Phase II Study of ROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer, Diffuse Gastric Cancer, Triple Negative Lobular Breast Cancer or CDH1-mutated Solid Tumours
Phase: PHASE2
Conditions: Lobular Breast Carcinoma, Gastric Cancer, Triple Negative Breast Cancer, CDH1 Gene Mutation
Sponsor: Royal Marsden NHS Foundation Trust

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ROLo: Phase II study of ROS1 
targeting with crizotinib in 
advanced E-cadherin negative, ER 
positive lobular breast cancer, 
diffuse gastric cancer, triple 
negative lobular breast cancer or 
CDH1-mutated solid tumours 
 
 
 
IRAS Number 
229356 
Sponsor protocol number 
CCR 4684 
EudraCT number 
2017-001680-20 
Clinicaltrials.gov Number 
NCT03620643 
REC Reference Number 
17/LO/2025 
Protocol version/date 
4.0, 05 Apr 2022 
 

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TABLE OF CONTENTS 
KEY CONTACTS ................................................................................................................. 6 
PARTICIPATING INVESTIGATORS AND SITES ...................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................ 8 
PROTOCOL SIGNATURES ................................................................................................. 10 
INVESTIGATOR SIGNATURE............................................................................................. 11 
1. PROTOCOL SUMMARY ................................................................................................ 12 
1.1 Primary objectives and endpoints ...................................................................................... 12 
1.2 Secondary objectives and endpoints .................................................................................. 12 
1.3 Exploratory objectives and endpoints ................................................................................ 13 
1.4 Design .............................................................................................................................. 13 
1.5 Administration schedule ................................................................................................... 14 
1.6 Treatment group ............................................................................................................... 14 
1.7 Trial timelines and accrual rate .......................................................................................... 14 
1.8 Role of study sponsor and funder ...................................................................................... 14 
2. INTRODUCTION .......................................................................................................... 15 
2.1 Background ....................................................................................................................... 15 
2.1.1 Lobular breast cancer ........................................................................................................... 15 
2.1.2 Diffuse gastric cancer ............................................................................................................ 15 
2.1.3 Triple negative lobular breast cancer ................................................................................... 15 
2.1.4 CDH1-mutated solid tumours ............................................................................................... 15 
2.2 Investigational medicinal products .................................................................................... 16 
2.2.1 Crizotinib ............................................................................................................................... 16 
2.2.1.1 Crizotinib clinical experience ......................................................................................... 16 
2.2.1.2 Crizotinib Pharmacokinetic Drug Interactions ............................................................... 16 
2.2.1.3 Crizotinib Pharmacodynamic drug interactions ............................................................. 17 
2.2.1.4 Crizotinib and fulvestrant ............................................................................................... 17 
2.2.2 Compatible adverse event profiles ....................................................................................... 17 
3. RATIONALE FOR THE PROPOSED TRIAL ........................................................................ 18 
4. TRIAL DESIGN ............................................................................................................. 23 
4.1 Clinical trial objectives and endpoints ................................................................................ 23 
4.1.1 Primary objectives and endpoints ........................................................................................ 23 
4.1.2 Secondary objectives and endpoints .................................................................................... 23 
4.1.3 Exploratory objectives and endpoints .................................................................................. 23 
4.2 Safety Review Committee ................................................................................................. 24 
4.3 Patient evaluability ........................................................................................................... 24 
4.4 Design of the clinical trial .................................................................................................. 24 
5. PATIENT SELECTION .................................................................................................... 26 
5.1 Eligibility criteria ............................................................................................................... 26 
5.1.1 Inclusion criteria: .................................................................................................................. 26 

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5.1.2 Exclusion criteria: .................................................................................................................. 28 
5.2 Patient enrolment ............................................................................................................. 30 
6. TREATMENT ............................................................................................................... 31 
6.1 Dosing schedule/treatment schedule................................................................................. 31 
6.2 Dose modifications ........................................................................................................... 31 
6.2.1 Dose reductions .................................................................................................................... 32 
6.2.1.1. Dose reduction for crizotinib ........................................................................................ 32 
6.2.1.2 Dose reduction for fulvestrant ....................................................................................... 34 
6.2.2 Dose interruptions, delays and re-treatment criteria .......................................................... 34 
6.3 Duration of treatment ....................................................................................................... 35 
6.4 Concomitant medication and treatment ............................................................................ 35 
6.5 Prohibited medication ............................................................................................................. 35 
6.6 
Permitted medications: ...................................................................................................... 36 
7. PHARMACEUTICAL INFORMATION .............................................................................. 37 
7.1 Supply of Investigational Medicinal Products ..................................................................... 37 
7.2 Crizotinib .......................................................................................................................... 37 
7.2.1 Formulation of Crizotinib ...................................................................................................... 37 
7.2.2 Storage conditions ................................................................................................................ 37 
7.2.3 Crizotinib administration ...................................................................................................... 37 
7.3 Fulvestrant ....................................................................................................................... 37 
7.3.1 Formulation of Fulvestrant ................................................................................................... 37 
7.3.2 Fulvestrant administration ................................................................................................... 38 
7.4 Study drug accountability .................................................................................................. 38 
8. INVESTIGATIONS SCHEDULE ........................................................................................ 39 
8.1 Pre-treatment evaluations ................................................................................................ 39 
8.1.1 Obtaining written informed consent .................................................................................... 39 
8.1.2 Evaluations within four weeks (28 days) .............................................................................. 40 
8.1.3 Evaluations within one week (seven days) ........................................................................... 41 
8.2 Evaluations during the trial ............................................................................................... 41 
8.2.1 Evaluations when disease progression is confirmed ............................................................ 43 
8.3 Evaluations at ‘off-study’ visit............................................................................................ 43 
8.4 Follow-up ......................................................................................................................... 44 
8.5 
Table 6: Schedule of events (Refer to sections 8.1.2-8.4 for details) ................................ 45 
9. PHARMACODYNAMIC ASSESSMENTS .......................................................................... 47 
9.1 Predictive biomarker assays .............................................................................................. 47 
9.1.1 Analysis of tumour biopsy material for predictive biomarker analysis ................................ 47 
9.1.2 Collection of plasma samples for circulating free DNA ........................................................ 47 
10. ASSESSMENT OF SAFETY ........................................................................................... 48 
10.1 Adverse event definitions ................................................................................................ 48 
10.1.1 Adverse event ..................................................................................................................... 48 
10.1.2 Adverse reaction (AR) ......................................................................................................... 48 
10.1.3 Serious adverse events (SAEs) ............................................................................................ 49 

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10.1. 4 Serious Adverse Reaction (SAR) ......................................................................................... 49 
10.1.5 Suspected, unexpected, serious, adverse reactions (SUSARs) ........................................... 49 
10.2 Operational definitions for (S)AEs .................................................................................... 49 
10.2.1 Assessment of Severity ....................................................................................................... 49 
10.2.2 Assessment of Seriousness ................................................................................................. 50 
10.2.3 Determining adverse event causality ................................................................................. 50 
10.2.4 Expectedness ...................................................................................................................... 50 
10.3 Recording and reporting of Serious Adverse Events (SAEs) / Serious Adverse Reactions 
(SARs) .................................................................................................................................... 51 
10.3.1 Reporting of Serious Adverse Events (SAEs) / Serious Adverse Reactions (SARs) ............. 51 
10.3.2 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................... 51 
10.3.2.1 Fatal or life-threatening SUSARs .................................................................................. 51 
10.3.2.2 Non-fatal and non-life-threatening SUSARs ................................................................ 52 
10.3.2.3 Minimum criteria for initial expedited reporting of SUSARs ....................................... 52 
10.3.2.4 Follow-up reports of SUSARs ....................................................................................... 52 
10.3.2.5 Format of the SUSARs reports ..................................................................................... 52 
10.3.3 Events exempt from being reported as SAEs ..................................................................... 52 
10.4 Recording of adverse events and serious adverse events in eCRFs .................................... 53 
10.5 Follow-up of adverse events ............................................................................................ 53 
10.6 Urgent safety measures ................................................................................................... 53 
10.7 Pregnancy ....................................................................................................................... 54 
11. ASSESSMENT OF EFFICACY ........................................................................................ 56 
11.1 Measurement of disease ................................................................................................. 56 
11.2 Timing and type of tumour assessments .......................................................................... 56 
11.2.1 Baseline evaluations ........................................................................................................... 56 
11.2.2 Evaluations during and at ‘off-study’ .................................................................................. 56 
11.3 Tumour response ............................................................................................................ 57 
11.3.1 Recording of response in the eCRF ..................................................................................... 57 
12. DISCONTINUATION OF TREATMENT/WITHDRAWAL FROM TRIAL .............................. 58 
13. DEFINING THE END OF TRIAL ..................................................................................... 59 
14. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................................ 60 
14.1 Statistical Analysis ........................................................................................................... 60 
14.1.1 Subject Replacement Strategy ............................................................................................ 61 
14.2 Safety ............................................................................................................................. 61 
14.3 Pharmacodynamics ......................................................................................................... 61 
14.4 Anti-tumour activity ........................................................................................................ 61 
14.5 Sample size considerations .............................................................................................. 62 
15. TRIAL COMMITTEES .................................................................................................. 63 
15.1 Trial management group ................................................................................................. 63 
15.2 Independent Data Monitoring Committee ....................................................................... 63 
15.3 Trial Steering Committee ................................................................................................. 63 
16. ADMINISTRATION ..................................................................................................... 64 

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16.1 Protocol deviations and amendments .............................................................................. 64 
16.2 Completion of the case report form (CRF) ........................................................................ 64 
16.3 Trial performance and monitoring ................................................................................... 64 
16.3.1 Management of the study .................................................................................................. 64 
16.3.2 Source document verification ............................................................................................ 65 
16.4 Clinical study report ........................................................................................................ 65 
16.5 Record retention ............................................................................................................. 66 
16.6 Ethical considerations ..................................................................................................... 66 
16.7 Indemnity ....................................................................................................................... 66 
16.8 Publication policy and press releases ............................................................................... 66 
16.9 Off-site study procedures in case of crisis situation .......................................................... 67 
17. REFERENCES ............................................................................................................. 68 
18. APPENDICES ............................................................................................................. 70 
18.1 APPENDIX 1: WHO PERFORMANCE SCALE ........................................................................ 70 
18.2 APPENDIX 2: DECLARATION OF HELSINKI ......................................................................... 71 
18.3 APPENDIX 3: MEASUREMENT OF DISEASE ........................................................................ 75 
18.4 APPENDIX 4: NEW YORK HEART ASSOCIATION (NYHA) SCALE ........................................... 81 
18.5 APPENDIX 5: LIST OF PROHIBITED DRUGS DURING THIS STUDY ........................................ 82 
18.6 APPENDIX 6: POTENTIAL SIGHT-THREATENING EVENTS (PSTE) AND SEVERE VISION LOSS 
(SVL) ...................................................................................................................................... 85 
18.7: Appendix 7:  Amendment History ................................................................................... 86 
 
 
 
 
 
 
 
 
 

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KEY CONTACTS 
Chief Investigator 
Dr Alicia Okines 
Consultant Medical Oncologist  
The Royal Marsden NHS Foundation Trust  
Breast Cancer Unit  
Fulham Road, London SW3 6JJ  
Tel: 020 7352 8171 
Email: Alicia.Okines@rmh.nhs.uk     
Lead Co-Investigator (Breast 
cancer) 
Professor Nicholas Turner 
Consultant in Medical Oncologist  
The Royal Marsden NHS Foundation Trust 
Breast Cancer Unit 
Fulham Road, London SW3 6JJ 
Telephone: 020 78118914  
Email: Nick.Turner@icr.ac.uk  
Sponsor 
The Royal Marsden NHS Foundation Trust  
Downs Road 
Sutton SM2 5PT 
Sponsor contact: Ann Gandolfi 
Clinical R&D Manager 
Email: Ann.Gandolfi@rmh.nhs.uk 
RM CTU Clinical Trial 
Coordinator 
ROLo Trial Manager  
Royal Marsden Clinical Trials Unit 
The Royal Marsden NHS Foundation Trust 
Telephone: 0208 915 6506 
Email:  ROLo.trial@rmh.nhs.uk  
Study statistician 
Kabir Mohammed 
RDSU, The Royal Marsden NHS Foundation Trust 
Downs Road, Sutton, SM2 5PT 
Tel: 02031865048 
Email: kabir.mohammed@rmh.nhs.uk 
Lead Co-investigator 
(Translational research) 
Professor Christopher Lord 
Team Leader and Reader in Cancer Genomics and Therapeutics,  
The Breast Cancer Now Toby Robins Breast Cancer Research Centre, 
The Institute of Cancer research, London, SW3 6JB, UK  
Tel: 020 7153 5190 
Email: Chris.Lord@icr.ac.uk  
Lead Co-Investigator (Gastric 
cancer) 
Dr Naureen Starling 
Consultant Medical Oncologist  
The Royal Marsden NHS Foundation Trust  
Fulham Road, London SW3 6JJ 
Tel: 020 7352 8171 
Email: Naureen.Starling@rmh.nhs.uk  

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PARTICIPATING INVESTIGATORS AND SITES 
 
 
Principal Investigator 
Site address 
Site 1 : 
Dr Alicia Okines 
Consultant Medical Oncologist 
Tel: 020 8118100 
Email: Alicia.okines@rmh.nhs.uk      
 
The Royal Marsden NHS Foundation Trust 
Fulham Road, London SW3 6JJ 
& 
Downs Road, Sutton SM2 5PT 
Site 2: 
Dr Anne Armstrong 
Consultant Medical Oncologist 
Tel: 0161 446 8138 
Email: anne.armstrong3@nhs.net 
 
The Christie NHS Foundation Trust 
Derek Crowther Clinical Trials Unit 
Wilmslow Road 
Manchester, M20 4BX 
Site 3: 
Professor Elinor Sawyer 
Consultant Medical Oncologist 
Tel: 02071884244 
Email: elinor.sawyer@kcl.ac.uk     
Guys and St Thomas’ NHS Foundation Trust 
Guys Hospital, 
Great Maze Pond, 
London, SE1 9RT 
Site 4: 
Dr Rebecca Roylance 
Consultant Medical Oncologist 
Tel: 020 3447 9072 
Email: Rebecca.Roylance@uclh.nhs.uk  
 
UCLH NHS Foundation Trust 
University College Hospital, 
235 Euston Road, 
London, NW1 2BU 
Site 5: 
Professor Carlo Palmieri 
Consultant Medical Oncologist 
Tel: 0151 794 9813 
Email: C.Palmieri@liverpool.ac.uk   
 
Clatterbridge Cancer Centre NHS 
Foundation Trust 
Clatterbridge Road, Bebington, 
Wirral, CH63 4JY 
Site 6 
Dr Iain Macpherson 
Consultant Medical Oncologist 
Tel: 0141 301 7000 
Email: Iain.MacPherson@glasgow.ac.uk    
 
Beatson West of Scotland Cancer Centre, 
1053 Great Western Road, 
Glasgow, 
Scotland. G12 0YN 
Site 7 
Dr Madeleine Hewish 
Consultant Medical Oncologist 
Tel:  01483 571122 
Madeleine.hewish@nhs.net  
St Luke’s Cancer Centre, 
Royal Surrey NHS Foundation Trust, 
Egerton Road, 
Guildford, 
GU2 7XX 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
Abbreviation 
Definition 
A 
ABPI 
Association of the British Pharmaceutical Industry  
AE 
Adverse event 
Alk phos 
Alkaline phosphatise 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
B 
BP 
Blood pressure 
BSA 
Body surface area 
C 
0C 
Degrees Celsius 
CI 
Chief Investigator  
CIRB 
Central Institutional Review Board 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CT 
Computerised tomography 
CTA 
Clinical trial authorisation 
CTC 
Clinical Trial Coordinator 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumour DNA 
CTU 
Clinical Trials Unit 
D 
Day 
Calendar day 
DCF 
Data clarification form 
E 
ECG 
Electrocardiogram 
EPD 
Early progressive disease 
F 
FDG 
Fluorodeoxyglucose 
G 
GCP 
Good Clinical Practice 
g/dL 
Gram(s) per decilitre 
GMP 
Good Manufacturing Practice 
GTAC 
Gene Therapy Advisory Committee 
H 
Hb 
Haemoglobin 
HR  
Hazard Ratio 
HCG 
Human chorionic gonadotropin 
HIV 
 
Human immunodeficiency virus 
I 
ICH GCP 
International Conference on Harmonisation of Good Clinical Practice 

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IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
ITF 
Investigator Trial File 
L 
LVEF 
Left ventricular ejection fraction 
M 
mg/m2 
Milligram per square metre 
MHRA 
Medicines and Healthcare products Regulations Agency  
MRI 
Magnetic resonance imaging 
N 
NCI 
National Cancer Institute 
P 
PD 
Progressive disease 
PET 
Positron emission tomography 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PR 
Partial response 
PRP 
Platelet-rich plasma 
Q 
QC 
Quality control 
QP 
Qualified Person 
R 
REC 
Research Ethics Committee 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RM 
Royal Marsden 
S 
SAE 
Serious adverse event 
SD 
Stable disease 
SGDCF 
Site generated data clarification form  
SDV 
Source data verification 
SOP 
Standard operating procedure  
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse (drug) reaction 
U 
ULN 
Upper limit of normal 
USM 
Urgent safety measure 
W 
WFI 
Water for Injection 
WBC 
White blood cell 
WHO 
World Health Organisation 

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PROTOCOL SIGNATURES 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Chief Investigator agrees to conduct the trial in compliance with the approved protocol and will 
adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 
(SI 2004/1031), amended regulations (SI 2006/1928) and any subsequent amendments of the clinical 
trial regulations, GCP guidelines, the Sponsor’s SOPs, and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for 
any other purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of the Sponsor 
I also confirm that I will make the findings of the study publicly available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the study will be given; and that any discrepancies from the study as planned 
in this protocol will be explained. 
 
Chief Investigator: 
Signature:  
...................................................................................................... 
Date: 
....../....../...... 
Name (please print): Dr Alicia Okines 
 
Lead Co-Investigator: 
Signature:  
...................................................................................................... 
Date: 
....../....../...... 
Name: (please print): Professor Nicholas Turner 
Statistician: 
Signature:  
...................................................................................................... 
Date:  
....../....../...... 
Name: (please print): Kabir Mohammed 
 
 
 
 
 
 
 
 

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INVESTIGATOR SIGNATURE 
 
I have read and agree to the protocol, as detailed in this document. I am aware of my responsibilities 
as an Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice 
(GCP)2, the Declaration of Helsinki (Appendix 2), the applicable regulations of the relevant NHS Trusts 
and the trial protocol. I agree to conduct the trial according to these regulations and guidelines and 
to appropriately direct and assist the staff under my control, who will be involved in the trial, and to 
ensure that all staff members are aware of their clinical trial responsibilities. 
 
INVESTIGATOR'S NAME: 
 
SIGNATURE: 
  
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, adopted by CPMP July 
1996. 

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1. PROTOCOL SUMMARY 
 
1.1 Primary objectives and endpoints 
 
Primary objective 
Endpoint 
To assess confirmed response rate by RECIST 
1.1 of crizotinib and fulvestrant in the breast 
cohort  
Confirmed response rate, by RECIST 1.1, of 
crizotinib and fulvestrant in advanced E-cadherin 
negative, ER positive lobular breast cancer 
 
To assess confirmed response rate by RECIST 
1.1 of crizotinib monotherapy in the diffuse 
gastric cancer, triple negative lobular breast 
cancer or CDH1-mutated solid tumour 
(basket) cohort 
Confirmed response rate, by RECIST 1.1, of 
crizotinib in advanced E-cadherin negative, 
diffuse gastric cancer, triple negative lobular 
breast cancer or CDH1-mutated solid tumour. 
 
1.2 Secondary objectives and endpoints 
 
Secondary objectives 
Endpoints 
To assess the overall safety and tolerability of 
crizotinib with fulvestrant in the breast cancer 
cohort and as monotherapy in the gastric 
cancer, triple negative lobular breast cancer 
or CDH1-mutated solid tumour (basket) 
cohort. 
 Overall safety and tolerability of crizotinib with 
Fulvestrant. Toxicity will be assessed by CTCAE 
(version 4) every 4 weeks during study 
treatment. Adverse events, including serious 
adverse events, will be recorded until 30 days 
after the last dose of study treatment with 
crizotinib. 
 
To assess the clinical benefit rate (response 
and stable disease lasting at least 24 weeks) 
in the breast cancer cohort 
Clinical benefit rate (response or stable disease 
lasting at least 24 weeks), assessed by RECIST 1.1 
by local radiology review. 
 
To assess progression-free survival in each 
cohort 
 
Progression-free survival, calculated from day 1 
of study treatment to the date of radiological 
disease progression or death from any cause. 
 
To assess overall survival in each cohort 
Overall survival, calculated from day 1 of study 
treatment to the date of death from any cause. 
 
 
 
 
 

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1.3 Exploratory objectives and endpoints 
 
Exploratory objectives 
Endpoints 
To assess the objective response rate in 
centrally confirmed E-Cadherin negative and 
CDH1 mutated tumours 
 
Objective response rate in centrally confirmed E-
cadherin negative and CDH1 mutated tumours 
 
To evaluate candidate predictive biomarkers 
of sensitivity or resistance to crizotinib in 
each cohort, including but not limited to 
tumour Ki67, E-cadherin expression, MET 
gene copy number CDH1 mutation status, 
PIK3CA and ESR1 mutations 
 
Objective response rate in patients with PIK3CA, 
ESR1, and CDH1 mutations or MET amplification 
in baseline plasma DNA 
To explore the predictive and/or 
pharmacodynamic characteristics of 
peripheral blood and additional tumour tissue 
biomarkers that may be relevant to the 
mechanism of action of or resistance to 
crizotinib. 
 
Exploratory assessment of biomarkers of 
response in baseline tumour biopsy, and of 
acquired resistance in progression biopsies and 
plasma DNA. 
 
 
1.4 Design 
 
Multi-centre study design, recruitment over 36 months from up to 8 high volume centres including 
the Royal Marsden. Parallel recruitment to breast and basket cohorts. 
Breast cohort treated with crizotinib and fulvestrant, basket cohort treated with crizotinib 
monotherapy.  
 
 
 
 
 
  
 
 
 
Crizotinib 250mg bd 
(monotherapy) 
Crizotinib 250mg bd 
plus Fulvestrant 500mg 
q28 days (plus loading 
dose at D15) 
Breast cohort: Lobular 
ER+/HER2- breast cancer 
n=29 
Basket cohort: Diffuse 
gastric cancer, triple 
negative lobular breast 
cancer or CDH1-mutated 
solid tumour 

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1.5 Administration schedule 
This is a phase II trial combining the ALK/ROS1 inhibitor crizotinib with the selective oestrogen 
receptor degrader, fulvestrant in advanced lobular breast cancer and of crizotinib monotherapy in 
advanced diffuse gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid tumours. 
 
1.6 Treatment group 
Patients with histological confirmation of E-cadherin negative, previously treated advanced lobular 
breast cancer or diffuse gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid 
tumours.  
 
1.7 Trial timelines and accrual rate 
A maximum of 29 breast cancer and 29 gastric cancer, triple negative lobular breast cancer or CDH1-
mutated solid tumour patients will be enrolled  
The anticipated accrual rate is 2 breast cancer and 2 gastric cancer, triple negative lobular breast 
cancer or CDH1-mutated solid tumour patients per month across up to 8 centres. It is anticipated that 
the duration of recruitment to the study will be 36 months. 
 
1.8 Role of study sponsor and funder 
For this trial some of the duties of the sponsor have been delegated to the Chief Investigator (CI), for 
example the CI has overall responsibility for the design and development of the protocol. The 
sponsorship agreement describes the allocation of such responsibilities, and a summary of this can be 
provided by the sponsor upon request. 
Breast Cancer Now and Pfizer are providing funding for the study.  Neither party contributed to the 
design or protocol development, but both parties independently reviewed the protocol during 
development. 
Neither Pfizer nor BCN will be involved in the conduct of the study, data analysis or interpretation, but 
both parties will be provided with study reports prior to submission for presentation and publication. 
 
 

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2. INTRODUCTION 
 
2.1 Background 
2.1.1 Lobular breast cancer 
 Lobular breast cancers are characterised by loss of function of the cell adhesion molecule, E-cadherin, 
due to mutations or epigenetic alterations in the tumour suppressor gene CDH1 [1]. In addition to the 
roles of E-cadherin in cell architecture and migration, the protein also appears to mediate signalling 
through EGFR and the Wnt pathway [2, 3]. Lobular cancers are typically ER and PgR positive and HER2 
negative [3], have a luminal A intrinsic subtype; as such hormonal therapy is the mainstay of treatment 
for advanced lobular breast cancer before chemotherapy is necessary after the development of 
resistance. Lobular breast cancers respond less well to chemotherapy than ductal carcinomas [4], 
therefore there is a real need to develop new agents for patients with disease progression despite 
prior hormonal therapy. There are currently no recruiting studies worldwide investigating novel 
therapies specifically for advanced lobular breast cancer patients. 
2.1.2 Diffuse gastric cancer  
Diffuse gastric cancers are similarly characterised by loss of function of the cell adhesion molecule, E-
cadherin, either due to germline mutations in CDH1 in the case of hereditary diffuse gastric cancer, or 
hypermethylation in the CDH1 promoter region in sporadic ally occurring forms of the disease[5].   
Diffuse gastric cancer is often poorly chemotherapy responsive but was commonly treated with 
standard first-line platinum-based chemotherapy, and second-line taxane-based chemotherapy. The 
introduction of the peri-operative platinum and taxane-containing FLOT regimen[6] has left many 
patients without a chemotherapy option following relapse.  The optimal treatment for this sub-type 
of gastric cancer remains controversial [7]. Although MET expression is common (39% in one study), 
MET gene amplification is reported in less than 10% of all gastric cancers, and 15% of the diffuse sub-
type[8] FGFR2 amplification is present in a further 10% of cases[9]. 
 
2.1.3 Triple negative lobular breast cancer  
Approximately 15% of invasive lobular carcinomas (ILC) are ER negative at the time of breast cancer 
diagnosis, or at relapse due to loss of ER expression.  Like triple negative invasive ductal cancers (IDC), 
triple negative ILC are associated with an inferior prognosis compared to ER positive/HER2 negative 
disease [16]. However, outcomes are similar to those expected for triple negative IDC [17]. 
E-cadherin loss is diagnostic of all subtypes of lobular breast cancer, including those which are ER 
negative. Despite being “triple negative,” in contrast to triple negative IDC, these uncommon ILC are 
usually luminal A or B and rarely basal intrinsic subtype [18, 19]. 
 
2.1.4 CDH1-mutated solid tumours 
A large study of over 5000 tumour samples has described CDH1 mutations in skin, bladder, colorectal, 
endometrial, oesophageal, renal, lung, ovarian, prostate and thyroid cancers [20]. 
 
 

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2.2 Investigational medicinal products 
2.2.1 Crizotinib 
Crizotinib is a small molecule inhibitor of the Anaplastic lymphoma kinase (ALK) receptor tyrosine 
kinase, the hepatic growth factor receptor (c-Met) and ROS1, which is licensed in ALK-positive 
advanced non-small cell lung cancer (NSCLC). The recommended dose schedule is 250mg bd taken on 
a continuous dosing schedule. 
2.2.1.1 Crizotinib clinical experience  
An open-label phase III trial of crizotinib compared to chemotherapy in patients with advanced ALK-
positive non-squamous, NSCLC reported significant prolongation of progression-free survival (PFS) 
with crizotinib (median, 10.9 months vs. 7.0 months; hazard ratio (HR) for progression or death with 
crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001).  Objective response rates were 
also increased with crizotinib (74% and 45%, respectively (P<0.001). median overall survival has not 
been reached, but 1-year overall survival was 84% with crizotinib and 79% with chemotherapy.  The 
most common adverse events with crizotinib were vision disorders, gastrointestinal toxicity 
(diarrhoea, nausea), and oedema [10].  
A single-arm study in NSCLC patients with ROS-1 re-arrangements also demonstrated promising 
efficacy from crizotinib; the objective response rate was 72%, median PFS was 19.2 months (95% CI, 
14.4 to not reached), and no new safety signals were observed [11].  
In advanced gastro-oesophageal cancer, four patients with MET amplification (measured by 
fluorescent in situ hybridisation) were treated with crizotinib, of whom two (50%) experienced tumour 
shrinkage[12]. Crizotinib has not been previously investigated in patients with breast cancer. 
2.2.1.2 Crizotinib Pharmacokinetic Drug Interactions  
Co-administration of crizotinib with strong CYP3A inhibitors may increase plasma crizotinib 
concentrations.  Therefore, concomitant use of such medications or grapefruit juice must be avoided. 
Co-administration of crizotinib with strong CYP3A inducers may reduce crizotinib plasma 
concentrations, so concomitant use of such medications must be avoided. 
Co-administration of crizotinib with agents which increase gastric pH (proton pump inhibitors, H2 
blockers, antacids) results in a minor reduction in crizotinib total exposure, so should be avoided 
unless clinically necessary. No adjustment to the starting dose of crizotinib is required in patients 
taking medications which increase gastric pH. 
Crizotinib is a moderate inhibitor of CYP3A and CYP2B6 and a weak inhibitor of UGT1A1, UGTB7, OCT1 
and OCT2, so may increase plasma concentrations of drugs which are substrates of these enzymes 
(such as alfentanil, cisapride, cyclosporine, ergot derivatives, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus (CYP 3A), bupropion and efavirenz (CYP 2B6), raltegravir, irinotecan (UGT1A1), morphine, 
naloxone (UGT2B7), metformin, procainamide (OCT 1 and 2)).   
Crizotinib may inhibit intestinal P-gp, therefore co-administration with substrates of P-gp (such as 
digoxin, dabigatran, colchicine and pravastatin) may increase their therapeutic effect and toxicity. 

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Concomitant administration of crizotinib with oral contraceptives may be reduced. 
2.2.1.3 Crizotinib Pharmacodynamic drug interactions 
Prolonged QT interval is observed with crizotinib; therefore concomitant administration with other 
medications known to prolong QT or induce Torsades de pointes is not permitted. 
Bradycardia has been reported with crizotinib, therefore use with other agents which can induce 
bradycardia (verapamil, diltiazem, beta-blockers, digoxin) should be avoided. 
2.2.1.4 Crizotinib and fulvestrant 
The selective estrogen receptor degrader (SERD) fulvestrant is an active hormonal therapy that 
inhibits and degrades the estrogen receptor, with anti-tumour activity in cancers that have progressed 
on prior endocrine therapy. Crizotinib has never been combined with fulvestrant clinically; however 
there are no overlapping toxicities.  A phase I study of crizotinib in combination with a different 
endocrine therapy, the non-steroidal anti-androgen, enzalutamide, reported no dose-limiting 
toxicities from the combination[13].   
 
2.2.2 Compatible adverse event profiles 
The dose limiting toxicities (DLT) in the phase I trial of Crizotinib were grade 3 transaminitis at the 
200mg od dose level and grade 3 fatigue in 2 patients at 300mg bd.  The maximum tolerated dose was 
established as 250mg bd [14]. 
There were no reported DLTs for fulvestrant (Howell et al., Lancet 1995), but dosing is limited by the 
volume acceptable for IM injection.  The CONFIRM trial necessitated two 5ml IM injections to deliver 
the monthly 500mg dose [15]. 
The adverse event profiles suggest that each combination has the potential to be well tolerated, 
with non-overlapping DLT.  
 
 

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3. RATIONALE FOR THE PROPOSED TRIAL 
Despite their characteristic defects in E-cadherin, there have been few clinical trials that have focused 
on invasive lobular breast cancers (ILCs), with ILC generally forming a small subgroup of ER+ breast 
cancer studies. This is because efforts to identify specific therapeutic targets associated with loss of E-
cadherin expression, the pathognomic alteration in this breast cancer subtype, have to date been 
limited to synthetic lethal screens in a non-tumour breast epithelial cell line model, MCF10A[16]. This 
particular effort identified crizotinib, a ROS1/MET/ALK inhibitor as selectively targeting this E-cadherin 
defective non-tumour epithelial cell line. However from this data it was not clear whether 
actionable/druggable E-cadherin synthetic lethal effects could be identified that operated in E-
cadherin defective breast tumour cells and in in vivo models of E-cadherin defective breast cancer. 
Furthermore it was not clear that actionable E-cadherin synthetic lethal effects could be identified 
that still operated in the face of the considerable molecular heterogeneity seen in human cancers. 
To model breast cancers with loss of E-cadherin, the Lord Lab (ICR, London) used CRISPR-Cas9 
mutagenesis in MCF7 breast tumour cells (ER-positive, luminal A, PIK3CA mutant; described hereafter 
as MCF7Parental cells) to generate daughter clones, MCF7A02, MCF7B04 and MCF7B05, with frameshift 
mutations in CDH1 and loss of E-cadherin expression (Fig. 1A). Compared to MCF7Parental cells, E-
cadherin defective cells displayed a rounded morphology seen in breast tumour cells harbouring 
naturally occurring E-cadherin mutations. MCF7A02 and MCF7Parental cells were used in two parallel 
functional screens to identify E-cadherin synthetic lethal effects: (i) a drug sensitivity screen where 
the relative sensitivity of cells to an in–house curated library of 80 small-molecule inhibitors was 
assessed and (ii) a parallel siRNA sensitivity screen targeting >1000 cell cycle control genes, kinase-
coding genes or DNA repair related genes. The drug sensitivity screens identified a series of candidate 
E-cadherin synthetic lethal drugs, including the ROS1/MET/ALK inhibitors crizotinib (PF02341066, 
Pfizer) and foretinib (GSK1363089, GSK) (Fig. 1B). The siRNA screens identified a series of candidate 
synthetic lethal effects including ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase, Fig. 1C). 
This raised the possibility that the synthetic lethality between ROS1 and E-cadherin in E-cadherin 
defective cells might be exploited by the use of ROS1 inhibitors such as crizotinib and foretinib. In 
validation experiments, each of the four individual ROS1 siRNAs from the ROS1 SMARTpool caused 
silencing of ROS1 and preferentially inhibited the E-cadherin deficient MCF7A02 clone and also an E-
cadherin defective MCF10A CDH1–/– non-tumour cell line (data not shown). Two further E-cadherin 
defective clones from the MCF7 CRISPR-Cas9 targeting, MCF7B04 and MCF7B05, were also significantly 
more sensitive to either foretinib or crizotinib than the parental cells (data not shown). Restoring E-
cadherin expression in MCF7A02 using a Flag-epitope tagged E-cadherin cDNA expression construct 
reduced foretinib sensitivity as well as sensitivity to an additional ROS1/MET/ALK inhibitor, TAE673 
(data not shown), confirming that E-cadherin influences the response to these agents. In assessing the 
effects of additional ROS1/MET/ALK inhibitors on E-cadherin isogenic cells, foretinib and crizotinib 
were found to give the greatest difference in drug sensitivity between E-cadherin wild type and 
defective cells (Fig. 1D), warranting their further investigation. The sensitivity of E-cadherin defective 
cells to foretinib was similar to that observed in HCC78 cells (Fig. 1E), which harbour a SLC34A2-ROS1 
gene fusion rearrangement rendering the cell line highly addicted to ROS1 kinase activity. E-cadherin 
defective cells were also more sensitive to a recently described ROS1 kinase inhibitor, PF-06463922 
(lorlatinib) (Fig. 1F). Transfection of E-cadherin defective MCF7A02 cells with increasing amounts of 
ROS1 siRNA enhanced the cell inhibitory effects of foretinib (Fig. 1G), whereas expression of a 
crizotinib-refractory p.G2032R mutant ROS1 fusion cDNA caused crizotinib resistance in E-cadherin 

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defective cells (data not shown), suggesting that ROS1 could be a critical foretinib target in E-cadherin 
defective cells. To assess whether the synthetic lethal effect of ROS1 inhibition could apply more 
widely in breast cancer with E-cadherin loss, in-house siRNA “Achilles’ Heel” screen data describing 
the kinase dependencies in 34 breast tumour cell lines was assessed (Fig 1 H). This identified ROS1 
siRNA as selectively targeting the E-cadherin deficient cohort (p<0.05, Fig. 1I). Validation experiments 
confirmed this observation (data not shown), suggesting that the synthetic lethal interaction between 
ROS1 inhibition and E-cadherin deficiency operated not only in isogenic models, but also in 
molecularly diverse models of breast cancer, suggesting that this synthetic lethal effect was relatively 
resistant to the effect of molecular heterogeneity. The sensitivity of the breast tumour cell line models 
to foretinib or crizotinib and also correlated with E-cadherin protein expression (Fig. 1J,K). By 
interrogating recently published data describing drug sensitivity effects in ex vivo cultured breast 
cancer explants, crizotinib was also found to be the most significant effect associated with CDH1 gene 
copy number loss (data not shown). In investigating the cellular phenotypes associated with these E-
cadherin selective effects, E-cadherin defective cells exposed to ROS1 inhibitors exhibited an increase 
in the proportion of cells with >4N DNA content (Fig. 1L), an increase in the frequency of cells with 
abnormal mitoses, particularly cells with multiple nuclei, an increase in expression of the G2/M DNA 
damage biomarker p21 and an increase in cellular apoptosis as assessed by PARP cleavage and caspase 
3/7 activity (data not shown). Live cell microscopy imaging indicated that in response to ROS1 
inhibitors, E-cadherin defective cells initiated cytokinesis but failed to complete invagination of the 
cell membrane at cleavage furrows, resulting in multinuclear cells (Fig 1M). This suggested that the E-
cadherin selective effects of ROS1 inhibitors might be explained by abnormal cytokinesis, and the 
formation of a multinuclear phenotype that could conceivably cause mitotic catastrophe. To assess 
the in vivo therapeutic potential of foretinib and crizotinib, the ability of these drugs to inhibit E-
cadherin defective invasive mammary carcinomas derived from K14cre;Cdh1F/F;Trp53F/F (KEP) mice 
was assessed; these mammary carcinomas show a strong resemblance to human pleomorphic ILCs. In 
mice that received the drug vehicle alone, tumour growth continued unabated; in contrast, both 
foretinib or crizotinib treatment had a strong anti-tumour effect on KEP tumour growth and extended 
the survival of tumour-bearing mice (Fig 1N and data not shown). We also assessed the anti-tumour 
effect of foretinib treatment in an E-cadherin defective patient-derived breast tumour xenograft (PDX) 
model, BCM2665, which was derived from a female with ER-negative, HER2-negative, basal-like breast 
cancer. As before, foretinib significantly inhibited the growth of established tumours (p<0.0001 
ANOVA) and extended the survival of mice (Fig 1O). These observations were also replicated in 
subcutaneous xenografts derived from the ER+ ILC cell line MDAMB134VI where mice were treated 
with crizotinib (data not shown). 
 

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Figure 1. ROS1/E-cadherin synthetic lethality in models of breast cancer 
 
48kDa 
E-cadherin 
ACTIN 
MC F7 A0 2 
105kDa 
MC F7 PAR EN TAL  
A. 
Target CDH1 null Target CDH1 WT 
0.25
0.5
1
2
4
0.000001
0.00001
0.0001
0.001
0.01
0.1
1
p-value
Diff
i
i i
f
ti
Crizotinib
Foretinib
Difference in surviving fraction 
Difference in Z score 
Target CDH1 null 
Target CDH1 WT 
-10
-5
0
5
10
0.000001
0.00001
0.0001
0.001
0.01
0.1
1
p-value
Diff
i
Z
ROS1
MCF7 Parental 
MCF7 A02 
Foretinib
Crizotinib
Alectininb
Cabozantinib
AZD3463
Ceritinib
0
2
4
6
SF50 mM
Surviving Fraction 
[Foretinib] (M) 
MCF10A CDH1+/+ 
MCF10A CDH1–/– 
HCC78 
10-8
10-7
10-6
10-5
0.0
0.5
1.0
6 day 
drug 
exposure 
10-8
10-7
10-6
10-5
0.0
0.5
1.0
PF-06463922 (M)
Surviving Fraction
MCF10A CDH1+/+ 
MCF10A CDH1-/- 
10-8
10-7
10-6
10-5
0
0.0
0.5
1.0
Foretinib(M)
Surviving Fraction
siCont
siROS1_20nM
siROS1_10nM
siROS1_5nM
siROS1_2.5nM
siROS1_1.25nM
siROS1_0.625nM
HCC1569
  
HCC1954
   
HCC202
    
HCC38
    
HCC70
    
HMT 3552  
HS5 78T    
JIMT 1   
MC F7     
MD AMB 134     
MD AMB 157  
MD AMB 231   
MD AMB 436     
MC F7    
MD AMB 453     
BT20
  
BT474
   
CAL120
    
CAL51
   
CAMA -1     
DU4475
 
E-cadherin 
ACTIN 
BT549
   
MD AMB 468  
SK BR3    
SU M1 49     
SU M4 4    
SU M5 2   
T47D    
VP2 29    
ZR7530
   
ACTIN 
105kDa 
38kDa 
E-cadherin 
MC F7 
HS5 78T 
JIMT 1 
HCC1 143 
MC F7 
HCC38 
MD AMB 436 
HCC2218 
MC F12A 
SU M1 59 
MC F7    
105kDa 
38kDa 
Muta%on(Promoter(methyla%on(Dele%on!
-2
-1
0
1
2
3
0.0001
0.001
0.01
0.1
1
p-value
ROS1
Difference in Z score 
Target E-cadherin defective Target E-cadherin wild type 
0.0
0.5
1.0
1.5
2.0
log AUC
**
Defective  WT    HCC78 
Foretinib 
p=0.003 
Student’s t-test 
Null
Wild type
HCC78
0.0
0.5
1.0
1.5
2.0
log AUC
*
Defective  WT    HCC78 
Crizotinib 
p=0.035 
Student’s t-test 
Vehicle 
8hrs foretinib exposure 
3.14% 
60.4% 
64.7% 
0.74% 
24hrs foretinib exposure 
48hrs foretinib exposure 
2n 4n 
>4n 
Relative cell number 
Relative PI-texas red signal intensity 
Relative PI-texas red signal intensity 
>4n  
fraction 
only 
% cells with 
>4n 
0 
60 
80 
120 
170 
(min) 
0 
50 
60 
70 
200 
10um 
10um 
10um 
10um 
10um 
10um 
10um 
10um 
10um 
10um 
10um 
10um 
30 
650 (min) 
Regression 
Regression 
Regression 
MCF7A02 vehicle 
MCF7A02 foretinib 
0
3
6
9
12
15
18
21
24
27
30
0
500
1000
1500
2000
2500
 Tumour volume
Vehicle
Crizotinib 25mg/kg
Crizotinib 50mg/kg
K14cre;Cdh1F/F;Trp53F/F  
Days after the initiation of treatment 
0
10
20
30
40
0.0
0.2
0.4
0.6
0.8
1.0
Tumour Volume (cm3)
Vehicle (n=11)
Foretinib (n=8)
Days after the initiation of treatment 
BCM2665 
B. 
C. 
D. 
E. 
F. 
G. 
H. 
I. 
J. 
K. 
L. 
M. 
N. 
O. 

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Figure 1 (previous page). ROS1/E-cadherin synthetic lethality in models of breast cancer.  
A. To identify candidate therapeutic targets for breast cancers with loss of E-cadherin, CRISPR-Cas9 
mutagenesis in MCF7 breast tumour cells (ER-positive, luminal A, PIK3CA mutant; described hereafter 
as MCF7Parental cells) was used to generate daughter clones, MCF7A02, MCF7B04 and MCF7B05, with 
frameshift mutations in CDH1 and loss of E-cadherin expression (MCF7A02and MCF7Parental cells shown 
in Figure). MCF7A02 and MCF7Parental cells were used in two parallel functional screens to identify E-
cadherin synthetic lethal effects: (i) a drug sensitivity screen where we assessed the relative sensitivity 
of cells to an in–house curated library of 80 small-molecule inhibitors that are either in clinical use for 
the treatment of cancer or in late-stage clinical development and (ii) a parallel siRNA sensitivity screen, 
using siRNA SMARTpools targeting >1000 cell cycle control genes, kinase-coding genes or DNA repair 
related genes. B. Volcano plot of data from drug sensitivity screens in MCF7parental and MCF7A02 cells. 
The difference in surviving fractions for each small-molecule concentration and p values for each 
MCF7parental vs. MCF7A02 comparison are shown. Red and blue dots represent different concentrations 
of either crizotinib or foretinib identified in the screen as selectively targeting MCF7A02 cells. C. Volcano 
plot of data from siRNA SMARTpool sensitivity screens in MCF7parental and MCF7A02 cells. Both cell lines 
were transfected with a siRNA library and cultured for six days. The difference in Z-scores and p values 
for each MCF7parental vs. MCF7A02 comparison are shown. Blue dot highlights ROS1 siRNA identified in 
the screen as selectively targeting MCF7A02 cells. D. Dot chart illustrating cell survival effects of 
ROS1/MET/ALK inhibitors in MCF7parental and MCF7A02 cells. SF50 = surviving fraction 50 (concentration 
required to cause 50 % reduction in survival). E, F. Dose-response survival curves in MCF10A CDH1+/+ 
and MCF10A CDH1–/– cells exposed to foretinib for six days or lorlatinib (PF-06463922). SLC34A2-ROS1 
translocation-positive HCC78 cells are shown as a positive control. G. Dose-response survival curves 
in MCF7A02 cells transfected with different concentrations of ROS1 siRNA SMARTpool and 
subsequently exposed to foretinib for six days. Increasing concentration of ROS1 siRNA caused a dose-
dependent reduction in foretinib SF50. H. Western blot illustrating E-cadherin expression in 37 breast 
tumour cell lines (including MCF7 as positive control). Cell line names are colour-coded according to 
the presence of CDH1 gene mutations, gene deletion events or CDH1 promoter hypermethylation 
events. I. Volcano plot of data from the siRNA SMARTpool sensitivity screens in each of the 37 breast 
tumour cell lines. Blue dot highlights ROS1 siRNA identified in the screen as selectively targeting E-
cadherin defective cells. J.K. Box whisker plots illustrating foretinib (J) or crizotinib (K) sensitivity in 12 
breast tumour cell lines, defined by log2 area under the curve (AUC) values. Log2 AUC values for 
SLC34A2-ROS1 translocation-positive HCC78 cells are shown as a positive control. L. FACS plots 
illustrating increase in DNA content in E-cadherin defective MCF7A02 cells exposed to foretinib, 
including enlarged image indicating >4n fraction. M. Time lapse microscopy images illustrating cell 
division in E-cadherin defective MCF7A02 cells exposed to foretinib. MCF7A02 cells were first transfected 
with a mCherry-H2B plasmid, to facilitate DNA visualization, and then exposed to foretinib for a 24-
hour period. Initial formation of the cleavage furrow, followed by formation of a multinuclear cell is 
highlighted with white arrows. N. Therapeutic response to foretinib treatment in mice bearing E-
cadherin deficient mammary tumours. Mammary tumour fragments from KEP mice were transplanted 
into recipient mice; once tumours had established, animals were treated over a 27-day period with 
either drug vehicle or crizotinib. ANOVA p<0.0001 for both foretinib treatment regimes compared to 
vehicle-treated mice. O. Therapeutic response to foretinib treatment in mice bearing BCM2665 PDX. 
BCM2665 was transplanted into 19 recipient mice; once tumours had established, animals were 

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treated over a 47-day period with either drug vehicle (n=11), or foretinib (25 mg/kg every other day, 
n= 8) as shown. ANOVA = p<0.0001.  
In addition to these effects in models of breast cancer, the effects of crizotinib in models of gastric 
cancer have also been assessed. A reanalysis of publically available crizotinib sensitivity data in 
gastric tumour cell lines indicates that those with reduced E-cadherin expression (defined by CDH1 
mRNA levels) are more sensitive to crizotinib that those with elevated levels of expression (Figure 2).  
 
 
Figure 2. Left: E-cadherin/CDH1 mRNA expression in gastric tumour cell lines profiled as part of the 
Broad institute Cancer Cell Encyclopedia (CCLE). Tumour cell lines were classified as “CDH1 null” or 
“CDH1 wild type” based on a threshold of 7 nominal units of expression. Right: Crizotinib sensitivity 
(as defined by concentration in micromols that causes 50 % inhibition, SF50) in the same gastric 
tumour cell line panel * p <0.05 Student’s t test. 
 
 
The pre-clinical data described above which underpin the scientific rationale for this study 
[17]demonstrated that in vivo crizotinib sensitivity is also seen in CDH1 null triple negative breast 
cancers. A further observation of a response to crizotinib in a triple negative lobular breast cancer 
organoid established from leptomeningeal cells (Fitzpatrick A. et al., unpublished data) supports this. 
These patients are excluded from the breast cancer cohort; as such patients would be unsuitable to 
receive fulvestrant with crizotinib. 
Across all anatomic sites, 4% of carcinomas had at least one CDH1 mutation in a study of 7578 primary 
carcinomas across 13 anatomic sites. Although breast and gastric cancers were the most common 
primary tumour sites harbouring CDH1 mutations, they were also detected in non-melanomatous skin 
cancers, bladder, colorectal, endometrial, lung, ovarian, prostate and thyroid cancers [20]. 
Fulvestrant is a selective oestrogen receptor down-regulator (SERD) delivered by intramuscular 
injection, with efficacy in previously treated ER positive breast cancer including the lobular sub-type 
[15, 18]. Fulvestrant 500mg is likely the most-efficacious hormone therapy after progression on prior 
hormonal therapy. 
CCLE mRNA expression
CDH1 null
CDH1 wt
0
5
10
15
mRNA expression
Crizotinib
CDH1 null
CDH1 wt
0
2
4
6
SF50 uM
*

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4. TRIAL DESIGN 
 
4.1 Clinical trial objectives and endpoints 
 
4.1.1 Primary objectives and endpoints 
Primary objective 
Endpoint 
To assess confirmed response rate by RECIST 
1.1 of crizotinib and fulvestrant in the breast 
cohort  
Confirmed response rate, by RECIST 1.1, of 
crizotinib and fulvestrant in advanced E-cadherin 
negative, ER positive lobular breast cancer 
To assess confirmed response rate by RECIST 
1.1 of crizotinib monotherapy in the diffuse 
gastric cancer, triple negative lobular breast 
cancer or CDH1-mutated solid tumour 
(basket) cohort. 
Confirmed response rate, by RECIST 1.1, of 
crizotinib in advanced E-cadherin negative, 
diffuse gastric cancer, triple negative lobular 
breast cancer or CDH1-mutated solid tumours. 
 
4.1.2 Secondary objectives and endpoints 
Secondary objectives 
Endpoints 
To assess the overall safety and tolerability of 
crizotinib with fulvestrant in the breast cancer 
cohort and as monotherapy in the gastric 
cancer, triple negative lobular breast cancer 
or CDH1-mutated solid tumour (basket) 
cohort. 
 Overall safety and tolerability of crizotinib with 
Fulvestrant. Toxicity will be assessed by CTCAE 
(version 4) every 4 weeks during study 
treatment. Adverse events, including serious 
adverse events, will be recorded until 30 days 
after the last dose of study treatment with 
crizotinib. 
To assess the clinical benefit rate (response 
and stable disease lasting at least 24 weeks) 
in the breast cancer cohort. 
Clinical benefit rate (response or stable disease 
lasting at least 24 weeks), assessed by RECIST 1.1 
by local radiology review. 
To assess progression-free survival in each 
cohort 
Progression-free survival, calculated from day 1 
of study treatment to the date of radiological 
disease progression or death from any cause. 
To assess overall survival in each cohort 
 
Overall survival, calculated from day 1 of study 
treatment to the date of death from any cause. 
 
4.1.3 Exploratory objectives and endpoints 
Exploratory objectives 
Endpoints 
To assess the objective response rate in 
centrally confirmed E-Cadherin negative and 
CDH1 mutated tumours 
Objective response rate in centrally confirmed E-
cadherin negative and CDH1 mutated tumours 

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To evaluate candidate predictive biomarkers 
of sensitivity or resistance to crizotinib in 
each cohort, including but not limited to 
tumour Ki67, E-cadherin expression, CDH1 
mutation status, PIK3CA and ESR1 mutations 
Objective response rate in patients with PIK3CA, 
ESR1, and CDH1 mutations in baseline plasma 
DNA 
To explore the predictive and/or 
pharmacodynamic characteristics of 
peripheral blood and additional tumour tissue 
biomarkers that may be relevant to the 
mechanism of action of or resistance to 
crizotinib  
Exploratory assessment of biomarkers of 
response in baseline tumour biopsy, and of 
acquired resistance in progression biopsies and 
plasma DNA. 
 
 
4.2 Safety Review Committee 
To monitor for unexpected adverse effects, we will perform a formal safety review after 3 and 6 
patients have received one cycle of treatment (28 days) of crizotinib and fulvestrant in the lobular 
breast cancer cohort and after 3 and 6 diffuse gastric cancer patients have received one cycle of 
crizotinib monotherapy (28 days) in the basket cohort. 
The SRC will consist of: 
• 
Principal Investigator or delegate from each investigational site 
• 
RM CTU CTC or delegate 
• 
Co-investigators Professor Turner and Dr Starling 
 
4.3 Patient evaluability 
All patients receiving at least one administration of the crizotinib will be considered evaluable for 
safety and tolerability. 
 
4.4 Design of the clinical trial 
This is a phase 2 trial which will investigate the efficacy and tolerability of crizotinib monotherapy in 
previously treated advanced diffuse gastric cancer, triple negative lobular breast cancer or CDH1-
mutated solid tumour patients and of crizotinib combined with fulvestrant in previously treated 
lobular breast cancer patients. 
The anticipated accrual rate is estimated at 4 patients per month across 8 centres. It is therefore 
expected that the trial will recruit over 18 months. 
 
 

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Figure 1: Study design 
 
 
Patients with previously treated E-cadherin negative 
advanced lobular breast or diffuse gastric cancer, 
triple negative lobular breast cancer or CDH1-
mutated solid tumours (Basket cohort) 
Lobular Breast Cohort: 
Doublet combination 
Crizotinib 250mg bd + fulvestrant 500mg q28 
days (plus loading dose at D15) 
28 day cycle 
29 patients 
Basket Cohort: 
Crizotinib 250mg bd continuous dosing 
28 day cycle 
29 patients 
 

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5. PATIENT SELECTION 
 
5.1 Eligibility criteria 
The patient must fulfil the eligibility criteria (listed in Sections 4.1.1 and 4.1.2). 
5.1.1 Inclusion criteria: 
1.  Patients with histological diagnosis of E-cadherin negative inoperable or metastatic diffuse 
gastric cancer (basket cohort), 
Or inoperable or metastatic, E-cadherin negative triple negative lobular breast cancer 
(basket cohort) 
Or inoperable or metastatic CDH1-mutated solid tumour with allele fraction ≥20% (basket 
cohort) 
Or recurrent inoperable locally advanced E-cadherin negative, ER positive/HER2 negative 
lobular breast cancer (breast cohort).  
Assessment of E-cadherin, ER and HER2 status as per local assessment. 
 
2.  Lobular breast cancer patients previously treated with at least one prior line of therapy 
including at least one prior line of hormone therapy and a CDK4/6 inhibitor for advanced 
disease or at least one line of hormone therapy and at least one line of chemotherapy for 
advanced disease, but no more than three prior lines of chemotherapy for advanced 
disease.   
Gastric cancer patients previously treated with at least one but no more than three lines of 
prior therapy for advanced disease OR relapsing within one year of completing (neo) 
adjuvant chemotherapy OR unsuitable for chemotherapy in the opinion of the investigator 
(for example patient choice not to have chemotherapy, or no suitable chemotherapy 
agent).  
Triple negative lobular breast cancer or CDH1-mutated solid tumour previously treated 
with at least one prior therapy for advanced disease, but no more than three prior lines of 
chemotherapy for advanced disease 
 
3.  Measurable disease (RECIST 1.1) 
 
4.  Haematological and biochemical indices within the ranges shown below. These 
measurements must be performed within one week (Day -7 to Day 1) before the patient 
goes in the trial. 
 
 
Laboratory Test 
Value required 
 
Haemoglobin (Hb) 
≥ 10.0 g/dL  
 
Absolute neutrophil count 
≥ 1.5 x 109/L  
 
Platelet count 
≥ 100 x 109/L 
 
Serum bilirubin  
 
 
≤ 1.5 x upper limit of normal (ULN) except for 
patients with documented Gilberts’ disease 
 
Alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST)  
≤ 2.5 x (ULN) unless raised due to tumour in 
which case up to 5 x ULN is permissible 

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Creatinine  
If creatinine > 1.5 times ULN then: 
Calculate creatinine clearance (as per 
standard of care) 
 
 
≤1.5 times ULN 
≥ 50 mL/min (uncorrected value) 
 
 
 
 
 
Coagulation 
    
INR <1.5 
APTT <1.5x ULN 
 
5. 
Female patients with child-bearing potential must have a negative urine or serum pregnancy 
test within 7 days prior to start of trial. Both male and female patients of reproductive 
potential must agree to use two forms of highly effective contraception (see below) for 2 
weeks before starting the study treatment, throughout the treatment period and for 90 days 
after discontinuation of treatment with crizotinib and 2 years after the last dose of 
fulvestrant.  
 
• 
Oral, intravaginal or transdermal combined hormonal contraception 
• 
Oral, injectable or implantable progesterone-only contraception  
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system,  
• 
Bilateral tubal occlusion  
• 
Vasectomised partner  
• 
Sexual abstinence* 
 
Key: * it is only considered highly effective if the patient is refraining from sexual intercourse 
during the entire period of risk associated with the study treatments 
 
The oral contraceptive pill may be ineffective when taken with crizotinib so is not an 
acceptable means of contraception for female patients during this study but can be used by 
female partners of male patients. 
 
6. 
18 years of age or over with written (signed and dated) informed consent and be capable of 
co-operating with treatment and follow-up. 
7. 
World Health Organisation (WHO) performance status 0,1 or 2 
8. 
Estimated life expectancy of at least 3 months in the opinion of the investigator 
9. 
Pre-/peri-menopausal ER+ lobular breast cancer patients must be willing to receive goserelin 
injections every 28 days. 
 
Pre- or peri-menopausal ER+ lobular breast cancer patients may be enrolled if they have 
ovarian suppression with the LHRH agonist goserelin. Patients must have commenced 
goserelin or an alternative LHRH agonist at least 4 weeks prior to Cycle 1 Day 1 and continue 
throughout the study. If a patient has received an alternative LHRH agonist at least 4 weeks 
prior to study entry, they must switch to goserelin for the duration of the trial. 

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Post-menopausal female patients, as defined by at least one of the following: 
• 
Age ≥60 years; 
• 
Age <60 years and cessation of regular menses for at least 12 consecutive months with 
no alternative pathological or physiological cause, and serum oestradiol and FSH levels 
within the institutional laboratory’s reference range for post-menopausal females; 
• 
Documented bilateral oophorectomy; 
• 
Medically confirmed ovarian failure. 
 
10. Signed and dated informed consent. 
11. Patients willing and able to comply with scheduled visits, treatment plans, laboratory tests, 
and other procedures. 
 
5.1.2 Exclusion criteria: 
1. Systemic chemotherapy or investigational medicinal products during the previous four 
weeks, or hormonal therapy within 7 days except luteinizing hormone-releasing hormone 
(LHRH) analogues for ovarian suppression.  Bisphosphonates or RANK ligand antagonists are 
permitted for the management of bone metastases.  
 
2. Previous treatment with any agent that inhibits ROS1 
 
3. Mixed ductal/lobular breast cancer, unless both ductal and lobular components are E-
cadherin negative by local assessment 
 
4. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 
weeks or radiation therapy within 14 days prior to study entry  
 
5. Patients with known symptomatic brain metastases requiring steroids, untreated brain 
metastases or spinal cord compression 
 
6. Any of the following within 12 months prior to study entry: myocardial infarction, 
uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart 
failure, cerebrovascular accident, or transient ischemic attack.  Uncontrolled hypertension 
or cardiac dysrhythmia including atrial fibrillation 
 
7. QT interval, corrected >470 ms or the use of bradycardic agents, drugs which prolong the QT 
interval and/or anti-arrhythmic agents within 5 half-lives before the first dose of crizotinib or 
during study treatment. 
 
8. Use of drugs that are known potent cytochrome P450 (CYP) 3A4 inhibitors or moderate or 
strong CYP 3A4 inducers within 12 days before the first dose of crizotinib. Use of CYP3A4 
substrates with a narrow therapeutic index (such as ciclosporin) is also not permitted within 
12 days prior or during the study treatment. 

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9. Patients on warfarin. Patients requiring anticoagulation for rate-controlled AF or previous 
venous thromboembolism should be switched to low-molecular weight heparin. 
 
10. Known HIV or AIDS-related illness, active infection requiring systemic therapy, or positive 
HBV or HCV test indicating acute or chronic infection 
 
11. Inability or unwillingness to swallow pills, or (for patients receiving fulvestrant) receive IM 
injections. 
 
12. Other severe acute or chronic medical condition or psychiatric condition, recent or active 
suicidal ideation or behaviour, or end stage renal disease on haemodialysis, or laboratory 
abnormality that may increase the risk associated with study participation or investigational 
products administration or may interfere with the interpretation of results and, in the 
judgment of the Investigator, would make the patient inappropriate study entry 
 
13. Persisting toxicity related to prior therapy >Grade 1 (except for stable peripheral neuropathy 
grade ≤2 or alopecia grade ≤2). 
 
14. Pregnancy or lactation.   
 
15. Diagnosis of other malignancy within 5 years, except for adequately treated basal cell or 
squamous cell skin cancer, or carcinoma in situ of the breast or cervix, or low-grade (Gleason 
≤6) prostate cancer 
 
16. Is a participant or plans to participate in another interventional clinical trial, whilst taking 
part in this study. Participation in an observational trial would be acceptable. 
 
17. Immunocompromised status due to current known active infection with HIV or due to the 
use of immunosuppressive therapies for other conditions 
 
18. Known prior or suspected hypersensitivity to investigational products or to any of the 
excipients 
 
19. Patients at risk for gastrointestinal perforation (due to e.g., history of diverticulitis).  
 
20. Any other condition which in the Investigator’s opinion would not make the patient a good 
candidate for the clinical trial. 
 
 
 
 
 
 
 

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5.2 Patient enrolment 
 
All patients who provide informed consent including any screen failures must be entered onto the 
patient enrolment log provided to the investigational site. 
Before enrolling the patient in the trial, the Investigator or designated representative should confirm 
the patient is eligible to enter the trial. An enrolment form should be completed prior to enrolment.  
To enrol a patient, email the completed enrolment form (see below). A trial number will be allocated. 
The original enrolment form should be filed within the Investigator Site File. 
 
To enrol a patient please email the completed eligibility and enrolment 
form to: 
ROLo.trial@rmh.nhs.uk (Monday – Friday 09:00-17:00) 
 
 
 

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6. TREATMENT 
 
6.1 Dosing schedule/treatment schedule 
 One treatment cycle for crizotinib is 28 days long with continuous dosing of crizotinib 250mg bd po. 
One treatment cycle for crizotinib + fulvestrant is 28 days long with continuous dosing of crizotinib 
250mg bd po and fulvestrant 500mg IM on D1 of each cycle (plus additional D15 loading dose 500mg 
IM in cycle 1 only). 
Patients with documented Gilbert’s disease with bilirubin >1.5-≤ 3x ULN should commence crizotinib 
at a reduced dose of 200mg bd. 
6.2 Dose modifications  
In the event of significant drug-related toxicity, crizotinib dosing may be interrupted or delayed and/or 
reduced, as described below. In the event of multiple toxicities, dose modification should be based on 
the worst toxicity observed. Patients are to be instructed to notify Investigators at the first occurrence 
of any adverse sign or symptom. 
Dose modifications may occur in three ways: 
• 
Within a cycle: dosing interruption until adequate recovery followed by dose reduction, if 
required; 
• 
Between cycles: next cycle administration may be delayed due to persisting toxicity when 
a new cycle is due to start; 
• 
At start of the new cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
Table 1. Common crizotinib toxicities 
Common crizotinib toxicities (>10%) 
Haematological: 
 
-Neutropenia (22%) 
-Anaemia (15%) 
-Leucopenia (15%) 
GI Disorders: 
 
-nausea (57%) 
-diarrhoea (54%) 
-Vomiting (51%) 
-constipation (43%) 
-Abdominal pain (21%) 
General disorders: 
 
-Oedema (49%) 
-Fatigue (30%) 
Cardiac: 
 
-Dizziness (25%) 
-Bradycardia (12%) 
General: 
Anorexia (30%) 
Eyes: 
Vision disorder (62%) 
Laboratory: 
Raised ALT/AST (32%) 
Cutaneous: 
Rash (13%) 
CNS 
-Neuropathy (25%) 

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6.2.1 Dose reductions 
6.2.1.1. Dose reduction for crizotinib 
Table 2. Management of haematological toxicity (Applies to Anaemia, neutropenia and 
thrombocytopenia only): 
CTCAE grade 
Action 
Grade 1-2 
Continue full dose 
Grade 3 (1st occurrence) 
Withhold crizotinib until recovers to grade ≤2 
then resume at same dose 
Grade 4 (1st occurrence) or recurrent grade 3 
Withhold crizotinib until recovers to grade ≤2 
then resume at 200mg bd 
Grade 4 (2nd occurrence) 
Permanently discontinue crizotinib 
 
Table 3. Management of non-haematological toxicity: 
AE and CTCAE grade 
Action 
Grade 1-2 
Add supportive medications if applicable. 
Continue full dose 
Grade 3-4 ALT or AST with grade 0-1 Bilirubin 
(1st occurrence) 
Withhold crizotinib until recovers to grade ≤1 
or baseline then resume at 250mg od. 
Escalate to 200mg bd if tolerated, 
Recurrent grade 3-4 ALT or AST with grade 0-
1 Bilirubin OR Grade 2-4 ALT or AST with 
Grade 2-4 Bilirubin 
Permanently discontinue crizotinib 
Any grade pneumonitis 
Withhold whilst pneumonitis investigated 
with High resolution CT scan.  Permanently 
discontinue crizotinib if diagnosis confirmed. 
Grade 3 QTc prolongation 
Withhold crizotinib until recovers to grade ≤1, 
correct electrolytes, then resume at 200mg 
bd 
Grade 4 QTc prolongation 
Permanently discontinue crizotinib 
 
-Dysgeusia (21%) 

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Grade 2-3 bradycardia 
Withhold crizotinib until recovers to grade ≤1 
or HR >60bpm. Evaluate concomitant 
medications. 
If causal drug identified and stopped, resume 
at previous dose once recovers to grade ≤1 or 
HR >60bpm. 
If no causal concomitant medication 
identified/stopped, resume at 250mg od 
upon recovery to grade ≤1 or HR >60bpm. For 
Grade 3 bradycardia, monitor pulse daily. 
Grade 4 bradycardia  
If causal concomitant medication 
identified/stopped, resume at 250mg od 
upon recovery to grade ≤1 or HR >60bpm. 
Monitor pulse daily. 
If no causal concomitant medication 
identified/stopped, permanently discontinue 
crizotinib 
Grade 3-4 cardiac failure 
Permanently discontinue crizotinib 
Grade 4 ocular disorder (visual loss) 
Permanently discontinue crizotinib.  
Ophthalmological evaluation consisting of best 
corrected visual acuity, retinal photographs, 
visual fields, optical coherence tomography 
(OCT) and other evaluations as appropriate 
for new onset of severe visual loss, should be 
performed.  
Ophthalmological evaluation is recommended 
if grade 1-3 vision disorder persists or 
worsens in severity. 
Any grade gastric perforation 
Permanently discontinue crizotinib 
Other grade 1 non-haematological toxicity 
Continue crizotinib and fulvestrant 
Other grade 2 non-haematological toxicity 
Interrupt crizotinib, add supportive 
medications if indicated (e.g. loperamide, 
cyclizine) 
Restart crizotinib at same dose level once 
resolved to grade 1 or less 

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Other grade 3 or recurrent grade 2 non-
haematological toxicity 
Interrupt crizotinib, add supportive 
medications if indicated (e.g. loperamide, 
cyclizine) 
Restart crizotinib at one lower dose level 
once resolved to grade 1 or less 
Other grade 4 or recurrent grade 3 non-
haematological toxicity 
Permanently discontinue crizotinib 
6.2.1.2 Dose reduction for fulvestrant 
No dose adjustments to fulvestrant are permitted. Fulvestrant should not be administered to patients 
with platelets <50x109/L 
Patients with unacceptable toxicity clearly attributable to fulvestrant may stop fulvestrant and 
continue with crizotinib monotherapy at the investigator’s discretion. 
 
6.2.2 Dose interruptions, delays and re-treatment criteria 
Treatment with crizotinib should be interrupted if a patient experiences a Grade ≥3 toxicity or grade 
2 toxicity lasting >3 weeks despite appropriate supportive treatment. 
Treatment with crizotinib plus/- fulvestrant may be interrupted for a maximum of 28 days until the 
toxicities have resolved or improved to Grade ≤ 1 and then the drug(s) should be dose-reduced as 
described in section 6.2.1 Dose modifications. 
If these toxicities have not resolved or improved to Grade ≤ 1 within this time frame then the patient 
should be withdrawn from the study. 
If despite appropriate dose reductions and or delays, the patient experiences unacceptable toxicities 
specifically attributed to either crizotinib or fulvestrant, then the patient may continue with single 
agent treatment without coming off study providing they have completed their first cycle with the 
combination treatment. The Chief Investigator should be notified if either IMP is discontinued in this 
way. 
Retreatment following interruption for drug related toxicity or at the start of any new cycle may not 
occur until all of the following parameters have been met: 
• Platelet count ≥50,000/mm3 
• Neutrophil count: ≥1000/mm3 and no fever 
• Grade 3 non-hematologic AEs have recovered to ≤ Grade 1 or baseline. 
 
 
 

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6.3 Duration of treatment 
Treatment should continue until (a) the patient asks to be withdrawn, (b) there is evidence of disease 
progression or (c) the patient is experiencing unacceptable toxicity or for any of the reasons listed in 
Section 11. 
6.4 Concomitant medication and treatment 
Concomitant medication may be given as medically indicated. Details (including doses, frequency, 
route and start and stop dates) of the concomitant medication given must be recorded in the patient’s 
medical records and the case report form (CRF). 
Radiotherapy may be given concomitantly for the control of bone pain, however these irradiated 
lesions will not be evaluable for response.  
The patient must not receive other anti-cancer therapy or investigational drugs while on the trial, 
other than bisphosphonates or RANK ligand antagonists for the management of metastatic bone 
disease. 
If medically feasible, patients taking regular medication, with the exception of drugs with the potential 
to prolong QTc and strong inhibitors or inducers of CYP3A4, should be maintained on their regular 
medications throughout the study period.  
6.5 Prohibited medication 
The following restrictions will be put in place in the study, please refer to Appendix 5 of this clinical 
study protocol for listings of relevant drugs. 
Table 4. Prohibited medications 
CYP3A inhibitors and CYP3A inducers: 
• 
Potent inhibitors or inducers of CYP3A4 and CYP3A4 substrates with narrow 
therapeutic indices (including but not limited to alfentanil, cisapride, cyclosporine, 
ergot derivatives, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) should be 
avoided within 2 weeks before the first dose of study treatment (3 weeks for St John’s 
Wort and 5 weeks for Phenobarbitone). 
• 
All patients should avoid concomitant herbal supplements and/or ingestion of foods 
known to potently modulate CYP3A4 enzyme activity from the time they enter the 
screening period until 2 weeks after the last dose of study treatment.  
Anticancer agents: 
• 
Investigational agents and other anticancer agents should not be given while the 
patient is on study treatment with the exception of hormonal therapy with LHRH 
analogues for ovarian suppression in pre- or peri-menopausal breast cancer patients. 
Radiotherapy: 
• 
Radical Radiotherapy should not be given while the patient is on study treatment.  

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• 
Palliative radiation for palliation of symptoms can be given at focal sites i.e. radiation 
for bony pain but cannot be given to target lesions. 
Bradycardic agents, anti-arrhythmics and agents which prolong QTc: 
 
• 
Avoid using crizotinib in combination with other bradycardic agents, medicinal 
products that are known to prolong QT interval and/or anti-arrhythmics. 
 
6.6 Permitted medications: 
 
Table 5. Permitted medications 
Standard therapies for pre-existing medical 
conditions 
e.g. anti-hypertensives 
Bisphosphonates 
e.g. pamidronate, zoledronic acid 
Receptor activator of nuclear factor kappa-B 
ligand (RANKL) 
e.g. denosumab 
Blood or platelet transfusions  
 
Granulocyte colony stimulating factor [G-CSF] 
G-CSF is NOT recommended for primary 
prophylaxis of neutropenia  
Therapeutic use for febrile neutropenia in 
which patients are felt to be at risk of infection 
related complications (ASCO guidelines) 
Secondary prophylaxis at the investigator’s 
discretion 
Erythropoietin 
Already receiving erythropoietin for > 1month 
at the time of screening 
Prophylactic erythropoietin should not be 
started during Cycle 1 of the study but may be 
started during Cycle 2 and after 
Anticoagulation 
 
Subcutaneous heparin is permitted. Patients 
receiving warfarin should be converted to 
heparin prior to commencing study treatment. 
Palliative radiation 
Palliative radiation for palliation of symptoms 
can be given at focal sites i.e. radiation for 
bony pain providing there is no evidence of 
progression 

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7. PHARMACEUTICAL INFORMATION 
 
7.1 Supply of Investigational Medicinal Products 
A complete certificate of analysis and a Qualified Person (QP) certification must be provided with each 
batch of IMP and be retained in the Investigator Trial File (ITF)/Pharmacy File. 
All study drugs will be packaged and labelled in accordance with local regulations and Good 
Manufacturing Practice, stating that the drug is for clinical trial use only and should be kept out of the 
reach and sight of children. Crizotinib will be labelled, QP released and distributed by Mawdsleys. 
Crizotinib will only be dispatched to sites after receipt of confirmation that the regulatory checklist is 
complete. 
Fulvestrant will not be supplied for this study and must be provided by sites for breast cancer patients 
enrolled in the study. 
For information on all IMP and re-ordering of supplies, contact the RM CTU CTC responsible for the 
trial who will arrange further supplies.  
 
7.2 Crizotinib 
7.2.1 Formulation of Crizotinib 
The Drug Product is intended for oral administration.  
 
7.2.2 Storage conditions 
The tablets do not require any special storage conditions.  All supplies must be stored in a secure, 
limited access storage area. 
 
7.2.3 Crizotinib administration 
Crizotinib will be administered orally twice a day for 28 days for each 28-day cycle. 
Patients should be instructed to take their dose at around the same time (no earlier than 1 hour and 
no later than 4 hours after the scheduled time) each day.  If a patient misses a scheduled daily dose, 
he or she should be instructed to skip that dose and to resume dosing with the next scheduled dose. 
Missed doses will not be made up.  
 
7.3 Fulvestrant 
7.3.1 Formulation of Fulvestrant 
Commercially available fulvestrant, 50mg/mL solution should be used. Complete information about 
fulvestrant formulation can be found in the SPC for Faslodex.  
Fulvestrant (Faslodex®) is supplied as two 5-mL clear neutral glass (Type 1) barrels, each containing 
250mg/5mL of fulvestrant solution for intramuscular injection and fitted with a tamper evident 

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closure.  The syringes are presented in a tray with polystyrene plunger rod and safety needles 
(SafetyGlideTM) for connection to the barrel.  
7.3.2 Fulvestrant administration 
Refer to the SPC for fulvestrant (Faslodex®) for instructions and steps necessary for drug preparation 
and administration.  
Fulvestrant will be administered on Days 1 and 15 during Cycle 1 and then on Day 1 of subsequent 
cycles thereafter. 
Fulvestrant 500mg will be administered intramuscularly into the buttocks slowly (1-2 minutes per 
injection) as two 5mL injections, one in each buttock.  Drug preparation and administration will be 
performed at the site by a physician, registered nurse or other qualified health care provider.  Refer 
to the SPC for Faslodex® for detailed administration instructions.  
 
7.4 Study drug accountability 
Accurate records of all IMP shipments, vials dispensed, and all vials returned must be maintained. 
This inventory record must be available for inspection at any time by the sponsor.  IMP supplies are 
to be used only in accordance with this protocol and under the supervision of the Investigator. 
The Investigator delegates responsibility for IMP management to the Pharmacist. The Pharmacist 
undertakes not to destroy any unused IMP unless directed to by the Sponsor. Any unused IMP must 
be destroyed according to hospital procedures and properly accounted for using the IMP Destruction 
Form and also on the IMP Accountability Record. During the course of the trial the Sponsor will check 
the numbers of tablets of crizotinib shipped to the centre, the number used, and the number 
destroyed or returned. The pharmacy will give an account of any discrepancy. 
 
 
 
 
 
 
 
 
 
 
 
 

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8. INVESTIGATIONS SCHEDULE 
In cases where a patient has investigations at a different hospital, for example weekly blood samples, 
then it is the Investigator’s responsibility to ensure he/she receives and reviews the results. The results 
must be recorded on the eCRF and the reports from the other hospitals must be available for source 
data verification. Laboratory reference ranges, including effective dates, and evidence of laboratory 
accreditation must be obtained from all laboratories used. 
 
8.1 Pre-treatment evaluations 
Details of all evaluations/investigations for enrolled patients, including relevant dates, required by the 
protocol must be recorded in the medical records so that the eCRF can be checked against the source 
data. 
Please also refer to the tabulated Schedule of Assessments in Section 8.5. 
 
8.1.1 Obtaining written informed consent 
Written informed consent must be obtained from the patient before any protocol-specific procedures 
are carried out and within four weeks before the patient’s first dose of the IMP (crizotinib +/- 
fulvestrant). Initial discussion and signing of the informed consent must not occur on the same day, 
as the patient must be given time to think about their commitment to the trial. 
Only the Principal Investigator (PI) and those Sub-Investigator(s) delegated responsibility by the PI, 
and have signed the Study Site Delegation Log, are permitted to gain informed consent from patients 
and sign the consent form. All signatures must be obtained before the occurrence of any medical 
intervention required by the protocol (ICH GCP 4.8.8 and 8.3.1.2). The date of the signatures of both 
the patient and the PI/Sub-Investigator should be the same. 
The PI or the Sub-Investigator must inform the patient about the background to, and present 
knowledge of the normal management of their disease. The PI or the Sub-Investigator must also 
inform the patient about the IMPs (Crizotinib and fulvestrant if applicable). The patient should be 
aware of the following points: 
• The known toxicity of the IMPs and the possibility of experiencing side effects. 
• That the IMP combination is new and that the exact degree of activity is at present unknown, 
but that treating him/her will contribute to further knowledge. 
• The potential dangers of becoming pregnant (or the patient’s partner becoming pregnant) and 
he/she has been given information about appropriate medically approved contraception.  
• The possibility that crizotinib may impair their fertility, so that fertility preservation measures 
such as egg or sperm banking can be considered if appropriate. 
• That he/she may refuse treatment either before or at any time during the trial and that refusal 
to participate will involve no penalty or loss of benefits to which they are otherwise entitled. 

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• Whom to contact for answers to pertinent questions about the research and their rights, and 
also who to contact in the event of a research-related injury. 
Where patients do not have English as a first language and have limited English comprehension; The 
Sponsor will arrange for the patient information sheet and consent form to be translated into the 
patient’s first language and the site will provide a translator if the investigator is confident this will 
allow full informed participation in the study.  Whenever the consent form is completed the 
translator should be asked to countersign to state that in their opinion the patient had full 
understanding and was able to give informed consent.  If a telephone translator is used then 
authorised electronic signature processes at the institution may be used. 
A copy of the consent form and patient information sheet must be given to the patient to keep and 
the original consent form and patient information sheet, must be filed in the Investigator Trial File 
(ITF) (unless otherwise agreed that the original consent form will be filed in the medical records and 
the copies kept in the ITF). 
 
8.1.2 Evaluations within four weeks (28 days)  
The following must be performed/obtained within the four weeks before the patient receives the 
first dose. 
• 
Written informed consent (as detailed in Section 7.1.1) 
• 
Demographic details 
• 
Medical history including prior diagnosis, prior surgery, prior treatments and any residual 
toxicities, concomitant diseases, concomitant treatment and allergies 
• 
Tumour biopsy (optional unless no archival recurrent tissue is available)  
• 
Tumour serum markers (CA15-3 and CA125 for breast cancer patients, CA19-9 and CEA for 
gastrointestinal cancer patients) 
• 
Radiological disease assessments: Radiological measurements (chest, abdominal, pelvis 
computerised tomography (CT) or magnetic resonance imaging (MRI) scan must be performed 
within four weeks before the patient receives the first dose. If additional scans of other 
anatomical sites are performed for accurate baseline assessment i.e. bone scan or MRI brain, 
then they must also be performed within this timeline. The baseline bone scan can be 
performed within 6 weeks prior to the first dose of treatment. 
Note that all adverse events (AEs), including serious adverse events (SAEs), must be monitored and 
recorded in the eCRF from the time the patient consents to any protocol-specific procedure. 
 
 
 

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8.1.3 Evaluations within one week (seven days)  
The following must be performed within one week before the patient receives the first dose: 
• 
Pregnancy test:  serum or urine human chorionic gonadotropin (HCG) test to rule out 
pregnancy at trial entry; results must be obtained and reviewed before the first dose of the 
IMP is administered if the patient is a woman of childbearing potential. 
• 
Clinical disease measurements, if applicable (i.e. patients with clinically assessable disease); 
• 
Physical examination: Cardiovascular, respiratory and abdominal examinations plus 
examination of other systems as clinically indicated. 
• 
WHO performance status evaluation 
• 
Adverse events 
• 
Vital signs: Height, weight, body surface area (BSA), WHO performance status, temperature, 
blood pressure (BP), respiratory rate, pulse oximetry and pulse rate; 
• 
Collection of plasma for ctDNA 
• 
ECG 
• 
Laboratory tests (blood & urine samples) to confirm eligibility. 
o Haematology – haemoglobin (Hb), white blood cells (WBC) with differential count 
(neutrophils and lymphocytes) and platelets 
o Coagulation-INR and APTT 
o Biochemistry – sodium, potassium, adjusted calcium, phosphate, magnesium, 
glucose, urea, creatinine, total protein, albumin, bilirubin, alkaline phosphatase (alk 
phos), alanine transferase (ALT) and aspartate aminotransferase (AST).  
 
8.2 Evaluations during the trial 
• Physical examination:  A complete physical examination will be performed within 24 hours 
before or on Days 1 and 15 of Cycle 1, and on the first day of each cycle subsequent cycle 
before crizotinib +/- fulvestrant administration.   
• WHO performance status (PS) will be repeated during Cycle 1 on (or within 24 hours before) 
Days 1 and 15 and on the first day of each cycle subsequent cycle before crizotinib +/- 
fulvestrant administration.   
• Bodyweight must be repeated every four weeks, on or within 24 hours before the first day of 
each cycle.  
• Vital signs, temperature, pulse rate, BP, pulse oximetry should be performed as follows:  
o Cycle 1 Day 1 pre-dose  

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o Prior to dosing on Cycle 1 Day 15  
o Day 1 of each subsequent cycle thereafter 
• Adverse events and concomitant treatments: At each visit, before administration of crizotinib 
+/- fulvestrant, an assessment of any AE experienced since the previous visit must be made 
by the Investigator or Research Nurse and the start and stop dates of the AE together with the 
relationship of the event to treatment with each IMP must be recorded in the medical records. 
All AEs must be graded according to NCI CTCAE Version 4.0. Any concomitant treatment must 
also be recorded in the medical records and in the eCRF. (See Section 9 for further details 
regarding AE reporting requirements.) 
• Laboratory tests: 
Haematology must be repeated 2-weekly on (or within 72 hours before) Day15 in cycle 1, prior 
to crizotinib +/- fulvestrant administration.  From cycle 2, the frequency of haematology will 
reduce to Day 1 (+/- 3 days) only.  
Biochemistry must be repeated weekly on (or within 72 hours before) Days 8, 15 and 22 of for 
the first two cycles.  From cycle 3, the frequency will reduce to Day 1 only (+/- 3 days).  
NB. Haematology and biochemistry may be performed up to 3 days before dosing in any cycle. 
o Haematology – haemoglobin (Hb), white blood cells (WBC) with differential count 
(neutrophils and lymphocytes) and platelets 
o Day 1 of each cycle (from cycle 2 onwards) Biochemistry & pregnancy test (pre-
menopausal females only).  – sodium, potassium, adjusted calcium, phosphate, 
magnesium, urea, creatinine, total protein, albumin, bilirubin, alkaline phosphatase 
(alk phos), alanine transferase (ALT) and aspartate aminotransferase (AST). 
o Day 8, 15 and 22  during cycles 1 & 2 only Biochemistry – sodium, potassium, adjusted 
calcium, phosphate, magnesium, urea, creatinine, total protein, albumin, bilirubin, 
alkaline phosphatase (alk phos), alanine transferase (ALT) and aspartate 
aminotransferase (AST) and glucose. 
❑ NB. As described in section 16.9 for crisis situations, biochemistry may be performed locally 
at the C1D8, C1D22, C2D8, C2D15 and C2D22 timepoints. 
• ECG: A resting ECG will be performed on day 1 of each cycle, except for cycle 1, for which it 
must have been performed within 7 days prior to D1. 
• Tumour serum markers (if applicable): must be repeated prior to day 1 of every cycle (4 
weeks). 
• Radiological assessment of disease: CT or MRI TAP must be repeated every 8 weeks of 
crizotinib +/- fulvestrant, with the first assessment scheduled on cycle 3 day 1 (+/- 3 days). 
After the 24 week scan the frequency of imaging may be reduced to every 12 weeks at the 
Investigator’s discretion. Other investigations such as MRI brain or bone scan to be performed 
only if clinically indicated. 

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• Collection of blood sample for circulating tumour DNA (Parts 1 and 2 will be collected on 
day1 pre-dose on all cycles and prior to D15 in cycle 1 only. A further sample is required at 
disease progression. 
• Tumour biopsy (optional): This will be performed at D15 of cycle 1 and after disease 
progression is confirmed radiologically in consenting patients.  
• Any patients within the breast cohort who are not receiving a bisphosphonate or  denosumab 
should be assessed at least annually for osteoporosis as per routine clinical practice. 
 
8.2.1 Evaluations when disease progression is confirmed 
If disease progression is confirmed clinically or radiologically, the following evaluations should be 
performed within 7 days: 
• 
Adverse events 
• 
Concomitant medications 
• 
Performance status 
• 
Collection of blood for ctDNA 
• 
Optional tumour biopsy in patients who have consented to this. 
 
8.3 Evaluations at ‘off-study’ visit 
Evaluations at the ‘off-study’ visit must be performed 28+/-3 days after the last dose of crizotinib.  The 
following investigations must be done: 
• 
a symptom-directed physical examination including WHO performance status, temperature, 
pulse rate, BP, bodyweight, BSA. 
• haematology tests: FBC 
• biochemistry tests: U&E, LFT, Calcium, CA15-3 and CA125 (breast cohort or basket cohort 
triple negative lobular breast patients) or CEA and CA19-9 (basket cohort gastrointestinal 
cancer patients), pregnancy test (pre-menopausal females only) 
• ECG  
• assessment of tumour disease with CT or MRI TAP, unless assessment has been performed 
within the previous four weeks (28 days); 
• assessment of AEs  
• assessment of concomitant treatments. 
• Optional tumour biopsy and collection of blood sample for circulating tumour DNA.  These 
should ideally be performed within 7 days of progression being identified.  
 
 

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8.4 Follow-up 
Patients will be followed up for safety for 28 days after the last administration of crizotinib.  If any AEs 
and SAEs are considered to have a highly probable, probable or possible causal relationship to 
crizotinib or fulvestrant, and are still present at 28 days after the last administration then the patient 
will be followed up monthly afterwards until resolution, to baseline or stabilisation of these events, 
unless the patient starts another anti-cancer treatment.  
Patients who stop study treatment for reasons other than disease progression will be followed-up for 
progression events with ongoing CT scans every 8 weeks, unless they withdraw their consent to this 
imaging follow-up. 
Patients will also be followed-up for survival every 6 months, usually by telephone, unless they 
withdraw consent to the study.

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8.5 
Table 6: Schedule of events (Refer to sections 8.1.2-8.4 for details) 
 
 
Screening 
(within 28 
days 
before 
first dose) 
Screening 
(within 7 
days 
before 
first dose) 
Day  
1  
 
+/- 1 
day 
Day  
8 
 
+/- 1 
day 
Day  
15 
 
+/- 1 
day 
Day  
22 
 
+/- 1 
day 
Day 29 
(Cycle 
2 D1) 
+/- 3 
days 
Cycle 2 
Day 8  
 
+/- 3 
days 
Cycle 2 
Day 15  
 
+/- 3 
days 
Cycle 2  
Day 22  
 
+/- 3 
days 
Cycle 3 
Day 1  
 
+/- 3 
days 
Cycle 4 
Day 1  
 
+/- 3 
days 
Day 1 
of each 
cycle 
+/- 3 
days 
Day 28 
after last 
dose 
+/- 3 
days 
Follow up 
(Every 8(d) 
weeks until 
progression) 
+/- 3 days 
At disease 
progression  
 
+/- 7 days 
Survival 
Follow 
Up 
(every 6 
months) 
Archival 
tumour tissue 
available 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI TAP  
(or PET/CT) 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
x 
 
 
Bone scan(a) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI brain(b) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour 
biopsy 
x(c) 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
 
x* 
 
Pregnancy 
test (if pre-
menopausal) 
 
x 
 
 
 
 
x 
 
 
 
x 
x 
x 
x 
 
 
 
ECG 
 
x 
 
 
 
 
x 
 
 
 
x 
x 
x 
x 
 
 
 
FBC 
 
x 
 
 
x 
 
x 
 
 
 
x 
x 
x 
x 
 
 
 
Coagulation 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U&E, LFT, 
Ca2+ 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
CA15-3 and 
CA125 (Breast 
patients) 
CEA and 
CA19-9 
(gastrointestin
al cancer 
patients) 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
x 
 
 
 

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Circulating 
tumour DNA 
 
x 
 
 
x 
 
x 
 
 
 
x 
x 
x 
 
 
x 
 
BP, Pulse, 
Temp, O2 sats,  
 
x 
x 
 
x 
 
x 
 
 
 
x 
x 
x 
x 
 
 
 
Body weight 
 
x 
 
 
x 
 
x 
 
 
 
x 
x 
x 
x 
 
 
 
Physical 
examination 
 
x 
x 
 
x 
 
X 
 
 
 
x 
x 
x 
x 
 
 
 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncological 
history, 
demographics 
and co-
morbidities 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check AEs 
 
x 
x 
 
x 
 
x 
 
 
 
x 
x 
x 
x 
 
x 
 
Check con-
meds 
x 
 
x 
 
x 
 
x 
 
 
 
x 
x 
x 
x 
 
x 
 
WHO PS 
 
x 
x 
 
x 
 
x 
 
 
 
x 
x 
x 
x 
 
x 
 
Check 
crizotinib 
compliance 
 
 
 
 
x 
 
x 
 
 
 
x 
x 
x 
 
 
 
 
Fulvestrant 
injections 
(breast cohort 
only) 
 
 
x 
 
x 
 
x 
 
 
 
x 
x 
x 
 
 
 
 
Survival FU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
*optional 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) 
For patients with known bone metastases a bone scan should be performed at baseline (within 6 weeks prior to first dose) then as clinically indicated 
b) 
Only required for patients with known CNS metastases or symptoms/signs suggestive of new brain metastases 
c) 
Optional unless no archival recurrent tissue biopsy is available 
d) 
Frequency may be reduced to every 12 weeks after cycle 6 at the investigator’s discretion

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9. PHARMACODYNAMIC ASSESSMENTS  
 
9.1 Predictive biomarker assays 
9.1.1 Analysis of tumour biopsy material for predictive biomarker analysis 
DNA extracted from archival or fresh tumour material (in those patients who consent to the optional 
tumour biopsies section 8.2.1) will be analysed for somatic mutations, which may represent putative 
predictive biomarkers. If possible, tumour biopsies will be undertaken at disease progression for 
analysis of putative biomarkers of resistance. 
Archival tumour material will be collected for all patients enrolled into the study. The tumour samples 
will preferably be in the form of a formalin fixed paraffin embedded block of tissue derived from a 
metastatic site (or the primary tumour for patients presenting with de novo metastatic disease). If this 
is not possible, 10-20 slides of freshly prepared unstained 5 micron sections from the archival tumour 
block may be provided. Analysis may be done retrospectively for patients. 
Core needle biopsies will be collected according to the institutional procedure and divided into 2 
samples, one to be snap frozen and one to be formalin fixed and embedded in paraffin (FFPE) as per 
local procedures for predictive biomarker analysis. 
Tumour biopsies will be analysed at the laboratories of the Institute of Cancer Research. Please refer 
to the Study Laboratory Manual for handling, storage and shipment of samples. 
 
9.1.2 Collection of plasma samples for circulating free DNA 
Blood sample 20mls in EDTA/Streck tubes for the analysis of circulating tumor DNA (ctDNA) will be 
taken and processed according to the lab manual. Samples will be analyzed in Professor Turner’s 
laboratory at the Institute for Cancer Research to identify somatic mutations, which may represent 
putative predictive biomarkers. This will be correlated with mutations detected in submitted tumour 
specimens.  
The plasma samples should be taken at  
• 
Prior to drug dosing: at screening Day -28 to Day-1 of Cycle 1  
• 
Cycle 2 onwards on Day 1  
• 
Off Study: ≤ 28 days after last dose of IMP, on progression 
 
 

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10. ASSESSMENT OF SAFETY 
 
10.1 Adverse event definitions 
10.1.1 Adverse event 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events 
resolve, stabilise or the patient starts another anti-cancer therapy.  
An AE is any untoward, undesired or unplanned occurrence in a patient administered an IMP. An AE 
can be a sign, symptom, disease, and/or laboratory or physiological observation that may or may not 
be related to the IMP.  
An AE includes but is not limited to those in the following list.  
• 
A clinically significant worsening of a pre-existing condition. This includes conditions that may 
resolve completely and then become abnormal again.  
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional. 
Other reportable events that must be treated as AEs are listed below:  
• 
Pregnancy exposure to the IMP. Any pregnancy occurring in a patient or a patient’s partner 
during treatment with an IMP or occurring within six months of the last IMP administration 
must be reported to the Sponsor in the same timelines as an SAE. These should be reported 
even if the patient is withdrawn from the trial. 
• 
Any AE associated with an overdose or incorrect administration of IMP. An overdose or 
incorrect administration of IMP is not an AE unless it results in untoward medical effects.  
• 
Any AE that could be related to the protocol procedures, and which could modify the conduct 
of the trial, including relevant abnormal laboratory values. Abnormal laboratory values 
deemed clinically significant by an investigator should be reported as adverse events. Grade 
3-4 neutropenia, any grade reduction in albumin and ALT/AST or creatinine elevation grade 1 
or more should be reported as an AE. 
 
10.1.2 Adverse reaction (AR) 
All untoward and unintended responses to the study drug related to any dose administered. All AEs 
judged by either the reporting investigator or the sponsor as having reasonable causal relationship to 
a medicinal product qualify as adverse reactions, i.e. an AR is possibly, probably or definitely related 
to the study drug. The expression reasonable causal relationship means to convey in general that there 
is evidence or argument to suggest a causal relationship. 
 
 
 
 

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10.1.3 Serious adverse events (SAEs) 
An SAE is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 
• 
is life-threatening; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation (some 
hospitalisations are exempt from SAE reporting – see Section 10.3.3); 
• 
results in persistent or significant incapacity or disability; 
• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event.* 
* A medically important event is defined as any event that may jeopardise the patient or may require 
intervention to prevent an SAE. It should be noted that medically important events might be 
identified before or at any point in the study.  
 
10.1. 4 Serious Adverse Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the reporting Investigator, believed with 
reasonable probability to be due to one of the trial treatments, based on the information provided. 
 
10.1.5 Suspected, unexpected, serious, adverse reactions (SUSARs) 
A SUSAR is a serious adverse reaction, the nature and severity of which is not consistent with 
the information about the medicinal product in question set out: 
• in the case of a product with a marketing authorisation, in the summary of product characteristics 
(SmPC) for that product 
 
• in the case of any other investigational medicinal product, in the investigator’s brochure (IB) 
relating to the trial in question 
 
10.2 Operational definitions for (S)AEs 
 
For eligible patients, SAE and adverse event (AE) collection and monitoring commences from the time 
the patient gives their written consent to participate in the trial and continues for 28 days after the 
last administration of crizotinib or fulvestrant (investigational medicinal product [IMP]).    
 
All AEs will be graded according to CTCAE version 4, recorded in the patient’s medical records and 
captured in the CRF. 
10.2.1 Assessment of Severity 
Serious Adverse Events and Serious Adverse Reactions should be reported to the sponsor as detailed 
in section 10.3. 

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10.2.2 Assessment of Seriousness 
The seriousness of an adverse event is assessed using the criteria outlined in section 10.1.3.  
 
In addition, for all crizotinib-treated patients, Grade ≥2 PSTE (except for Visual field defect, for which 
Grade ≥3 is the standard) or SVL should be treated as Serious Adverse Events, regardless of relatedness 
to study drug. Please refer to APPENDIX 6. 
 
10.2.3 Determining adverse event causality 
The relationship of an AE to the IMP is determined as follows. 
Highly probable 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible 
• 
Starts within a time related to the IMP administration and 
• 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the trial drug is not likely to 
have had an association with the observed effect. 
Not related 
• 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness, progressive malignancy etc.) and must provide his/her opinion of the causal 
relationship between each AE and IMP. This may require instituting supplementary investigations of 
significant AEs based on their clinical judgement of the likely causative factors and/or include seeking 
a further opinion from a specialist in the field of the AE. 
 
10.2.4 Expectedness 
An assessment of expectedness will be made by the Chief Investigator (or delegate) against section 4.8 
of the current versions of the crizotinib or fulvestrant SmPC.  

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10.3 Recording and reporting of Serious Adverse Events (SAEs) / Serious Adverse 
Reactions (SARs) 
 
10.3.1 Reporting of Serious Adverse Events (SAEs) / Serious Adverse Reactions 
(SARs) 
 
All SAEs / SARs occurring from the time of written informed consent until 28 days post 
cessation of trial treatment must be recorded on the SAE Report Form and emailed to 
ROLo.trial@rmh.nhs.uk or faxed to 0208 915 6762  to RM CTU within 24 hours of the site staff 
becoming aware of the event.  
 
Each episode of an SAE must be recorded on a separate SAE report form. The NCI CTCAE Version 4.0 
must be used to grade each SAE, and the worst grade recorded. If new or amended information on a 
previously reported SAE becomes available, the Investigator should report this to the Sponsor on a 
new SAE report form. 
 
RM-CTU will inform the sponsor/CI and Pfizer about the event and once all resulting queries 
have been resolved, the SAE report form will be retained in the site file. 
 
For each SAE / SARs, the following information will be collected: 
• 
Full details in medical terms and case description 
• 
Event duration (start and end dates, if applicable) 
• 
Action taken 
• 
Outcome 
• 
Seriousness criteria 
• 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
• 
Whether the event would be considered expected or unexpected. 
 
Any change of condition or other follow-up information should be faxed to RM CTU at least 
within 24 hours of the information becoming available. Events will be followed up until the 
event has resolved or a final outcome has been reached.   
 
Should the Investigator become aware of any drug-related SAEs after the patient goes ‘off study’, these 
must also be reported to the Sponsor within the specified timelines above. 
10.3.2 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
 
All SUSARs (as defined in section 10.1.5) are subject to expedited reporting. The Sponsor delegates the 
responsibility of SUSAR notification to the Chief Investigator. The Chief Investigator must report all the 
relevant safety information previously described, to the Sponsor, MHRA and REC. The Chief 
Investigator shall inform all investigators concerned of relevant information about SUSARs that could 
adversely affect the safety of subjects. 
10.3.2.1 Fatal or life-threatening SUSARs 
All parties listed in 10.3.2 must be notified as soon as possible but no later than 7 calendar days after 
the trial team and Sponsor has first knowledge of the minimum criteria for expedited reporting. 
 
In each case relevant follow-up information should be sought and a report completed as soon as 
possible. It should be communicated to all parties within an additional 8 calendar days. 

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10.3.2.2 Non-fatal and non-life-threatening SUSARs 
All other SUSARs and safety issues must be reported to all parties listed in 9.3.2 as soon as possible but 
no later than 15 calendar days after first knowledge of the minimum criteria for expedited reporting. 
Further relevant follow-up information should be given as soon as possible. 
10.3.2.3 Minimum criteria for initial expedited reporting of SUSARs 
Information on the final description and evaluation of an adverse reaction report may not be available 
within the required time frames for reporting. For regulatory purposes, initial expedited reports should 
be submitted within the time limits as soon as the minimum following criteria are met: 
a) A suspected investigational medicinal product, 
b) An identifiable subject (e.g. trial subject code number), 
c) An adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship, 
d) An identifiable reporting source, 
 
And, when available and applicable: 
a) A unique clinical trial identification (EudraCT number or in case of non-European Community 
trials the sponsor's trial protocol code number) 
b) A unique case identification (i.e. sponsor's case identification number). 
10.3.2.4 Follow-up reports of SUSARs 
In case of incomplete information at the time of initial reporting, all the appropriate information for 
an adequate analysis of causality should be actively sought from the reporter or other available 
sources. Further available relevant information should be reported as follow-up reports. 
In certain cases, it may be appropriate to conduct follow-up of the long-term outcome of a particular 
reaction. 
10.3.2.5 Format of the SUSARs reports 
Electronic reporting is the expected method for expedited reporting of SUSARs to the competent 
authority. The format and content as defined by the competent authority should be adhered to. 
 
10.3.3 Events exempt from being reported as SAEs 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed. The events must still be recorded 
in the appropriate section of the case report form (CRF). 
Screening period – SAEs occurring in the period prior to administration of crizotinib +/-fulvestrant from 
the time of informed consent to the day prior to cycle 1 day 1 are exempt from reporting if they are 
not related to the design or conduct of the trial. 
Elective admissions – Elective admissions to hospital for procedures which were planned and 
documented in the medical records at the time of consent are not SAEs, and do not require SAE 
reporting.  
Hospitalisation associated with disease progression does not require SAE reporting, but associated 
AEs should be fully documented in the CRF. 

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10.4 Recording of adverse events and serious adverse events in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients. All concomitant medications, 
including herbal medications and supplements must be recorded. Any therapy used to treat the event 
must be recorded. The eCRF will be reconciled with the safety database during and at the end of the 
trial. Therefore, the sites should ensure the data entered on the SAE report form and the data entered 
into the eCRF are consistent. The Safety Review Committee and the Investigator(s) will regularly review 
the safety data from both the safety and the clinical database. 
 
10.5 Follow-up of adverse events 
Follow-up will continue until all the necessary safety data for the event has been gathered and until 
the AE or SAE has resolved, returned to baseline or stabilised. The Sponsor will make requests for 
further information to the trial site at regular intervals. Requested follow-up information should be 
reported to the Sponsor in a timely manner and as soon as possible after receipt of the follow-up 
request. For fatal or life-threatening cases, follow-up information should be reported as soon as 
possible. 
Any SUSAR related to the IMP will need to be reported to the Sponsor irrespective of how long after 
IMP administration the reaction has occurred. 
10.6 Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical trial against any immediate hazard to their health or safety. This includes 
procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health.  
USMs may be taken without prior authorisation from the competent authority. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
• 
Email: ROLo.trial@rmh.nhs.uk  or 
• 
Telephone: 0208 915 6506; or  
• 
Fax: 0208 915 6762   
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
Why action was taken. 
 
The Sponsor will then notify the MHRA and the relevant REC immediately and in any event no later 
than three days of USM initiation, give written notice to the MHRA and the relevant REC of the 
measures taken and the circumstances giving rise to those measures. The initial notification to the 
MHRA and REC should be by telephone. A notice in writing must be sent within 3 days. The notice 
should set out the reasons for the USM and the plan for further action. 

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10.7 Pregnancy 
The Investigator must make every effort to try and ensure that a clinical trial patient or a partner of a 
clinical trial patient does not become pregnant during the trial or for 90 days afterwards (basket 
cohort), 2 years after (breast cohort). This should be done as part of the consent process by explaining 
clearly to the patient the potential dangers of becoming pregnant and also providing each patient with 
information about appropriate medically approved contraception. Two forms of medically approved 
highly effective methods contraception should be used, such as:  
• 
oral contraceptives and an intra-uterine device (IUD) 
• 
intra-uterine device (IUD) and your partner has had a vasectomy or you have had bilateral 
tubal occlusion  
Female patients with child-bearing potential must have a negative urine or serum pregnancy test 
within 7 days prior to start of trial. Both male and female patients of reproductive potential must agree 
to use two forms of highly effective contraception (see below) for 2 weeks before starting the study 
treatment, throughout the treatment period and for 90 days after discontinuation of treatment with 
crizotinib and 2 years after the last dose of fulvestrant.  
• 
Oral, intra-vaginal or transdermal combined hormonal contraception 
• 
Oral, injectable or implantable progesterone-only contraception  
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system,  
• 
Bilateral tubal occlusion  
• 
Vasectomised partner  
• 
Sexual abstinence* 
Key: *it is only considered highly effective if the patient is refraining from sexual intercourse during the 
entire period of risk associated with the study treatments 
The oral contraceptive pill may be ineffective when taken with crizotinib so is not an acceptable means 
of contraception for female patients during this study but can be used by female partners of male 
patients 
It should be explained to the patient that if his partner is pregnant or breast-feeding when he enters 
the trial, the patient should use barrier method contraception (condom plus spermicidal gel) to 
prevent the unborn baby or the baby being exposed to the crizotinib+/-fulvestrant.  
However, if a patient or a partner of a patient does become pregnant, the reporting procedures below 
must be followed. 
Any pregnancy occurring in a patient or a patient’s partner during treatment with an IMP or occurring 
within 90 days of last crizotinib administration or 6 months of last fulvestrant administration (breast 
cohort) must be reported to the Sponsor within 24 hours of the site staff becoming aware of it using a 
Pregnancy Notification Form.  

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In addition, due to the effect of crizotinib on oral contraception, all pregnancies should be treated as 
adverse events, as per section 10.1.1. 
It is the Investigator’s responsibility to obtain consent for follow-up from the patient or patient’s 
partner. The Sponsor will follow-up all pregnancies for the pregnancy outcome via the Investigator and 
document on the pregnancy form. 
The Investigator must ensure that all patients are aware at the start of a clinical trial of the importance 
of reporting all pregnancies (in themselves and their partners) that occur whilst being treated with the 
IMP and occurring up to six months after the last IMP administration. The Investigator should offer 
counselling to the patient and/or the partner, and discuss the risks of continuing with the pregnancy 
and the possible effects on the foetus. Monitoring of the patient and the baby should continue until 
the conclusion of the pregnancy, if the patient or patient’s partner has consented to this. 
 
 
 

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11. ASSESSMENT OF EFFICACY 
 
11.1 Measurement of disease 
Disease must be measured according to the RECIST criteria (version1.1) given in Appendix 3. 
 
11.2 Timing and type of tumour assessments 
A thorough clinical and radiological evaluation of malignancy, as judged appropriate by the 
Investigator, and in line with the protocol, must be performed before starting the investigational 
medicinal product (IMP). The same methods that detect evaluable lesions at baseline must be used to 
follow these lesions throughout the trial. To ensure compatibility, the radiological assessments used 
to assess response must be performed using identical techniques. Imaging based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the anti-
tumour effect of a treatment. 
All radiological assessments must be performed within four weeks before starting treatment. The 
interval between the last anti-cancer therapy and these measurements must be at least four weeks 
(28 days). All clinical measurements to assess response must be done within one week before the 
patient starting treatment. 
All complete (CR) and partial responses (PR) must be confirmed by two consecutive observations not 
less than four weeks apart. 
Copies of the scans must be available for external independent review if requested by the Sponsor. 
 
11.2.1 Baseline evaluations 
These must include radiological measurements and as indicated chest, abdominal and pelvic 
computerised tomography (CT) scans, magnetic resonance imaging (MRI), bone scan and/or clinical 
measurements as appropriate. All areas of disease present must be documented (even if specific 
lesions are not going to be followed for response) and the measurements of all measurable lesions 
must be recorded clearly on the scan reports. Any non-measurable lesions must be stated as being 
present. For clinical measurements, documentation by colour photography including a ruler to 
estimate the size of the lesion is strongly recommended, as this aids external independent review of 
responses. (See Section 1.2.1 of RECIST 1.1 criteria) 
 
11.2.2 Evaluations during and at ‘off-study’ 
Tumour assessments must be repeated every 2 cycle(s)/8 weeks if continuous treatment or more 
frequently, when clinically indicated. All lesions measured at baseline must be measured at every 
subsequent disease assessment and recorded clearly on the scan reports. All non-measurable lesions 
noted at baseline must be noted on the scan report as present or absent. 
All patients, who are removed from the trial for reasons other than progressive disease, must be re-
evaluated at the time of treatment discontinuation (+/- 28 days), unless a tumour assessment was 
performed within the previous four weeks. 

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It is the responsibility of the Principal Investigator to ensure that the radiologists are aware of the 
requirement to follow-up and measure every target lesion mentioned at baseline and comment on the 
non-target lesions in accordance with RECIST 1.1 criteria. 
 
11.3 Tumour response 
All patients who meet the eligibility criteria will receive at least two cycles of trial medication and have 
a baseline assessment of disease will be evaluable for response by RECIST criteria. To be assigned a 
status of complete response (CR) or partial response (PR), changes in tumour measurements must be 
confirmed by repeat measurements performed no less than four weeks after the response criteria are 
met. To be assigned a status of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once and at least six weeks after the initial dose of the investigational medicinal 
products (IMP) crizotinib +/- fulvestrant are given. 
Should rapid tumour progression occur before the completion of 4 weeks the patient will be classified as 
having early progression (EP). 
Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it 
under another response category, for example, when baseline and/or follow-up assessment is not 
performed or not performed appropriately.  
Expert reviewers appointed by Sponsor may undertake an independent review of all the Investigator’s 
assessed objective responses (CR and PR). The expert reviewers will include at least one specialist who 
is not an Investigator in the trial. In case of disagreement between the Investigator’s and the expert 
reviewers’ assessment, discussion will take place between the two parties in order to reach a 
consensus. However, if it is not forthcoming, the assessment of the expert reviewers will be retained 
in the clinical study report. The eCRF will reflect the Investigator’s opinion and the primary analysis of 
response will be based upon local assessment of response. 
 
11.3.1 Recording of response in the eCRF 
The applicable overall response category for each visit that includes disease assessment must be 
recorded in the eCRF, even though the criteria for determination of CR or PR by the protocol must be 
confirmed after two consecutive observations, no less than four weeks apart. 
 
 

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12. DISCONTINUATION OF TREATMENT/WITHDRAWAL FROM TRIAL 
 
The Investigator must make every reasonable effort to keep each patient on trial for the whole 
duration of the trial (i.e. until 28 days after last combination therapy administration). However, if the 
Investigator removes a patient from the trial or if the patient declines further participation, final ‘off-
study’ assessments should be performed before any therapeutic intervention. All the results of the 
evaluations and observations, together with a description of the reasons for withdrawal from the trial, 
must be recorded in the medical records and in the eCRF. 
Patients who are removed from the trial due to adverse events (clinical or laboratory) will be treated 
and followed according to accepted medical practice. All pertinent information concerning the 
outcome of such treatment must be recorded in the eCRF and on the serious adverse event (SAE) 
report form where necessary. 
The following are justifiable reasons for the Investigator to withdraw a patient from trial. 
• 
Unacceptable toxicity 
• 
AE/SAE 
• 
Withdrawal of consent 
• 
Serious violation of the trial protocol (including persistent patient attendance failure and 
persistent non-compliance) 
• 
Sponsor’s decision to terminate the trial 
• 
Withdrawal by the Investigator for clinical reasons not related to the IMP 
• 
Evidence of disease progression 
• 
Symptomatic deterioration 
Patients that are discontinued from the study are still evaluable as defined in section 14.1 

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13. DEFINING THE END OF TRIAL 
  
The ‘end of trial’ is defined as the date when the last patient has completed the ‘off-study’ visit or the 
final follow-up visit (whichever is the latter). 
It is the responsibility of the Sponsor to inform the Medicines and Healthcare products Regulations 
Agency (MHRA) and the Main Research Ethics Committee (REC) within 90 days of the ‘end of the trial’ 
that the trial has closed. 
In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by the 
Sponsor, the Sponsor will notify the MHRA and the Main REC within 15 days of the decision and a 
detailed, written explanation for the termination/halt will be given. 
The entire trial will be stopped when: 
• 
The drug is considered too toxic to continue treatment before the required number of patients 
being recruited. 
• 
The stated number of patients to be recruited is reached. 
• 
The stated objectives of the trial are achieved. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.  
In terminating the trial, Sponsor and the Investigators must ensure that adequate consideration is 
given to the protection of the patient’s interest. 
 
 
 

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14. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 
An interim analysis will be conducted after the first 10 patients in the first stage of each cohort have 
been recruited and treated and have at least reached their 1st scan. 
The final analysis will be conducted after one of the following conditions is met. 
• 
The trial is terminated early (for example, due to toxicity). 
• 
All patients have had the opportunity to receive 1 cycle of treatment and have completed their 
‘off-study’ visit (i.e. 28 days after the last dose of crizotinib +/- fulvestrant). 
Once one of the conditions is met, a data cut-off date will be established. All patient visits occurring 
on or before this date will be analysed and summarised in the final clinical study report. Any data 
collected after this date will be summarised in a supplemental report.  
 
14.1 Statistical Analysis 
Data will be presented in a descriptive fashion. Variables will be analysed to determine whether the 
criteria for the trial conduct are met. This will include a description of patients who did not meet all 
the eligibility criteria, an assessment of protocol violations, IMP accountability and other data that 
impact on the general conduct of the trial. 
Baseline characteristics will be summarised for all enrolled patients.  
Treatment administration will be described for all cycles. Dose administration, dose modifications or 
delays and the duration of therapy will be described. 
The statistical analysis below will be performed in each cohort separately. 
Primary Endpoint 
Response rate will be described as a proportion of patients with a best overall response of CR or PR 
with the 95% CI.  Patients who stop study treatment before the first response evaluation scan has been 
performed with clinical progression will be treated as disease progression.  
Secondary Endpoints 
Toxicities will be presented as frequencies and proportions for each cohort separately. 
Clinical benefit rate will be presented as the proportion of patients with a best over response of CR, 
PR or SD maintained for a minimum of 6 months, with the 95% CI.  
Progression free survival will be calculated using Kaplan Meier methods. This will be defined from the 
date 1 of study treatment to date of radiological disease progression or death from any cause. Any 
progression free surviving patients will be censored at last follow up. 
Overall survival will be calculated using Kaplan Meier methods. This will be defined from the date 1 
of study treatment to date of death from any cause. Any patients who are alive or lost to follow-up 
will be censored at last follow up. 

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Exploratory Endpoints 
The objective response rate in each cohort will be presented in patients with centralised confirmed E-
cadherin negative and CDH1 mutated tumours. The objective response rate will also be presented in 
patients with PIK3CA, ESR1 and CDH1 mutations and other biomarkers. These will be presented with 
95% CIs. 
14.1.1 Subject Replacement Strategy 
Patients who have died or withdrew before treatment started or did not complete the required safety 
observations will be replaced.  Patients who stop the study treatment prior to response evaluation for 
reasons other than progression (patient choice or toxicity) will also be replaced. 
 
14.2 Safety 
Safety data will be collected from the date of written consent. Safety variables will be summarised by 
descriptive statistics. Laboratory variables will be described using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
Adverse events (AEs) will be reported for each dose level and presented as tables of frequency of AEs 
by body system and by worse severity grade observed. Tables should indicate related and unrelated 
events. Laboratory data will be presented by cohort at each observation time. Values outside normal 
limits will be identified and summarised by frequency distribution. 
 
14.3 Pharmacodynamics 
Archival tumour and/or baseline fresh tumour biopsy will be tested centrally for E-cadherin by 
immunohistochemistry and subjected to sequencing using next generation sequencing (NGS). RNA will 
be extracted for gene expression studies. These studies will be repeated on the end of tumour biopsy 
and baseline and end of treatment plasma DNA. 
Mutations detected on the baseline biopsy/plasma DNA sample will be tracked on subsequent plasma 
DNA samples and correlated with treatment response. 
Objective response rate will be calculated in patients with centrally confirmed E-cadherin negative and 
CDH1 mutated baseline tumours and patients with PIK3CA, ESR1, and CDH1 mutations or MET 
amplification in baseline plasma DNA.  There will be no formal statistical analysis of this exploratory 
endpoint. 
 
14.4 Anti-tumour activity 
Documenting anti-tumour activity is the primary objective of this trial. Patients must receive at least 
one cycle of the trial medication to be evaluable for response. Objective responses as defined by 
RECIST 1.1, the best tumour response achieved by each patient while on trial and the progression free 
survival, and duration of response will be presented in the data listings. Clinical benefit rate will be 
defined as the proportion of patients with a partial or complete response or stable disease lasting at 
least 24 weeks. 
 

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14.5 Sample size considerations  
 
Optimal Simon 2 stage design for each cohort. 
Breast cancer cohort: Fulvestrant alone is anticipated to have a response rate (RR) of 5% in the 
population studied, due the extent of prior pre-treatment.  Therefore 29 patients are required to 
exclude a RR of 5% and detect a 20% RR (p0=0.05, p1=0.2, power 80%, alpha 0.05). A single response 
in the first 10 evaluable patients is required to proceed to the second stage.  Four patients with tumour 
response among the total of 29 evaluable patients in both stages are required to reject the null 
hypothesis. 
Gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid tumour (basket) cohort:  
In this cohort, 29 patients are required to exclude a RR of 5% and detect a 20% RR (p0=0.05, p1=0.2, 
power 80%, alpha 0.05). A single response in the first 10 evaluable patients is required to proceed to 
the second stage.  Four patients with tumour response among the total of 29 evaluable patients in 
both stages are required to reject the null hypothesis. 
 
 

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15. TRIAL COMMITTEES 
 
15.1 Trial management group 
The Trial Management Group (TMG) comprises the Chief Investigator, other co-investigators, the study 
statistician and RM CTU CTC.  The TMG will be responsible for the day-to-day running and management 
of the trial and will meet by teleconference 3-6 monthly and in person as needed. The Trial 
Management Group will also act as the safety review committee and has an independent chair. The 
role of the committee is to review the safety of the first 3 and 6 breast cohort patients to receive one 
cycle of the treatment combination of fulvestrant with crizotinib  and to also review safety of the first 
3 and 6 basket cohort patients to have received one cycle of crizotinib monotherapy. 
 
15.2 Independent Data Monitoring Committee 
Reports to the IDMC will be produced by the statistician. The data monitoring committee will be 
informed in writing of the safety review committee’s assessment of toxicity for the first 3 and 6 lobular 
breast cancer patients receiving one cycle of crizotinib and fulvestrant and the first 3 and 6 basket 
cohort patients receiving 1 cycle of crizotinib monotherapy.   
The IDMC will meet after the first stage where 10 patients have been recruited and have at least 1 
scan. The IDMC will consider data in accordance with the statistical analysis plan and will be advisory 
to the TSC.  
 
15.3 Trial Steering Committee 
A Trial Steering Committee (TSC) will provide overall supervision for the ROLo Trial.  The ultimate 
decision for the continuation of the trial lies with the TSC.  
 
 

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16. ADMINISTRATION 
This trial is conducted under a clinical trial authorisation (CTA) and approval from the Medicines and 
Healthcare products Regulations Agency (MHRA) and the relevant Research Ethics Committee(s) will 
be obtained before the start of this trial. This trial is sponsored by The Royal Marsden NHS Foundation 
Trust (RM). Applicable regulatory requirements are described in this section. 
 
16.1 Protocol deviations and amendments 
Do not deviate from the protocol unless approval has been obtained from the Sponsor.  
Eligibility waivers are strictly prohibited. 
Amendments to the protocol may only be made with the approval of the Sponsor, CI and statistician. 
A protocol amendment will be subject to review by the sponsor. Ethics Committee favourable opinion 
(and MHRA approval if appropriate) will be obtained by the RM CTU CTC  on behalf of the CI before 
the amendment can be implemented and incorporated into the protocol if necessary. 
 
16.2 Completion of the case report form (CRF) 
Electronic CRFs (eCRFs) will be used to collect the data. The Investigator is responsible for ensuring the 
accuracy, completeness, clarity and timeliness of the data reported in the eCRFs. 
Only the Investigator and those personnel who have signed the Study Team Responsibilities Signature 
Log/Delegation Log provided by the RM CTU and have been authorised by the Investigator should 
enter or change data in the eCRFs. All protocol required investigations must be reported in the eCRF. 
The Investigators must retain all original reports, traces and images from these investigations for 
future reference.  
Data will be entered directly into eCRFs by authorised site personnel. 
Once data has been entered by the site personnel on the eCRF, the data will be reviewed and checked 
for error and inconsistencies by the RM CTU CTC. 
Once the patient is ‘off study’ and the eCRF has been fully completed, the Investigator must provide 
an electronic sign-off to authorise the complete subject casebook. 
 
16.3 Trial performance and monitoring 
16.3.1 Management of the study 
The RM CTU Clinical Trials Coordinator will be responsible for the day-to-day coordination and 
management of the trial. The RM Clinical Trials Unit will act as custodian of the data on behalf of the 
sponsor. The RM CTU is responsible for all duties relating to pharmacovigilance in accordance with 
section 9. 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified and the 
organisational preparations made with the trial centre. The Sponsor must be informed immediately of 
any change in the personnel involved in the conduct of the trial. 

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During the trial the RM CTU is responsible for monitoring data quality in accordance with Royal 
Marsden Hospital’s standard operating procedures (SOPs). Before the trial start, the Investigator will 
be advised of the anticipated frequency of the monitoring visits. The Investigator will receive 
reasonable notification before each monitoring visit. 
It is the responsibility of the Clinical Coordinator to: 
• 
review trial records and compare them with source documents; 
• 
check pharmacodynamics samples and storage; 
• 
discuss the conduct of the trial and the emerging problems with the Investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; and 
• 
verify that the available facilities remain acceptable. 
 
All unused drug supplied must be returned to the supplier, or if authorised by Sponsor properly 
destroyed at the Investigator site by an authorised person who will provide signed confirmation.  
It is the responsibility of the Sponsor to inform the Main REC within 90 days of the ‘end of the trial’ 
(i.e. last patient study visit) that the trial has closed. 
 
16.3.2 Source document verification 
Source documents are original documents, data, and records (e.g., hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-
technical departments involved in the clinical trial). 
All data collected in the eCRF must be verifiable by the source data. Therefore, it is the Investigator’s 
responsibility to ensure that both he/she and his/her study team records all relevant data in the 
medical records. The Investigator must allow the CTM direct access to relevant source documentation 
for verification of data entered into the eCRF, taking into account data protection regulations. Entries 
in the eCRF will be compared with patients’ medical records and the verification will be documented 
on the source data verification (SDV) form and the monitoring report.  
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the Sponsor appointed to audit the trial, and by regulatory authorities. 
Details will remain confidential and patients’ names will not be recorded outside the hospital. 
 
16.4 Clinical study report 
All clinical data will be presented at the end of the trial on final data listings. The CI, RM CTU CTC and 
RM statistician will prepare a clinical study report based on the final data listings. The report will be 
submitted to the Investigator(s) for review and confirmation it accurately represents the data collected 
during the course of the trial. A summary of the final clinical report will be provided by the Sponsor to 
the MHRA and to the Research Ethics Committee. 

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16.5 Record retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical trial and the quality of the data produced to be 
evaluated and verified. These essential documents (including those detailed in Chapter V of Volume 
10 (Clinical Trials) of The Rules Governing Medicinal Products in the European Union based upon 
Section 8 of the ICH GCP Guidelines), including source documents such as scans, trial related 
documents and copies of the eCRFs, associated audit trail and serious adverse event (SAE) report 
forms, shall show whether the Investigator has complied with the principles and guidelines of Good 
Clinical Practice (GCP). 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for 5 years. 
Records must not be destroyed without prior written approval from the Sponsor. 
The medical files of trial subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
 
16.6 Ethical considerations 
Before starting the trial, the protocol, patient information sheet and consent form must be approved 
by the ICR/RM joint Committee for Clinical Research and the appropriate Ethics Committee.  
The confidentiality of patients participating in this trial will be protected and each participant will be 
assigned a unique trial number at the point of registration which will be used to identify eCRFs and 
anything else sent to the sponsor or other third parties. No patient identifiable data will be shared 
outside of the participating site. 
It is the Chief/Principal Investigator’s responsibility to update patients (or their authorised 
representatives, if applicable) whenever new information (in nature or severity) becomes available 
that might affect the patient’s willingness to continue in the trial. The Chief/Principal Investigator must 
ensure this is documented in the patient’s medical notes and the patient is re-consented. 
The Sponsor and Chief/Principal Investigator must ensure that the trial is carried out in accordance 
with the GCP principles and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 
2006/1928 as amended). 
16.7 Indemnity 
This trial is being carried out under the auspices of The Royal Marsden NHS Foundation Trust. 
Indemnity for participating hospitals is provided by the usual NHS indemnity arrangements for clinical 
negligence. 
 
16.8 Publication policy and press releases 
The trial results will be submitted for publication in a relevant medical journal with authorship 
according to the criteria defined by the ICMJE (http://www.icmje.org). These state that: Authorship 
credit should be based 1) substantial contributions to conception and design, acquisition of data, or 

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analysis and interpretation of data; 2) drafting the article or revising it critically for important 
intellectual content; and 3) final approval of the version to be published. Authors should meet 
conditions 1, 2, and 3.  
Draft publications (manuscripts, abstracts, slides and posters) should be submitted to the RM CTU 
Clinical Trial Coordinator for circulation to the relevant parties and the statistician to allow sufficient 
time for review prior to submission. 
The Sponsor shall receive copies of abstracts, slides, posters and manuscripts for review in advance 
of submission.   
The results of the breast and basket cohorts may be presented and published separately or 
combined.  
Following publication, the sponsor will produce a lay summary of the results to be published on the 
Royal Marsden’s website or upon request to be distributed to study participants. 
 
16.9 Off-site study procedures in case of crisis situation 
 
In cases of emergencies including, but not limited to viral pandemics, natural disasters or war, to 
continue patient safety and minimise risks to the study integrity, certain study procedures may be 
conducted remotely for patients included in the study. Any such changes will be temporary and based 
upon a risk assessment specific to the crisis and the MHRA and Ethics committee will be informed as 
required. 
Temporary study changes will include: 
1. Study visits conducted by telephone 
2. Laboratory testing performed at the patient’s local hospital or GP surgery 
3. Study drug shipped from the site to the patient 
4. Remote monitoring and source data verification performed by the study monitor 
 
Additional changes including, but not limited to drug holidays and deferral of imaging may be applied 
on a case-by case basis, as assessed necessary by the PI.  
All temporary study changes will be discussed with the patient and documented in the site file. 
 
 
 
 
 

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17. REFERENCES 
Note for Guidance on Good Clinical Practice. ICH Topic E6. CSMP/ICH/135/95. EMEA, May 1996, 
updated September 1997 with post Step 4 errata included  
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States relating to 
the implementation of good clinical practice in the conduct of clinical trials on medicinal products for 
human use. Official Journal of the European Communities L121/34-44 
Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human 
use to the competent authorities, notification of substantial amendments and declaration of the end 
of the trial. October 2005. ENTR/F2/BL D(2003) CT 1 (Revision 2) 
Detailed guidance on the application format and documentation to be submitted in an application for 
an Ethics Committee opinion on the clinical trial on medicinal products for human use. February 2006. 
ENTR/CT 2 (Revision 1) 
Detailed guidance on the collection, verification and presentation of adverse reaction reports arising 
from clinical trials on medicinal products for human use. April 2006. ENTR/CT 3 (Revision 2) 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 1031) 
COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for 
good clinical practice as regards investigational medicinal products for human use, as well as the 
requirements for authorisation of the manufacturing or importation of such products. Official Journal 
of the European Union L 91/13 
The Medicines for Human use (Clinical Trials) Amendment Regulations 2006 (Statutory Instrument 
2006/1928). 
 
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Discov, 2018. 8(4): p. 498-515. 
18. 
Di Leo, A., et al., Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized 
CONFIRM trial. J Natl Cancer Inst, 2014. 106(1): p. djt337. 
 
 
 
 

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18. APPENDICES 
 
18.1 APPENDIX 1: WHO PERFORMANCE SCALE 
 
Activity Performance Description 
Score 
 
 
Fully active, able to carry out all normal activity without restriction. 
0 
 
 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, for example, light housework, office work. 
1 
 
 
Ambulatory and capable of all self-care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours.  
2 
 
 
Capable of only limited self-care. Confined to bed or chair more than 50% of waking 
hours.  
3 
 
 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
 
4 
 

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18.2 APPENDIX 2: DECLARATION OF HELSINKI 
 
Recommendations guiding physicians in biomedical research involving human subjects 
 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, amended by the 29th 
World Medical Assembly, Tokyo, Japan, October 1975, 
and 
the 35th World Medical Assembly, Venice, Italy, October 1983 
and 
the 41st World Medical Assembly, Hong-Kong, September 1989 
and 
the 48th General Assembly, Somerset West, Republic of South Africa, October 1996 
 
 
INTRODUCTION 
 
It is the mission of the physician to safeguard the health of the people. His or her knowledge and 
conscience are dedicated to the fulfilment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
“The health of my patient will be my first consideration”, and the International Code of Medical 
Ethics declares that, “A physician shall act only in patient’s interest when providing medical care 
which might have the effect of weakening the physical and mental condition of the patient”. 
 
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of 
disease. 
 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. 
This applies especially to biomedical research. 
 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognised between medical 
research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, 
the essential object of which is purely scientific and without implying direct diagnostic or therapeutic 
value to the person subjected to the research. 
 
Special caution must be exercised in the conduct of research that may affect the environment, and 
the welfare of animals used for research must be respected. 
 
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association has 
prepared the following recommendations as a guide to every physician in biomedical research 

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involving human subjects. They should be kept under review in the future. It must be stressed that 
the standards as drafted are only a guide to physicians all over the world. Physicians are not relieved 
from criminal, civil and ethical responsibilities under the laws of their own countries. 
 
I - BASIC PRINCIPLES 
 
1. Biomedical research involving human subjects must conform to generally accepted scientific 
principles and should be based on adequately performed laboratory and animal experimentation 
and on a thorough knowledge of the scientific literature. 
 
2. The design and performance of each experimental procedure involving human subjects should 
be clearly formulated in an experimental protocol which should be transmitted for consideration, 
comment and guidance to a specially appointed committee independent of the investigator and 
the sponsor provided that this independent committee is in conformity with the laws and 
regulations of the country in which the research experiment is performed. 
 
3. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given his or her consent. 
 
4. Biomedical research involving human subjects cannot legitimately be carried out unless the 
importance of the objective is in proportion to the inherent risk to the subject. 
 
5. Every biomedical research project involving human subjects should be preceded by careful 
assessment of predictable risks in comparison with foreseeable benefits to the subject or to 
others. Concern for the interests of the subject must always prevail over the interests of science 
and society. 
 
6. The right of the research subject to safeguard his or her integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject to minimise the impact of 
the study on the subject’s physical and mental integrity and on the personality of the subject. 
 
7. Physicians should abstain from engaging in research projects involving human subjects unless 
they are satisfied that the hazards involved are believed to be predictable. Physicians should 
cease any investigation if the hazards are found to outweigh the potential benefits. 
 
8. In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
 
9. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may 
entail. He or she should be informed that he or she is at liberty to abstain from participation in 
the study and that he or she is free to withdraw his or her consent to participation at any time. 

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The physician should then obtain the subject’s freely given informed consent, preferably in 
writing. 
 
10. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship to him or her or may consent under duress. 
In that case the informed consent should be obtained by a physician who is not engaged in the 
investigation and who is completely independent of this official relationship. 
 
11. In case of legal incompetence, informed consent should be obtained from the legal guardian in 
accordance with national legislation. Where physical or mental incapacity makes it impossible to 
obtain informed consent, or when the subject is a minor, permission from the responsible 
relative replaces that of the subject in accordance with national legislation. 
 
12. The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that the principles enunciated in the present Declaration are complied with. 
 
 
II - MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (Clinical research) 
 
1.  In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgement it offers hope of saving life, re-establishing health 
or alleviating suffering. 
 
2. The potential benefits, hazards and discomfort of a new method should be weighed against the 
advantages of the best current diagnostic and therapeutic methods. 
 
3. In any medical study, every patient - including those of a control group, if any - should be assured 
of the best-proven diagnostic and therapeutic method. This does not exclude the use of inert 
placebo in studies where no proven diagnostic or therapeutic method exists. 
 
4. The refusal of the patient to participate in a study must never interfere with the physician-
patient relationship. 
 
5. If the physician considers it essential not to obtain informed consent, the specific reasons for this 
proposal should be stated in the experimental protocol for transmission to the independent 
Committee (1,2). 
 
6. The physician can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is justified by its 
potential diagnostic or therapeutic value for the patient. 
 
 
 
 
 

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III - NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS (Non-clinical 
biomedical research) 
 
1. In the purely scientific application of medical research carried out on a human being, it is the 
duty of the physician to remain the protector of the life and health of that person on whom 
biomedical research is being carried out. 
 
2. The subjects should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient’s illness. 
 
3. The investigator or the investigating team should discontinue the research if in his/her or their 
judgement it may, if continued, be harmful to the individual. 
 
4. In research on man, the interest of science and society should never take precedence over 
considerations related to the wellbeing of the subject. 
 

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18.3 APPENDIX 3: MEASUREMENT OF DISEASE 
Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (version 1.1) 
[Eisenhauer, 2009] 
Baseline documentation of target and non-target lesions  
• 
All baseline lesion assessments must be performed within 28 days of randomizations.  
• 
Lymph nodes that have a short axis of <10mm are considered non-pathological and should not be 
recorded or followed.  
• 
Pathological lymph nodes with <15mm and but 10mm short axis are considered non measurable.  
• 
Pathological lymph nodes with 15mm short axis are considered measurable and can be selected 
as target lesions, however lymph nodes should not be selected as target lesions when other 
suitable target lesions are available.  
• 
Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, should be identified as target lesions, and recorded and measured at 
baseline. These lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging techniques 
or clinically).  
Note: Cystic lesions thought to represent cystic metastases should not be selected as target lesions 
when other suitable target lesions are available.  
Note: Measurable lesions that have been previously irradiated and have not been shown to be 
progressing following irradiation should not be considered as target lesions.  
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by CT or MRI can be considered measurable. Bone scans, FDG-PET scans or X-rays 
are not considered adequate imaging techniques to measure bone lesions.  
• 
All other lesions (or sites of disease) should be identified as non-target and should also be recorded 
at baseline. Non-target lesions will be group by organ. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up.  
Efficacy assessment  
Disease progression and response evaluations will be determined according to the definitions 
established in the Response Evaluation Criteria in Solid Tumours (RECIST 1.1) [Eisenhauer, 2009].  
See the Time and Events Table (Section 3.8) for the schedule of efficacy assessments. Assessments 
must be performed on a calendar schedule and should not be affected by dose interruptions/delays. 
For post baseline assessments, a window of 14 days is permitted to allow for flexible scheduling.  
• 
The following are required at baseline: CT for Chest/Abdomen/Pelvis or MRI for Abdomen/Pelvis 
and clinical disease assessment for palpable lesions, brain scan and bone scan. At each post 
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except for brain scan and bone scans. Brain and Bone scans should be performed as clinically 
indicated.  
Confirmation of CR and PR are required per protocol. Confirmation assessments must be performed 
no less than 4 weeks after the criteria for response have initially been met and may be performed at 
the next protocol scheduled assessment. If a confirmation assessment is performed prior to the next 
protocol schedule assessment, the next protocol scheduled evaluation is still required (e.g. evaluations 
must occur at each protocol scheduled time point regardless of unscheduled assessments).  
A baseline bone scan is required for all subjects with known bone metastases. For subjects without 
bone disease at baseline, subsequent bone scans should only be performed as clinically indicated (e.g. 
presentation of bone pain). For subjects with bone disease at baseline, a bone scan is required as 
clinically indicated. In addition, in order to assign a response of CR in a subject with bone disease at 
baseline, a bone scan must be performed within 1 week before or  4 weeks after the set of images 
showing CR in other sites of disease.  
A baseline brain scan is only required for patients with known or suspected brain metastases.  For 
subjects with CNS disease at baseline, a brain scan is required as clinically indicated. In addition, in 
order to confirm a CR in a subject with brain disease at baseline, a brain scan must be performed within 
1 week before or 4 weeks after the 1st set of images showing CR in other sites of disease.  
Assessment guidelines  
Please note the following:  
• 
The same diagnostic method, including use of contrast when applicable, must be used throughout 
the study to evaluate a lesion.  
• 
All measurements should be taken and recorded in millimetres (mm), using a ruler or callipers.  
• 
Ultrasound is not a suitable modality of disease assessment. If new lesions are identified by 
ultrasound, confirmation by CT or MRI is required.  
• 
Fluorodeoxyglucose (FDG)-PET is generally not suitable for on-going assessments of disease. 
However, FDG-PET can be useful in confirming new sites of disease where a positive FDG-PET scans 
correlates with the new site of disease present on CT/MRI or when a baseline FDG-PET was 
previously negative for the site of the new lesion. FDG-PET may also be used in lieu of a standard 
bone scan providing coverage allows interrogation of all likely sites of bone disease and FDG-PET 
is performed at all assessments.  
• 
If PET/CT is performed then the CT component can only be used for standard response 
assessments if performed to diagnostic quality, which includes the required anatomical coverage 
and prescribed use of contrast. The method of assessment should be noted as CT on the CRF.  
Clinical Examination: Clinically detected lesions will only be considered measurable when they are 
superficial (e.g., skin nodules). In the case of skin lesions, documentation by colour photography, 
including a ruler/callipers to measure the size of the lesion, is required. [Eisenhauer, 2009].  
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.  

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Minimum size of a measurable baseline lesion should be twice the slice thickness, with a minimum 
lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but when used, the technical 
specification of the scanning sequences should be optimised for the evaluation of the type and site of 
disease and lesions must be measured in the same anatomic plane by use of the same imaging 
examinations. Whenever possible the same scanner should be used. [Eisenhauer, 2009].  
X-ray: In general, X-ray should not be used for target lesion measurements owing to poor lesion 
definition. Lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung; however chest CT is preferred over chest X-ray [Eisenhauer, 2009].  
Brain Scan: If baseline brain scans are required, then contrast enhanced MRI is preferable to contrast 
enhanced CT.  
Bone Scan (typically bone scintigraphy): If a bone scan is performed and a new lesion(s) is equivocal, 
then correlative imaging (i.e., X-ray, CT, or MRI) is required to demonstrate malignant characteristics 
of the lesion(s).  
Note: PET [FDG or fluoride] may be used in lieu of a standard bone scan providing coverage allows 
interrogation of all likely sites of bone disease and PET is performed at all assessments.  
Guidelines for Evaluation of Disease  
Measurable and Non-measurable Definitions  
Measurable lesion: A non-nodal lesion that can be accurately measured in at least one dimension 
(longest dimension) of  
10 mm with MRI or CT when the scan slice thickness is no greater than 5mm. If the slice thickness is 
greater than 5mm, the minimum size of a measurable lesion must be at least double the slice thickness 
(e.g., if the slice thickness is 10 mm, a measurable lesion must be 20 mm).  
10 mm calliper/ruler measurement by clinical exam or medical photography.  
20 mm by chest x-ray.  
Additionally, lymph nodes can be considered pathologically enlarged and measurable if 15mm in the 
short axis when assessed by CT or MRI (slice thickness recommended to be no more than 5mm). At 
baseline and follow-up, only the short axis will be measured [Eisenhauer, 2009].  
Non-measurable lesion: All other lesions including lesions too small to be considered measurable 
(longest diameter <10 mm or pathological lymph nodes with 10 mm and <15 mm short axis) as well as 
truly non-measurable lesions, which include: leptomeningeal disease, ascites, pleural or pericardial 
effusions, inflammatory breast disease, lymphangitic involvement of the skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques [Eisenhauer, 2009].  
Measurable disease: The presence of at least one measurable lesion. Palpable lesions that are not 
measurable by radiologic or photographic evaluations may not be utilized as the only measurable 
lesion.  

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Non-Measurable only disease: The presence of only non-measurable lesions. Note: non-measurable 
only disease is not allowed per protocol.  
Response Criteria  
Evaluation of target lesions  
Definitions for assessment of response for target lesion(s) are as follows:  
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must 
be <10mm in the short axis.  
• 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as a reference, the baseline sum of the diameters (e.g. percent change from baseline).  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for progressive disease.  
• 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. 
percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since 
treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.  
• 
Not Applicable (NA): No target lesions at baseline.  
• 
Not Evaluable (NE): Cannot be classified by one of the five preceding definitions.  
Note: 
• 
If lymph nodes are documented as target lesions the short axis is added into the sum of the 
diameters (e.g. sum of diameters is the sum of the longest diameters for non-nodal lesions and 
the short axis for nodal lesions). When lymph nodes decrease to non-pathological size (short axis 
<10mm) they should still have a measurement reported in order not to overstate progression.  
• 
If at a given assessment time point all target lesions identified at baseline are not assessed, sum 
of the diameters cannot be calculated for purposes of assessing CR, PR, or SD, or for use as the 
nadir for future assessments. However, the sum of the diameters of the assessed lesions and the 
percent change from nadir should be calculated to ensure that progression has not been 
documented. If an assessment of PD cannot be made, the response assessment should be NE.  
• 
All lesions (nodal and non-nodal) should have their measurements recorded even when very small 
(e.g. 2 mm). If lesions are present but too small to measure, 5 mm should be recorded and should 
contribute to the sum of the diameters, unless it is likely that the lesion has disappeared in which 
case 0 mm should be reported.  
• 
If a lesion disappears and reappears at a subsequent time point it should continue to be measured. 
The response at the time when the lesion reappears will depend upon the status of the other 
lesions. For example, if the disease had reached a CR status then PD would be documented at the 
time of reappearance. However, if the response status was PR or SD, the diameter of the 

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reappearing lesion should be added to the remaining diameters and response determined based 
on percent change from baseline and percent change from nadir.  
Evaluation of non-target lesions  
Definitions for assessment of response for non-target lesions are as follows:  
• 
Complete Response (CR): The disappearance of all non-target lesions. All lymph nodes identified 
as a site of disease at baseline must be non-pathological (e.g. <10 mm short axis).  
• 
Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) or lymph nodes identified as a 
site of disease at baseline ≥ 10 mm short axis.  
• 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
• 
Not Applicable (NA): No non-target lesions at baseline.  
• 
Not Evaluable (NE): Cannot be classified by one of the four preceding definitions.  
Note:  
• 
In the presence of measurable disease, progression on the basis of solely non-target disease 
requires substantial worsening such that even in the presence of SD or PR in target disease, the 
overall tumour burden has increased sufficiently to merit discontinuation of therapy.  
• 
Sites of non-target lesions, which are not assessed at a particular time point based on the 
assessment schedule, should be excluded from the response determination (e.g. non-target 
response does not have to be "Not Evaluable").  
New lesions  
New malignancies denoting disease progression must be unequivocal. Lesions identified in follow-up 
in an anatomical location not scanned at baseline are considered new lesions.  
Any equivocal new lesions should continue to be followed. Treatment can continue at the discretion 
of the investigator until the next scheduled assessment. If at the next assessment the new lesion is 
considered to be unequivocal, progression should be documented.  
Evaluation of overall response  
Table 22 presents the overall response at an individual time point for all possible combinations of 
tumour responses in target and non-target lesions with or without the appearance of new lesions for 
subjects with measurable disease at baseline.  
 
 
 
 

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Table 7: Evaluation of Overall Response for Subjects with Measurable Disease at Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR  
CR or NA  
No  
CR  
CR  
Non-CR/Non-PD or NE  
No  
PR  
PR  
Non-PD or NA or NE  
No  
PR  
SD  
Non-PD or NA or NE  
No  
SD  
NE  
Non-PD or NA or NE  
No  
NE  
PD  
Any  
Yes or No  
PD  
Any  
PD  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= 
Not applicable, and NE=Not Evaluable  
Note:  
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having "symptomatic 
deterioration." Objective response status is determined by evaluations of disease burden. Every effort 
should be made to document the objective progression even after discontinuation of treatment.  
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of CR depends on this determination, it is recommended that the residual lesion be 
investigated (fine needle aspirate/biopsy) to confirm the CR.  
Evaluation of best overall response  
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence and will be determined based on the investigators’ assessment of response at 
each time point.  
 
To be assigned a status of SD, follow-up disease assessment must have met the SD criteria at least 
once after first dose at a minimum interval of 4 weeks. 
  
If the minimum time for SD is not met, best response will depend on the subsequent assessments. For 
example, if an assessment of PD follows the assessment of SD and SD does not meet the minimum 
time requirement the best response will be PD. Alternative subjects lost to follow-up after an SD 
assessment not meeting the minimum time criteria will be considered not evaluable.  
 
Confirmation Criteria (recommended):  
To be assigned a status of PR or CR, a confirmatory disease assessment should be performed no less 
than 4 weeks (28 days) after the criteria for response are first met.  

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18.4 APPENDIX 4: NEW YORK HEART ASSOCIATION (NYHA) SCALE 
 
Class I – patients with cardiac disease but without resulting limitation of physical activity; ordinary 
physical activity does not cause undue dyspnoea (or fatigue, palpitation or anginal pain) 
Class II – patients with cardiac disease resulting in slight limitation of physical activity; they are 
comfortable at rest; ordinary physical activity results in dyspnoea (or fatigue, palpitation or anginal 
pain) 
Class III – patients with cardiac disease resulting in marked limitations of physical activity; they are 
comfortable at rest; less than ordinary physical activity causes dyspnoea (or fatigue, palpitation or 
anginal pain) 
Class IV – patients with cardiac disease resulting in inability to carry out physical activity without 
discomfort; symptoms of dyspnoea (or of angina) may be present even at rest; if any physical activity 
is undertaken, discomfort is increased.  
 
 

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18.5 APPENDIX 5: LIST OF PROHIBITED DRUGS DURING THIS STUDY 
 
CYP3A inhibitors 
Aprepitant 
itraconazole 
ketoconazole 
clarithromycin 
erythromycin 
telithromycin 
diltiazem 
mifepristone 
verapamil 
Fluconazole 
norfloxacin 
voriconazole 
Cimetidine (weak) 
norfluoxetine 
grapefruit, grapefruit juice 
or any product containing 
grapefruit 
nelfinavir 
nefazodone 
Herbal remedies 
Esomeprazole (weak) 
Pantoprazole (weak) 
Omeprazole (weak) 
Indinavir 
ritonavir 
saquinavir 
Palonosetron 
 
 
CYP3A inducers 
carbamazepine, oxcarbazepine 
pioglitazone 
rifampicin 
dexamethasone and other 
glucocorticoids 
phenobarbitone 
rifapentine 
felbamate 
phenytoin 
St. John’s wort 
modafinil 
primidone 
Troglitazone 
nevirapine 
rifabutin 
 
Sensitive CYP3A substrates with a Narrow Therapeutic Range 
alfentanil, 
ergotamine, 
sirolimus 
aripiprazole 
fentanyl 
tacrolimus 
astemizole 
halofantrine 
terfenadine 
cisapride 
pimozide 
triazolam 
cyclosporine 
quinidine 
 
 
For a more extensive list please go to this website:  
https://drug-interactions.medicine.iu.edu/MainTable.aspx 
 
 

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Medications which cause bradycardia or prolongation of the QT interval: 
Crizotinib can cause prolongation of the QT interval and bradycardia. Co-treatment with other 
bradycardic agents, anti-arrhythmics or medications which prolong the QT interval should therefore 
be avoided. Examples are listed below: 
Medicinal products known to prolong QT 
Bradycardic agents 
Anti-arrhthymics: 
Sotalol 
Quinine, 
 
Amiodarone, 
Disopyramide, Procainamide, Flecainide, Dofetilide 
Non-hydropyridine 
calcium 
channel 
blockers 
(verapamil, 
diltiazem) 
 
Antibiotics: Moxifloxacin, clarithromycin, ciprofloxacin, 
levofloxacin, Ofloxacin, Trimethorprim, Azithromycin, 
erythromycin 
 
Beta-blockers 
Anticonvulsants: Fosphenytoin, felbamate 
 
Clonidine 
Antidepressants: Mirtazapine, citalopram, venlafaxine, 
paroxetine, 
fluoxetine, 
sertraline, 
trazodone, 
escitalopram, clomipramine, amitriptyline, imipramine, 
nortryptyline, desimipramine, doxepin, trimipramine, 
protriptyline 
 
Guanfacine 
Anti-fungal: Voriconazole, fluconazole, ketoconazole, 
itraconazole 
 
Digoxin 
Antihistamines: 
Astemizole, 
terfenadine, 
diphenhydramine 
 
Mefloquine 
Anti-hypertensive: Nicardipine, israpidine, Moexipril 
 
Anticholinesterases 
Antipsychotic 
medications: 
Clozapine, 
ziprasidone, 
Thioridazine, risperidone, mesoridazine, quetiapine, 
haloperidol, 
pimozide, 
amisulpride, 
sertindole, 
iloperidone, paliperidone, chlorpromazine 
 
Pilocarpine 
Anti-emetics: Dolasetron, domperidone granisetron, 
levomepromazine, ondansetron, palonosetron 
 
 
Anti-malarials: Chloroquine, halofantrine, artenimol + 
piperaquine 
 
 
Anti-viral: Foscarnet, ritonavir, atazanavir 
 
 
Bronchodilators: Albuterol, salmeterol, metaproterenol, 
terbutaline, 
levalbuterol, 
ephedrine, 
phenylpropanolamine 
 
 
CNS 
stimulants: 
amphetamine, 
methylphenidate, 
dexmethylphenidate, lisdexfetamine 
 
 

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Sedatives:  Chloral hydrate, droperidol 
 
 
Miscellaneous:   
Alfuzosin, 
Amantadine, 
Atomoxitine 
,Cisapride, 
Famotidine, 
Fingolimod, 
Indapamide, 
Ivabradine, 
Levomethadryl, 
Lithium, 
Mefloquine, 
Methadone, 
Midodrine, 
Mizolastine, 
Octreotide, 
Oxytocin, 
Pentamadine, 
Ritodrine, 
Sildenafil, 
Solifenacin, 
Tacrolimus, Tizanidine, Tolterodine, Vardenafil 
 
 
 
 
 
 

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18.6 APPENDIX 6: POTENTIAL SIGHT-THREATENING EVENTS (PSTE) AND SEVERE 
VISION LOSS (SVL) 
 
Based on US-FDA guidance, in all crizotinib-treated patients, Grade ≥2 PSTE (except for Visual field 
defect, for which Grade ≥3 is the standard) or SVL should be treated as Serious Adverse Events, 
regardless of relatedness to study drug. Please report these cases to the Sponsor and Pfizer, as 
specified in the protocol, within 24 hours of you or your staff member becoming aware of them. 
The following MedDRA preferred terms are considered indicative of a PSTE or SVL event: 
 
Amaurosis 
Amaurosis fugax 
Blindness 
Blindness cortical 
Blindness day 
Blindness night 
Blindness transient 
Blindness unilateral 
Hemianopia 
Hemianopia heteronymous 
Hemianopia homonymous 
Optic atrophy 
Optic ischaemic neuropathy 
Optic nerve disorder 
Optic neuropathy 
Quadranopia 
Retinopathy 
Sudden visual (or vision) loss 
Toxic optic neuropathy 
Tunnel vision 
Visual cortex atrophy 
Visual field defect 
Visual pathway disorder 
Retinal oedema 
Retinal detachment 
Maculopathy 
Iritis 
Uveitis 
Visual field test abnormal 
 
 
The occurrence of Grade ≥2 of any of these events should be treated as a SAE, except for Visual field 
defect, for which only Grade ≥3 should be treated as a SAE. Grade 2 events are considered to be PST 
and Grade ≥3 events are considered to be SVL. 
 
 

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18.7: Appendix 7:  Amendment History 
 
Protocol 
version/date 
 
Reason for amendment 
Version 1.0, 
23/10/2017 
 
- 
Version 2.2, 
11/12/2018 
Addition of overall survival (OS) as a secondary endpoint. 
 
Addition of CA125 testing for lobular breast patients added into the amended 
protocol (in text and schedule of events table) as it is frequently a more useful 
tumour marker than CA15-3 for patients with peritoneal disease.  
 
Removal of prior fulvestrant as an exclusion criterion  
  
In Appendix 3 RECIST measurement of disease, the previous wording was 
incorrect therefore wording under section “Efficacy assessment” was 
amended.  
  
The Schedule of Events table amended to include:  
• 
An extra CA125 test (for Breast patients).  
• 
A “Survival follow-up (every 6 months)” column and row.  
• 
The position of the "Day 28+/- 3 days after last dose" column has been 
re-arranged and moved from the end column to follow the "after D1 
of each cycle" column.  
• 
Added in wording "Follow Up" to the “Every 8 weeks until progression 
column” for clarity.  
 
Version 3.0, 
13/08/2020 
Renaming of the gastric cancer cohort to a basket cohort that also includes 
triple negative lobular breast cancer or CDH1-mutated solid tumour patients.  
 
Addition of inclusion criterion for E-cadherin negative patients in both the 
breast and basket cohorts. 
 
Addition of two new investigator sites. 
 
Amendment to pregnancy prevention guidance following update to SmPC for 
fulvestrant IMP. 
 
Typographical, grammatical and formatting changes to the study protocol and 
patient information sheets. 
a. Changed ‘histologically’ to ‘histological’ for inclusion criterion 1 
regarding diagnosis. 
b. Correction of referral in section 10.1.3 ‘Serious Adverse Events’ of the 
protocol. 
c. Update to inclusion criteria regarding creatinine clearance measured if 
creatinine is abnormal. 
d. Added ‘Streck’ tube alongside EDTA for collection of plasma samples 
in section 9.1.2 of the protocol. 

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e. Typographical and formatting changes to the ‘Schedule of events’ 
table in section 8.5 of the protocol and the Patient Information Sheet. 
f. Numbered the tables throughout the protocol.  
g. Removed ‘Survival’ from ‘Follow up’ on the schedule of events table 
on the patient information sheets for both cohorts. 
h. Data Monitoring Committee (DMC) changed to Independent Data 
Monitoring Committee (IDMC) throughout the protocol. 
The assessment window for the 28 day Safety follow up visit is stated 
as +/- 3 days. 
 
List of prohibited medications and medications that cause bradycardia and 
prolong QT interval updated in Appendix 5. 
 
Addition of Amendment History as Appendix 7. 
 
Wording added to section 8.1.1 of the protocol to describe consent and 
recruitment of non-English speaking patients. 
 
Version 4.0, 
dated 
05/04/2022 
 
1. Inclusion criterion 2 states that lobular breast cancer patients could 
have received either one line of chemotherapy or one line of therapy 
with CDK4/6 inhibitor. 
2. Differentiated previous treatment between gastric cancer patients 
and triple negative lobular breast cancer or CDH1-mutated solid 
tumour patients. 
3. Inclusion criterion for triple negative lobular breast cancer patients 
(basket cohort) and lobular breast cancer cohort patients updated to 
include E-cadherin negative status. 
4. Added wording to section 4.2 of the protocol to align with section 15.1 
that Safety Reviews are also required in the basket cohort too when 3 
and 6 diffuse gastric cancer patients have been recruited. 
5. Amended exclusion criterion 7 in section 5.1.2 of the protocol. The 
period of 12 days washout before the first dose of crizotinib changed 
to 5 half-lives for bradycardic agents, drugs which prolong the QT 
interval and/or anti-arrhythmic agents. 
6. Instruction added to section 6.1 of the protocol for reduced starting 
dose of crizotinib for patients with documented Gilbert’s disease. 
7. Instructions added to Table 3 in section 6.2.1.1 of the protocol for 
management of non-haematological toxicities. 
8. Glucose was already collected as part of the biochemistry tests at the 
screening 7 days visit. Now added to the text with the other 
biochemistry parameters on section 8.1.3 of the protocol. 
9. Clarified that the biochemistry parameters required at day 1 of each 
cycle are required from cycle 2 onwards in section 8.2 of the protocol. 
10. Definition of abnormal values that constitute reporting as adverse 
events has been clarified in section 10.1.1 of the protocol. 
11. Section 16.9 ‘Off-site study procedures in case of crisis situation’ 
added to the protocol to account for adjustments made in study 
conduct due to emergency situations such as the Covid-19 pandemic. 
Note added to section 8.2 to allow biochemistry tests to be performed 
locally at visits C1D8, C1D22, C2D8, C2D15 and C2D22 in cases of crisis 
situations. 

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12. As biopsies should only be derived from metastatic tissue, the 
statement “diagnostic tumour” has been removed from section 9.1.1 
of the protocol. Added statement that the sample can be from the 
primary tumour for patients presenting with de novo metastatic 
disease. 
13. Reduced the systems required for physical examination at the 
evaluations within one week visit in section 8.1.3 of the protocol. 
14. The baseline bone scan performed at baseline can be within 6 weeks 
prior to the first dose of treatment instead of 4 weeks. This instruction 
has been added to section 8.1.2 of the protocol for evaluations during 
screening and also Table 6 for the schedule of events. 
15. Typographical and formatting changes.