence will be estimated (with associated
confidence limits). Subgroup analysis based on HR status (HR+, HR-) will be performed using the
same endpoints as in the analysis of all patients. The trial is not powered to detect differences
within these subgroups thus these analyses will be descriptive in nature unless changes are made
to the design of the trial or there is an increase in sample size.
6.3 Primary endpoint
Disease free suruival (DFS) is defined as time from randomisation to the date of first event; with
events contributing to the analysis defined as loco-regional and distant breast cancer recurrence,
new primary breast cancer (ipsilateral or contralateral) and death without disease relapse
(intercurrent death). First local recurrence and first distant recurrence will be recorded on separate
parts of the CRF. In the event of local recurrence, all patients must be followed up for distant
recurrence, second malignancy and survival. Similarly in the case of second malignancy, patients
should continue to be followed for distant recurrence and where possible the relation of any
subsequent distant recurrence and/or death to the primary or second cancer should be
established.
In the case of a second malignancy and subsequent distant recurrence, only distant recurrence
attributable to the primary breast cancer will be included as a DFS event. In the event of
uncertaintv about the relation of the distant recurrence it will be assumed that the recurrence is
related to the primary breast cancer.
Date of suspicion of relapse, action taken to confirm relapse and date relapse confirmed will all be
recorded on the CRF.
Relapse will be categorised as follows:
. Ipsilateral breast,
. Axillary nodal relapse or relapse to the supraclavicular nodes (Loco-regional),
o Distant relapse (Distant),
. Contralateral breast disease (malignant) (2nd primary).
Any relapse requires treatment to be stopped, and thus is included as an event. Any malignant
contralateral breast disease will be included as a second primary, and relapse with supraclavicular
disease will be included as local relapse according to TNM classification v7.
lz/uJ/zut'r


REACT Statistical Analvsis Plan - Version 1.0
tsreast cancer' deaths will be all deaths with breast cancer specified as a cause of death and
receive the protocol
deaths from any cause following a distant relapse. Patients may continue to
treatment after a second (non-breast) primary is diagnosed'
6.4 Secondary endpoints
Overall survaval
Overall survival time will be calculated as date of randomisation until the date of death from any
cause or censored at the date the patient was last seen alive. The Kaplan-Meier method will be
used to estimate overall survival and differences between treatment groups will be compared
using the log rank test. Multivariable analysis will be performed using the Cox proportional hazards
model to adjust for known clinical prognostic factors. The proportional hazards assumption of the
Cox model will be assessed using the stphtest command in Stata. The ITT population will be used
for this analvsis.
6.5 Baseline characteristics
All baseline characteristics will be tabulated by treatment group. No formal tests shall be made
between the groups unless there appears to be a large difference between the treatment groups
with regard to a particular baseline variable. In this case a test for difference may be considered.
6.6 Patient flow through trial
A CONSORT diagram will be presented to show the flow of patients through the trial.
6.7 Treatment compliance
patients who deviate from their randomised treatment will be investigated. Numbers deviating and
reasons for this will be tabulated by treatment group.
6.8 Exploratory analyses
Additional analyses other than those listed as primary and secondary above may be performed as
appropriate.
7.O Data monitoring and interim analyses
An Independent Data Monitoring and Committee (IDMC) has been set up to monitor the progress
of the trial, They will meet at regular intervals as they see fit but at least annually. Following each
t2


REACT Statistical Analysis Plan - Version 1.0
meeting, they will report their findings and recommendations to the chairs of the Trial
Management Group and Trial Steering Committee. All interim analyses will be supplied in
confidence by the trial statistician to the IDMC together with any other analyses the IDMC request.
The IDMC will advise on the frequency of reviews of the data on the basis of accrual and event
rates,
8.0 Procedures for monitoring data accuracy and data entry quality assutianoe
Data entry and management are conducted according to relevant SOPS at ICCG (Imperial) and
GBG. Details of the data accuracy checking procedure can be found in the central statistical data
monitoring plan, stored in the statistical TMF.
9.0 Analysis Programs
Analysis will be conducted using Microsoft Excel, SPSS and Stata version 10.0 (or subsequent
versions). Programs will be in the relevant ANALYSES directory.
10.0 Analysis program locations
All programs will be stored in the analyses folder for REACT on the ICR-CTSU seruer (ANALYSES
directory). Only the REACT trial statistician(s), ICR-CTSU IT staff and, if appropriate, Translational
Analyst Scientist, Director and Deputy Directors of ICR-CTSU will be able to see the analysis folder.
Programmes will be stored under the type of analysis e.g. IDMC meeting. All official analysis
reports that are to be circulated externally of ICR-CTSU will be password protected. Hard copies
of reports will be stored securely in the statistical section of the REACT trial master file held in a
locked fire proof cupboard with restricted access.
11.O Refercnces
None
Lucy Kilburn
t3
r2/03/2014