Conditions: Breast Cancer
Keywords: Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
A single centre, single arm phase II study of alternating eribulin and hormonal therapy in 12 patients with locally advanced or metastatic breast cancer who have received at least one hormonal therapy and at least one chemotherapy in the metastatic setting.

Detailed description:
12 patients with locally advanced or metastatic breast cancer who have received at least one hormonal therapy and at least one chemotherapy in the metastatic setting will be enrolled to receive treatment. Once patients are consented and have completed on study screening, eribulin and Aromatase Inhibitor (AI) treatment will be alternated for up to 9 months, until disease progression or unacceptable toxicities, whichever is sooner. Patients will then attend a safety follow-up visit 4 weeks after completing treatment.

Eribulin (Halaven®) is a non-taxane microtubule dynamics inhibitor. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into non-productive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.

Eribulin is licenced for the treatment of patients with locally advanced or metastatic breast cancer who have previously received at least one chemotherapeutic regimen for the treatment of advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments.

The aim of this study is to alternate eribulin and aromatase inhibitors, examining whether there may be breakthrough relapse during the AI therapy or on the other hand we can extend the duration that eribulin may be used for. Importantly, blood based biomarkers, the tumour derived fraction of circulating free DNA (cfDNA) termed circulating tumor DNA (ctDNA), and circulating tumour cells will be measured. A major aim of this study is to test whether biomarkers fluctuate between chemotherapy and AI treatment in the setting of advanced breast cancer.

Arms:
arm 1: 3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner.

Interventions: intervention 1: Eribulin
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
Study Title: 
ALERT: A phase II study of alternating eribulin and hormonal therapy 
in pre‐treated ER+ve breast cancer. 
 
 
Protocol Number: 
C/31/2014 
 
 
Product: 
Eribulin 
 
 
Sponsor: 
Imperial College London 
 
 
EudraCT Number: 
2014‐004112‐11 
 
 
Development Phase: 
II 
 
 
Final Protocol Date: 
Version 3.0, 2 1 / 0 6 / 2 0 1 7  
 
 
 
 
 
 
 
 
 
 
 
Property of: CRUK Imperial Centre: Clinical Trials Section (CCTS) May 
not be used, divulged or published without the consent of CCTS 


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CONTACT LIST 
 
Chief Investigator: 
Dr. Laura Kenny 
Imperial College London 
1st Floor ICTEM 
Hammersmith Hospital Campus 
 Du Cane Road 
London  W12 ONN 
 
Email:   l.kenny@imperial.ac.uk 
Tel: 
 +44(0)20 7594 2806 
 
 
Sponsor: 
Imperial College London 
Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
 
Contact: Gary Roper 
Head of Regulatory Compliance 
Email: gary.roper@imperial.ac.uk 
Tel:   +44 (0)20 7594 1872 
Funders: 
 
  Eisai Ltd 
EMEA Knowledge Centre 
Mosquito Way 
Hatfield 
Hertfordshire AL10 9SN 
www.eisai.co.uk 
Tel: +44 (020) 8600 1400 
Fax: +44 (020) 845676 1400 
 
Action Against Cancer 
Regency Chambers 
Jubilee Way 
Bury 
Lancashire BL9 0JW 
 
Trial Coordinator: 
Anna Kasim 
CRUK Imperial Centre: Clinical Trials Section 
Department of Surgery and Cancer 
Imperial College London 
3rd Floor Radiotherapy Building 
Hammersmith Hospital Campus 
Du Cane Road 
London W12 0NN 
 
  Email:  alert@imperial.ac.uk 
  Tel: 
  +44 (0)20 3313 0648 
  Fax: 
+44 (0)20 7311 7443 


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Trial Statistician 
Xinxue Liu 
Trial Statistician 
Imperial Clinical Trials Unit 
School of Public Health 
Imperial College London 
Stadium House 
68 Wood Lane 
London W12 7RH 
Email: xinxue.liu@imperial.ac.uk 
Tel: +44 (0)207 594 1739 
 
 
 
 
Protocol Development Group: 
Professor Justin Stebbing 
Professor of Cancer Medicine & Medical Oncology 
Imperial College London 
Email: j.stebbing@imperial.ac.uk 
 
Dr. Laura Kenny 
Consultant Medical Oncologist 
Imperial College London 
Email: l.kenny@imperial.ac.uk 
 
Professor Jacqui Shaw 
Professor of Translational Cancer Genetics 
University of Leicester 
Email: js39@leicester.ac.uk 
 
Mr. Philip Badman 
Clinical Trials Manager 
Imperial College London 
Email:   p.badman@imperial.ac.uk 
 
Helen Graham 
Lead Cancer Research Nurse 
NIHR Clinical Research Network: 
North West London 
Email: helen.graham@imperial.ac.uk 
 
 
 
 
Professor Charles Coombes 
Professor of Medical Oncology 
Imperial College London 
Email: c.coombes@imperial.ac.uk 
 
Dr. Susan Cleator 
Consultant Medical Oncologist 
Imperial College Healthcare NHS Trust 
Email: Susan.Cleator@imperial.nhs.uk 
 
Dr. Kevin Blighe 
Trial Statistician 
Imperial College London 
Email: k.blighe@imperial.ac.uk 
 
Dr. Jonathan Krell 
Consultant Oncologist 
Imperial College London 
Email: j.krell@imperial.ac.uk 
  
Miss Anna Kasim  
Trial Coordinator 
Imperial College London 
Email:  a.kasim@imperial.ac.uk 


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Laboratories: 
Department of Surgery and Cancer 
Imperial College London 
Hammersmith Campus 
1st Floor ICTEM Building (L‐Block) 
Du Cane Road 
London, W12 0NN 
 
Contact: Allison Hills 
Email:   a.hill@imperial.ac.uk 
Tel: 
07793 066270 
 
 
CNA Research Lab 
Level 3 Robert Kilpatrick Clinical Sciences 
Building, University of Leicester, Leicester Royal 
Infirmary, 
Leicester, LE2 7LX 
 
Contact: Professor Jacqui Shaw 
Email: js39@le.ac.uk 
Tel: +44(0) 116 525 3148 
 
 
 
IMP Manufacturing Facilities: 
Company Name: NerPharma 
Viale Pasteur 10, Nerviano 20014, Italy 
Tel: +39 0331581111 
 
Contact: Luigi Mombelli 
Title: QA Head 
Tel: +39 0331581393 
 
IMP Distributor: 
Company Name: Catalent (UK) Pharma Solutions 
Wingate Industrial Estate, Westhoughton, Bolton, Lancs, BL5 3XX 
 
Contact: Yecara Parkinson 
Title: Project Manager 
Tel: +44 01942 845473 
Fax: +44 01942 799799 


5.2.2. 
Physical examination and performance status............................................................................ 23 
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TABLE OF CONTENTS 
 
 
 
CONTACT LIST ............................................................................................................................................... 2 
 
TABLE OF CONTENTS..................................................................................................................................... 5 
 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................................ 9 
 
TRIAL SUMMARY .........................................................................................................................................11 
 
1. 
BACKGROUND AND RATIONALE...........................................................................................................13 
 
1.1. 
Breast Cancer ....................................................................................................................................... 13 
 
1.2. 
Investigational Agent ........................................................................................................................... 13 
 
1.3. 
Clinical Studies...................................................................................................................................... 13 
 
1.4. 
Aromatase Inhibitors (AI) ..................................................................................................................... 14 
 
1.5. 
Rationale .............................................................................................................................................. 14 
1.5.1. 
Biomarkers .................................................................................................................................. 15 
 
1.6. 
Risk / Benefit Assessment..................................................................................................................... 16 
1.6.1. 
Potential Benefits ........................................................................................................................ 16 
1.6.2. 
Potential Risks ............................................................................................................................. 16 
1.6.3. 
Overall benefit‐risk assessment .................................................................................................. 16 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................................................17 
 
2.1. 
Primary objective and endpoint ........................................................................................................... 17 
 
2.2. 
Secondary objectives and endpoints .................................................................................................... 17 
 
2.3. 
Translational objectives and endpoints................................................................................................ 17 
 
3. 
STUDY DESIGN.....................................................................................................................................17 
 
3.1. 
Overall study design ............................................................................................................................. 17 
 
3.2. 
Treatment regimens ............................................................................................................................. 17 
 
3.3. 
Follow‐up.............................................................................................................................................. 18 
 
3.4. 
Study termination................................................................................................................................. 18 
3.4.1. 
Treatment after study termination ............................................................................................. 18 
 
4. 
PATIENT SELECTION AND RECRUITMENT..............................................................................................18 
 
4.1. 
Screening and enrolment ..................................................................................................................... 18 
 
4.2. 
Subject Selection................................................................................................................................... 19 
4.2.1. 
Inclusion Criteria.......................................................................................................................... 19 
4.2.2. 
Exclusion criteria ......................................................................................................................... 19 
 
5. 
STUDY PLAN AND PROCEDURES...........................................................................................................20 
 
5.1. 
Study schedule...................................................................................................................................... 20 
 
5.2. 
Procedures and measurements ............................................................................................................ 23 
5.2.1. 
Demographic data and medical history....................................................................................... 23 


8. 
STATISTICAL ANALYSES ........................................................................................................................33 
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5.2.3. 
ECOG Performance Status ........................................................................................................... 23 
5.2.4. 
Vital signs..................................................................................................................................... 23 
5.2.5. 
ECG .............................................................................................................................................. 24 
5.2.6. 
Laboratory Evaluations ................................................................................................................ 24 
5.2.7. 
Tumour assessments ................................................................................................................... 24 
5.2.8. 
Treatment Compliance (Patient Diary)........................................................................................ 25 
5.2.9. 
Concomitant Medications ........................................................................................................... 25 
 
5.3.       Exploratory Research............................................................................................................................ 25 
5.3.1. 
Exploratory biomarker research .................................................................................................. 25 
5.3.2. 
Chain of custody of biological samples........................................................................................ 25 
 
5.4.       Total Blood Volumes............................................................................................................................. 26 
 
6. 
STUDY TREATMENT .............................................................................................................................26 
 
Trial treatment must begin within 1 week of the patient being enrolled into the study. Trial patients will be 
administered alternating regimes of 3 x 3 weekly cycles of intravenous eribulin over 2‐5 minutes on days 1 
and 8 of every 21 day cycle, followed by 9 weeks of AI treatment, followed again by 3 x 3 weekly cycles of 
eribulin and 9 weeks of an AI. ........................................................................................................................... 26 
 
6.1.       Non Investigational Medicinal Products............................................................................................... 26 
 
6.2.       Investigational Medicinal Product Details............................................................................................ 26 
6.2.1. 
Supply, packaging and labelling................................................................................................... 27 
6.2.2. 
Storage and Dispensing ............................................................................................................... 27 
6.2.3. 
Dosage and Duration ................................................................................................................... 27 
6.2.4. 
Dose Modifications for Eribulin ................................................................................................... 27 
6.2.5. 
Accountability.............................................................................................................................. 28 
6.2.6. 
Drug interactions/Precautions .................................................................................................... 28 
6.2.7. 
Overdose of IMP .......................................................................................................................... 29 
 
6.3.       Permanent discontinuation of study medication and withdrawal from study ................................. 29 
6.3.1. 
Permanent discontinuation of study medication ........................................................................ 29 
6.3.2. 
Withdrawal from study ............................................................................................................... 29 
6.3.3. 
Procedures for withdrawal from study ....................................................................................... 30 
 
7. 
PHARMACOVIGILANCE ........................................................................................................................30 
 
7.1.       Definition of an adverse event (AE) ...................................................................................................... 30 
7.1.1. 
Disease progression..................................................................................................................... 30 
7.1.2. 
New cancers ................................................................................................................................ 30 
 
7.2.       Recording of adverse events ................................................................................................................ 30 
 
7.3.       Severity of adverse events .................................................................................................................... 31 
 
7.4.       Causality of adverse events .................................................................................................................. 31 
 
7.5.       Abnormal laboratory test results ......................................................................................................... 31 
 
7.6.       Definitions of Serious Adverse Events (SAE) ......................................................................................... 31 
 
7.7.       Reporting of SAEs ................................................................................................................................. 32 
 
7.8.       Definition of a Serious Adverse Reaction (SAR) .................................................................................... 32 
 
7.9.       Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR).............................................. 32 
 
7.10.     Reporting of SUSARs............................................................................................................................. 32 
 
7.11.     Annual Reporting of Serious Adverse Reactions................................................................................... 33 
 
7.12.     Pregnanacy........................................................................................................................................... 33 


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8.1. 
Sample size and power considerations................................................................................................. 33 
 
8.2. 
Analysis Plan......................................................................................................................................... 33 
8.2.1. 
Deviations from the statistical plan............................................................................................. 33 
8.2.2. 
Efficacy analysis ........................................................................................................................... 34 
8.2.3. 
Safety analysis ............................................................................................................................. 34 
8.2.4. 
Translational analysis/ Exploratory Analysis ............................................................................... 34 
 
9. 
REGULATORY, ETHICAL AND LEGAL ISSUES ..........................................................................................34 
 
9.1. 
Declaration of Helsinki ......................................................................................................................... 34 
 
9.2. 
Good Clinical Practice ........................................................................................................................... 34 
 
9.3. 
Independent Ethics Committee/Institutional Review Board Approval ................................................. 35 
9.3.1. 
Initial approval............................................................................................................................. 35 
9.3.2. 
Approval of amendments ............................................................................................................ 35 
9.3.3. 
Annual safety reports and end of trial notification ..................................................................... 35 
 
9.4. 
Regulatory authority approval ............................................................................................................. 35 
 
9.5. 
Insurance .............................................................................................................................................. 35 
 
9.6. 
Informed consent ................................................................................................................................. 35 
 
9.7. 
Contact with General Practitioner........................................................................................................ 36 
 
9.8. 
Subject confidentiality .......................................................................................................................... 36 
 
9.9. 
Data protection .................................................................................................................................... 36 
 
9.10. 
End of trial ............................................................................................................................................ 36 
 
9.11. 
Study documentation and data storage............................................................................................... 36 
 
10. 
DATA AND STUDY MANAGEMENT ...................................................................................................37 
 
10.1. 
Source data .......................................................................................................................................... 37 
 
10.2. 
Language.............................................................................................................................................. 37 
 
10.3. 
Data collection ..................................................................................................................................... 37 
 
10.4. 
Electronic recording of data ................................................................................................................. 37 
 
10.5. 
Data management ............................................................................................................................... 37 
 
10.6. 
Study Management Structure .............................................................................................................. 37 
10.6.1. 
Trial Steering /Independent Data Monitoring Committee .......................................................... 37 
10.6.2. 
Trial Management Group ............................................................................................................ 38 
 
10.7. 
Monitoring ........................................................................................................................................... 38 
 
10.8. 
Quality Control and Quality Assurance ................................................................................................ 38 
 
10.9. 
Disclosure of data and publication ....................................................................................................... 38 
 
11. 
REFERENCES ....................................................................................................................................40 
 
12. 
SIGNATURE PAGES ..........................................................................................................................41 
 
13. 
APPENDICES ....................................................................................................................................45 


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LIST OF TABLES 
 
Table 1: 
Schedule of Assessments 
Table 2: 
Treatment Schedule 
Table 3: 
ECOG Performance Status 
Table 4: 
Volume of blood to be drawn from each patient 
Table 5: 
Dose reduction recommendations 
 
 
LIST OF FIGURES 
 
Figure 1: 
Study Flow Chart 
 
 
LIST OF APPENDICES 
 
Appendix A: 
Guidelines for Evaluation of Objective Tumour Response using RECIST v1.1 
(Response Evaluation Criteria in Solid Tumours) 


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 ABBREVIATIONS AND DEFINITION OF TERMS  
 
 
Abbreviation Explanation 
 
AE 
Adverse event 
AI 
ALT 
Aromatase Inhibitor 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under plasma concentration‐time curve 
CBR 
cfDNA 
Clinical Benefit Rate 
Circulating free deoxyribonucleic acid 
CI 
Chief investigator 
CNS 
CNV 
CR 
CRUK 
Central Nervous System 
Copy Number Variation 
Complete response (RECIST) 
Cancer Research UK 
CRF 
Case report form 
CSR 
Clinical study report 
CT 
Computerised tomography 
CTC 
Circulating tumour cell 
CTCAE 
Common Terminology Criteria for Averse Events 
CYP34A 
Cytochrome P34A 
DNA 
Deoxyribonucleic acid 
DTCs 
ECOG 
eCRF 
Disseminated Tumour Cells 
Eastern Cooperative Oncology Group 
Electronic Case Report Form 
EDC 
Electronic data capture 
ER+ve 
ECG 
Oestrogen Receptor Positive 
Electrocardiogram 
FFPE 
Formalin Fixed Paraffin Embedded 
HER2 
GMP 
Human Epidermal Growth Factor Receptor 2 
Good Manufacturing Practice 
IB 
Investigator Brochure 
ICH GCP 
ICHTB 
CCTS 
IEC 
IES 
IMP 
International Conference on Harmonisation – Good Clinical Practice 
Imperial College Healthcare NHS Tissue Bank 
Cancer Clinical Trials Section 
Independent Ethics Committee 
Intergroup Exemestane Study 
Investigational medicinal product 
IRB 
Institutional Review Board 
ITTS 
Intention to treat analysis set 
MBC 
MedDRA 
MHRA 
mL 
Metastatic Breast Cancer 
Medical Dictionary for Regulatory Activities 
Medicines and Healthcare products Regulatory Agency 
Millilitre 
mm 
Millimetre 
MRI 
Magnetic resonance imaging 
NCI‐CTCAE 
NE 
National Cancer Institute‐Common Terminology Criteria for Adverse Events 
Non‐evaluable (RECIST) 
NTL 
Non‐Target Lesion 
ORR 
Objective response rate 


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OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression Free Survival 
PR 
PgR 
Partial response 
Progesterone receptor 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease (RECIST) 
SNP 
SOP 
SPC 
SSPM 
Single Nucleotide Polymorphism 
Standard Operating Procedure 
Summary Product Characteristics 
Study Specific Procedure Manual 
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TL 
Target Lesion 
TMG 
TPC 
TSC 
ULN 
Trial Management Group 
Treatment of Physician’s Choice 
Trial Steering Committee 
Upper Limit of Normal 


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TRIAL SUMMARY 
 
 
Title: 
A phase II study of alternating eribulin and hormonal therapy in pre‐treated 
ER+ve breast cancer. 
Objectives: 
Primary: 
   To assess the efficacy of eribulin when prescribed in alternating cycles with 
an Aromatase Inhibitor (AI) based on progression free survival (PFS) 
Secondary: 
   To assess the efficacy of eribulin when prescribed in alternating cycles with 
an Aromatase Inhibitor (AI) based on clinical benefit rate (CBR) 
   To  assess  the  safety  and  tolerability  of  eribulin  when  prescribed  in 
alternating cycles with an AI 
Translational: 
   To observe whether circulating tumour cells (CTCs) and the tumour derived 
fraction of circulating free DNA (cfDNA) termed ctDNA, increase during 
hormonal therapy suggesting relapse off chemotherapy 
Endpoints: 
Primary: 
 
PFS rate at the following fixed time points: at 3, 6 and 9 months(as 
estimated by Kaplan‐Meier curve). 
Secondary: 
 
CBR  defined  as  the  proportion  of  patients  whose  best  overall 
response, according to RECIST v1.1 is either a complete response (CR), 
partial response (PR) or stable disease (SD) for at least 6 months. 
  Safety and tolerability as assessed by adverse events (AEs) and serious 
adverse events (SAEs) according to the Common Terminology Criteria for 
Adverse Events (NCI‐CTCAE v 4.03) 
Translational: 
   To measure alterations in CTCs and cfDNAs from baseline and at 9, 18 and 
36  weeks  after  start  of  treatment  and  associate  these  with  clinical 
outcomes 
Design: 
A single centre, single arm phase II study of alternating eribulin and hormonal 
therapy in 12 patients with locally advanced or metastatic breast cancer who 
have received at least one chemotherapy in the metastatic setting. 
Sample size: 
12 patients 
Main inclusion 
criteria: 
1.  Written informed consent prior to admission to this study 
2.  Aged 18≥over 
3.  Histologically confirmed ER+ve metastatic breast cancer according to local 
criteria 
4.  ECOG performance status 0 – 2 
5.  Have progressed after at least 
one chemotherapy regime for 
advanced/metastatic disease 


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6.  Patients must have had at least one prior line of chemotherapy treatment 
in the metastatic setting prior to enrollment in the study. 
7.  At least one measurable site of locally advanced and/or metastatic disease 
that can be accurately assessed by CT/MRI scan at baseline (RECIST v1.1)¹ 
8.  Life expectancy of ≥6 months 
9.  Adequate organ function 
10.  Postmenopausal as defined by age >50, no menstruation for >2 years, 
previous oophorectomy or lab results confirming this status 
11.  Premenopausal if has been subject to ovarian ablation/ suppression at 
least 3 weeks prior to commencing AI therapy² 
¹RECIST v1.1 updated and now considers bone metastasis with an identifiable 
soft tissue mass to be measurable disease. Therefore, patients with bone 
metastasis are eligible, provided they have evaluable disease. 
² A pregnancy test is required if patient is premenopausal and has been 
subject to ovarian ablation/ suppression at least 3 weeks prior to commencing 
AI therapy. 
Main exclusion 
criteria: 
1.  Triple negative or HER2 positive cancer 
2.  Hypersensitivity to the active substance or to any of its excipients 
3.  History of  another primary malignancy within 5  years prior to  starting 
study treatment, except adequately treated basal or squamous cell 
carcinoma of the skin, carcinoma in site and the disease under study 
4.  Evidence of uncontrolled active infection 
5.  Severe hepatic impairment (Child‐Pugh C) 
6.  Evidence of significant medical condition or laboratory finding which, in 
the opinion of the Investigator, makes it undesirable for the patient to 
participate in the trial 
7.  Concurrent therapy with any other investigational agent or everolimus 
8.  Concomitant  use  within  14  days  prior  to  commencement  of  study 
treatment of any investigational agent 
9.  Uncontrolled abnormalities of serum potassium, sodium, calcium 
(corrected) phosphate or magnesium levels 
10. Pregnant  or  lactating  women.  Effective  non‐hormonal contraception is 
mandatory for all patients of reproductive potential 
11. Evidence of ovarian activity 
12. Prior eribulin therapy 


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1. 
BACKGROUND AND RATIONALE 
 
1.1.    Breast Cancer 
 
Breast cancer is one of the most common causes of morbidity and mortality in women. In 2007, in 
the UK alone, 45,972 new cases were diagnosed with 12,047 deaths in 2008 (CRUK, 2010). Breast 
cancer mortality has been steadily decreasing over the last twenty years as a result of screening and 
improvements in treatment. The majority of breast cancer patients are diagnosed with early stage 
disease and treated with curative intent by surgery, followed by various combinations of adjuvant 
chemotherapy, radiotherapy, hormonal therapy and trastuzumab depending on tumoural expression 
of oestrogen receptor alpha (ERα), progesterone receptor (PgR) and HER2. Despite these 
improvements, approximately 6% of patients have metastatic disease at diagnosis and a further 30% 
of patients will suffer relapse and eventually die of their disease. While there has been improvement 
in the long term survival rate from metastatic breast cancer (MBC), it remains incurable and the 
current median overall survival remains approximately 24 months (Giordano, et al., 2004). The goals 
of treatment in MBC are to treat symptoms, improve quality of life and prolong survival. 
 
Over 70% of breast cancers are oestrogen receptor positive (ER+ve) and endocrine therapy is the 
treatment of choice, except in the presence of rapidly progressive visceral disease or where disease is 
known to be insensitive or resistant to endocrine therapy. Current endocrine therapy for 
postmenopausal  women  with  HER2  negative  breast  cancer  includes  tamoxifen,  anastrozole, 
letrozole, exemestane and fulvestrant. 
 
1.2.    Investigational Agent 
 
Eribulin (Halaven®) is a non‐taxane microtubule dynamics inhibitor.   Eribulin inhibits the growth 
phase of microtubules without affecting the shortening phase and sequesters tubulin into non‐ 
productive aggregates. Eribulin exerts its effects via a tubulin‐based antimitotic mechanism leading 
to G2/M cell‐cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after 
prolonged mitotic blockage. 
 
Eribulin is licenced for the treatment of patients with locally advanced or metastatic breast cancer 
who have previously received at least one chemotherapeutic regimen for the treatment of advanced 
disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or 
metastatic setting unless patients were not suitable for these treatments. 
 
1.3.    Clinical Studies 
 
The efficacy of eribulin in breast cancer is primarily supported by two randomised phase 3 trials. 
 
In the EMBRACE study (NCT00388726) 762 women with locally recurrent or metastatic breast cancer 
were randomly allocated to treatment groups (508 eribulin, 254 treatment of physician’s choice 
(TPC)). Overall survival was significantly improved in women assigned to eribulin (median 13.1 
months, 95% CI 11∙8–14∙3) compared with TPC (10.6 months, 9∙3–12∙5; hazard ratio 0∙81, 95% CI 
0∙66–0∙99; p=0∙041). The most common adverse events in both groups were asthenia or fatigue (270 
[54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia 
(260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral 
neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring 
in 24 (5%) of 503 patients (Cortes , et al., 2011; Twelves, et al., 2010). 


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In the second study (NCT00337103) 1102 women with locally advanced or metastatic breast cancer 
were randomised to receive either eribulin monotherapy or capecitabine monotherapy. The primary 
analysis for OS was based on 905 (82%) events or deaths in the trial. The median OS among patients 
receiving Eribulin was 15.9 months and 14.5 months in the capecitabine group. The hazard ratio (HR) 
for  OS  (Eribulin vs  Capecitabine) was  0.879 (95% CI,  0.770 to  1.003), and  a  p‐value of  0.0560 
(Kaufman PA, et al., 2012). Progression free survival was similar between eribulin and capecitabine 
with medians of 4.1 months vs 4.2 months (HR 1.08; [95% CI: 0.932, 1.250]) respectively.  Objective 
response rate was also similar between eribulin and capecitabine; 11.0% (95% CI: 8.5, 13.9) in the 
eribulin group and 11.5% (95% CI: 8.9, 14.5) in the capecitabine group (Twelves, et al., 2010). 
 
Eribulin is a standard of care in many women with advanced breast cancer. 
 
1.4.    Aromatase Inhibitors (AI) 
 
In contrast to premenopausal women, in whom most of the oestrogen is produced in the ovaries, in 
postmenopausal women oestrogen is mainly produced in peripheral tissues of the body. Because 
some breast cancers respond to oestrogen, lowering oestrogen production at the site of the cancer 
(i.e. the adipose tissue of the breast) with aromatase inhibitors has been proven to be an effective 
treatment for hormone‐sensitive breast cancer in postmenopausal women. We have performed 
many of the large studies of aromatase inhibitors, such as the IES trial, at Charing Cross Hospital and 
Imperial College, London. 
 
Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts 
androgens into oestrogens by a process called aromatization. As oestrogen receptor positive breast 
cancers are stimulated by oestrogens, decreasing their production is a way of suppressing recurrence 
of the breast tumour tissue. The main source of oestrogen is the ovaries in premenopausal women, 
while in post‐menopausal women most of the body's oestrogen is produced in peripheral tissues 
(outside the CNS), and also a few CNS sites in various regions within the brain. 
 
The recent past has witnessed the appearance of substantial data relating to endocrine therapy of 
breast cancer. In the adjuvant therapy setting in early breast cancer, several large, well‐conducted, 
randomized, double‐blind clinical trials have provided evidence for the value of the third‐generation 
aromatase inhibitors (AI) anastrozole, exemestane, and letrozole in postmenopausal women. The 
three major studies to date [i.e., Arimidex, tamoxifen alone, or in combination (ATAC), Intergroup 
Exemestane Study (IES), and letrozole after 5 years of tamoxifen (MA.17)] evaluated three different 
populations of women from the standpoints of duration of prior tamoxifen and thus time since the 
treatment of the primary breast cancer. A consistent pattern of improvement in disease‐free survival 
was seen whether the control arm was tamoxifen (ATAC and IES) or placebo following tamoxifen 
(MA.17). From a toxicity standpoint, the major findings with the AIs were a decreased incidence of 
thromboembolic events and endometrial cancers but an increase in musculoskeletal complaints and 
potential for decreasing bone density. 
 
1.5.    Rationale 
 
The aim of this study is to alternate eribulin and aromatase inhibitors, examining whether there may 
be breakthrough relapse during the AI therapy or on the other hand we can extend the duration that 
eribulin may be used for. Importantly, blood based biomarkers, the tumour derived fraction of cfDNA 
(ctDNA), and circulating tumour cells will be measured. A major aim of this study is to test whether 
biomarkers fluctuate between chemotherapy and AI treatment in the setting of advanced breast 
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1.5.1.            Biomarkers 
 
The hypothesis to be tested is that specific circulating biomarkers whether circulating free DNA 
(cfDNA) or in circulating tumour cells (CTCs) can facilitate the earlier detection of breast cancer 
potentially improving management. The aim is to demonstrate that a circulating phenotype is an 
important prognostic and predictive factor for relevant clinical outcomes in breast cancer. 
 
1.5.1.1. 
Circulating tumour cells 
 
Several  groups,  including  our  own,  have  reported  that  measuring  CTCs  by  the  widely  used 
CellSearch® method and DTCs in bone marrow can help in cancer prognosis and follow‐up (Bidard, et 
al., 2014). Here, we wish to address whether circulating markers have the potential to: (a) predict 
breast cancer outcome; (b) predict response to therapies; (c) predict relapse; and (d) detect small 
changes that have clinical consequences. 
 
Patient benefit would also be achieved if our non‐invasive test(s) predict disease progression at a 
time when additional therapy can be given with potential life‐prolonging intent, or to decide who 
would benefit from a change in therapy. Once validated in breast cancer, the markers could be 
applied to other cancers that are distinguished by resectable primary cancers and micrometastases, 
such as colorectal cancer. 
 
Studies of CTCs have generally recruited individuals with newly diagnosed metastatic cancer, with 
recent data also indicating their prognostic value in the adjuvant setting. Their role in advanced 
patients has not been established so at Imperial, CTCs were measured in 43 individuals with 
metastatic breast cancer estimated to have less than 6 months to live who had exhausted standard 
therapeutic options. Remarkably, those with a CTC count of ≤100 had a median of 182 days to live, 
compared with those with a CTC count of >100 who had a median of 17 days until death (p = 0.009, 
Log Rank, HR 3.1, 95% CI 1.4‐7.3). We thus found that a CTC count of >100 is associated with 
imminent death (Stebbing, et al., 2014). Provided external validity is demonstrated, such information 
would be useful for patients and their families who often request specific prognostic clarity and could 
improve the quality of end‐of‐life care. 
 
 
1.5.1.2. 
Circulating free DNA (CfDNA) 
 
CfDNA was first described over 60 years ago. Elevated levels of cfDNA are seen in cancer in part due 
to reduced DNase activity. Elevated levels of cfDNA in plasma were suggested for the diagnosis of 
breast  cancers  and  qualitative  tests  showed  increased  cfDNA  integrity/size  in  breast  cancers. 
However elevated levels of cfDNA are sometimes seen in benign breast disease; therefore levels of 
cfDNA are not tumour specific markers. Specific patterns in cfDNA (e.g. mutations, loss of 
heterozygozity, hypermethylation) have the potential to provide tumour specific markers and have 
been more widely investigated. These and other studies highlight the potential of cfDNA as a 
circulating biomarker in cancer. In our first study using just 2 circulating markers we showed that 
cfDNA was more sensitive than either CTCs or disseminated tumour cells (DTCs) for detecting 
evidence of minimal residual disease in primary breast cancer patients (Shaw, et al., 2000). We then 
demonstrated amplified HER2 in cfDNA up to 10 years after treatment in asymptomatic patients, 
suggesting persistent micrometastases and a dormant state and confirmed persistence of ctDNA 
using whole genome approaches (Shaw, et al., 2012). 
 
We were the first group to assay the whole genome in cfDNA isolated from breast cancer patients 
using Affymetrix® SNP 6.0 Array, which features single nucleotide polymorphism (SNP) and non‐ 


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polymorphic probes for detection of copy number variation (CNV). These CNVs are amplified or 
deleted regions of the genome, which are recognised as a major source of normal human genome 
variability and contribute significantly to phenotypic variation. Our cfDNA results from 65 patients 
highlight several novel findings of importance for patients with breast cancer. Firstly, we were able to 
distinguish between patients with primary breast cancer and healthy female controls (p < 0.0001) 
and between pre‐operative breast cancer patients and patients on follow‐up after surgery and 
treatment (p = 0.002) by concordance of SNP genotype calls. Principal component analysis of SNP 
and copy number results also separated cfDNA of  pre‐surgical breast cancer patients from the 
healthy controls suggesting that the disease status is reflected within these profiles. Secondly, results 
from 50 patients on follow‐up were striking, and demonstrate for the first time that some tumour‐ 
specific CNVs remain detectable in cfDNA a decade after treatment and during clinical remission. 
About one third of cfDNAs had a “normal” cfDNA profile as would be expected if these patients are 
cured. However, the remainder showed persistence of tumour associated CNVs, again suggesting 
persistent micrometastases and a dormant state (Shaw, et al., 2011). 
 
Recent parallel sequencing data also indicate that the cancer genome can change with the evolution 
of metastatic disease. In support of this, our data shows that plasma cfDNA evolves in time and both 
the frequency and the nature of these changes are indicative of breast cancer evolution: We saw 
evidence of changes in CNVs detected between paired plasma samples (taken a mean of 6.1 and 9 
years after surgery) notably in 8 patients who relapsed. These CNVs were absent in the matched 
normal leucocyte DNA samples and in cfDNA of healthy controls: this suggests the existence of 
cancer markers that are long lasting and a better sensitivity of cfDNA. This is one study in which we 
wish to understand the role of these molecules better. The study strengthens the established 
collaboration between the Cancer Research UK Centres at Leicester and Imperial College. 
 
1.6.    Risk / Benefit Assessment 
 
1.6.1.            Potential Benefits 
 
Eribulin and AIs are known to be effective and safe in this patient population, and it is believed that 
alternating eribulin therapy with an AI may increase duration of response seen when the 2 agents are 
used sequentially and that exposure to chemotherapy may cause re‐sensitization of cancers to 
endocrine therapy previously thought to have become ineffective . 
 
1.6.2.            Potential Risks 
 
Common side effects (≥1/10) of eribulin are standard chemotherapy toxicities such as: 
 
 
Bone 
marrow 
suppression 
manifested 
as 
neutropenia, 
leukopenia, 
anaemia, 
thrombocytopenia with associated infections 
 
 
New onset or worsening of pre‐existing peripheral neuropathy 
 
 
Gastrointestinal toxicities manifested as anorexia, nausea, vomiting, diarrhoea, constipation 
and stomatitis 
 
 
Fatigue, alopecia, increased liver enzymes, sepsis and musculoskeletal pain syndrome 
 
AIs can cause arthralgias and osteoporosis. 
 
1.6.3.            Overall benefit‐risk assessment 
 
In the advanced cancer setting that has been chosen for this study, prolonged survival rates are very 
low and there is a large unmet clinical need for controlling disease progression, indeed in some 
cases, palliative treatment may be the best that can be offered. 


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Although there can be no certainty of clinical benefit to patients the non‐clinical and clinical safety 
profile of eribulin has not identified any risks that would preclude investigation in this setting.  Thus 
the risk‐benefit assessment for this study supports the inclusion of patients with advanced cancer, 
according to the proposed study design. 
 
2.       STUDY OBJECTIVES AND ENDPOINTS 
 
2.1. Primary objective and endpoint 
 
Objective 
Endpoint 
To    assess    the    efficacy    of    eribulin    when 
prescribed 
in 
alternating 
cycles 
with 
an 
Aromatase Inhibitor (AI) based on progression 
free survival (PFS). 
• PFS rate at the following fixed time points: at 
3, 6 and 9 months(as estimated by Kaplan‐Meier 
curve). 
 
 
2.2. Secondary objectives and endpoints 
 
Objective 
Endpoint 
To    assess    the    efficacy    of    eribulin    when 
prescribed 
in 
alternating 
cycles 
with 
an 
Aromatase Inhibitor (AI) based on clinical benefit 
rate (CBR). 
CBR defined as the proportion of patients whose 
best overall response, according to RECIST v1.1, 
is either a complete response (CR), partial 
response (PR) or stable disease (SD) for at least 6 
months. 
To assess the safety and tolerability of eribulin 
when prescribed in alternating cycles with an AI. 
Safety and  tolerability as  assessed by  adverse 
events (AEs) and serious adverse events (SAEs) 
according to the Common Terminology Criteria 
for Adverse Events (NCI‐CTCAE v 4.03). 
 
 
2.3. Translational objectives and endpoints 
 
Objective 
Endpoint 
To  observe  whether  circulating  tumour  cells 
(CTCs) and circulating free DNA (cfDNA) levels 
increase during hormonal therapy suggesting 
relapse off chemotherapy. 
To measure alterations in CTC and cfDNA levels 
from baseline and at 9, 18 and 36 weeks after 
start of treatment, and associate these with 
clinical outcomes. 
 
 
 
3. 
STUDY DESIGN 
 
3.1.    Overall study design 
 
This is a single centre, single arm phase II study of alternating eribulin and hormonal therapy in 12 
patients with locally advanced or metastatic breast cancer who have received at least one 
chemotherapy in the metastatic setting. 
 
3.2.    Treatment regimens 
 
12 patients with locally advanced or metastatic breast cancer who have received at least one 
chemotherapy in the metastatic setting will be enrolled to receive treatment as per Figure 1. 


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Figure 1: Study Flow Chart 
 
ER+ve metastatic or locally advanced breast cancer patients 
who have received at least one chemotherapy in the 
metastatic setting 
 
 
 
 
Consent and On Study Screening 
n = 12 
 
 
 
 
 
Alternating eribulin and AI treatment for up to 9 months, 
until disease progression or unacceptable toxicities ‐ 
whichever is sooner 
 
 
 
 
 
Safety Follow‐up visit 4 weeks after completing treatment 
 
 
3.3.    Follow‐up 
 
Patients will be followed up as described in Table 1 with an end of study safety visit 4 weeks after 
completion of study treatment. 
 
3.4.    Study termination 
 
The study will be terminated when all patients on study treatment have permanently discontinued 
study medication due to progression or unacceptable toxicities and have completed their 4 week 
safety follow‐up visit. 
 
3.4.1.            Treatment after study termination 
 
Following participation in the study, patient care will be decided by their local doctor according to 
usual practice. 
 
 
 
4.       PATIENT SELECTION AND RECRUITMENT 
 
4.1.    Screening and enrolment 
 
Each patient will undergo screening assessment to confirm eligibility. Tumour assessments and other 
clinical data obtained as standard of care prior to consent may be used for the study provided they 
comply with the protocol specified timelines. Written informed consent will be obtained before the 
subject undergoes any study specific procedures. 
 
Each potential patient will be assigned a  unique identifier number for  use during the  trial.    A 
complete record of all patients who enter screening for the study, and also those who go on to be 
enrolled, must be maintained at each site. The local investigator is responsible for ensuring that this 


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record includes the allocated trial ID as well as the patient identifiable data including name, hospital 
number and date of birth. 
 
Eligible patients who take part in the study must meet all of the listed inclusion criteria and none of 
the exclusion criteria. 
 
4.2. Subject Selection 
 
4.2.1. 
Inclusion Criteria 
 
Patients who meet all of the following inclusion criteria will be considered eligible for this study: 
1.   Written informed consent prior to admission to this study 
2.   Aged 18≥over 
3.   Histologically confirmed ER positive metastatic breast cancer according to local criteria. 
4.   ECOG performance status 0 – 2 
5.   Have progressed after at least one chemotherapy regime for advanced/metastatic disease 
6.   Patients must have had at least one prior line of chemotherapy treatment in the metastatic 
setting prior to enrollment in the study. 
7.   At least one measurable site of locally advanced and/or metastatic disease that can be 
accurately assessed by CT/MRI scan at baseline (RECIST v1.1)¹ 
8.   Life expectancy of ≥6 months 
9.   Adequate organ function, as defined by: 
 
Haemoglobin (Hb) ≥ 9 g/dL 
 
Absolute Neutrophil Count (ANC) 1.5 10⁹/L 
 
Platelet count (Plts) 100 10⁹/L 
 
White Blood Cell (WBC) ≥ 3.0 x 10⁹/L 
 
Serum albumin ≤ 1.5 ULN 
 
Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 x ULN if 
no demonstrable liver metastases or ≤ 5 x ULN in the presence of liver metastases. 
 
ALP ≤ 5 x ULN 
 
Total bilirubin ≤ 1.5 x ULN if no demonstrable liver metastases or ≤ 3 x ULN in the 
presence of liver metastases 
 
Creatinine ≤ 1.5 x ULN or creatinine clearance >50ml/min 
10. Postmenopausal   as   defined   by   age   >50,   no   menstruation   for   >2   years,   previous 
oophorectomy or lab results confirming this status 
11. Premenopausal if has been subject to ovarian ablation/ suppression at least 3 weeks prior to 
commencing AI therapy² 
¹ RECIST v1.1 updated and now considers bone metastasis with an identifiable soft tissue mass 
to be measurable disease. Therefore, patients with bone metastasis are eligible, provided they 
have evaluable disease. 
² A pregnancy test is required if patient is premenopausal and has been subject to ovarian 
ablation/ suppression at least 3 weeks prior to commencing AI therapy. 
 
 
4.2.2. 
Exclusion criteria 
 
Patients who meet any of the following exclusion criteria will not be considered eligible for this 
study: 
1.   Triple negative or HER2 positive cancer 
2.   Hypersensitivity to the active substance or to any of its excipients 


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3.   History of another primary malignancy within 5 years prior to starting study treatment, 
except adequately treated basal or squamous cell carcinoma of the skin, carcinoma in site 
and the disease under study 
4.   Evidence of uncontrolled active infection 
5.   Severe hepatic impairment (Child‐Pugh C) 
6.   Evidence of significant medical condition or laboratory finding which, in the opinion of the 
Investigator, makes it undesirable for the patient to participate in the trial 
7.   Concurrent therapy with any other investigational agent or everolimus 
8.  Concomitant use within 14 days prior to commencement of study treatment of any 
investigational agent 
9.   Uncontrolled abnormalities of serum potassium, sodium, calcium (corrected) phosphate or 
magnesium levels 
10. Pregnant or lactating women. Effective non‐hormonal contraception is mandatory for all 
patients of reproductive potential 
11. Evidence of ovarian activity 
12. Prior eribulin therapy 
 
 
 
 
5.       STUDY PLAN AND PROCEDURES 
 
5.1.    Study schedule 
 
After signing written informed consent, patients will undergo a 28 day screening period.    Once 
confirmed as eligible, patients will remain on treatment for up to nine months or until disease 
progression, unacceptable toxicities or patient choice, whichever is sooner.  While receiving study 
treatment patients will be reviewed at the time‐points scheduled in Table 1.  A +/- 1 week window is 
permitted for the scheduled week 18 study assessments visit. Patients will attend an end of study 
safety visit 4 weeks after completing study treatment.  For assessment details see Table 1. 


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Table 1: Schedule of Assessments 
Time‐point → 
Assessment ↓ 
Screening 
Treatment 
FU 
‐4 to 0 weeks 
1 week 
9 weeks 
12 weeks 
(Month 3) 
18 weeks10 
24 weeks 
(Month 6) 
27 weeks 
36 weeks 
(Month 9) 
End of 
Treatment5 
Safety FU6 
Informed Consent 
X 
Eligibility checklist 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test9 
X 
Haematology2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
Tumour Evaluation (RECIST v1.1) 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Sample CTC 
X 
X 
X 
X 
X 
Blood Sample cfDNA 
X 
X 
X 
X 
X 
Start of Eribulin 3x3 weekly 
Cycles4 
X 
X 
AI Dispensing4 
X 
X 
AI Accountability 
X 
X 
X 
Primary Tumour Sample 
X 
Biopsy of Recurrent Disease 
X7 
X8 
 
1. Vital signs include weight, pulse and blood pressure 
2. Haematology: Haemoglobin, Leukocyte, Neutrophils, Lymphocytes, Platelets 
3. Biochemistry: ALT, AST, Alkaline phosphatase, Bilirubin (total), Calcium (total), Creatinine (total), Random glucose, Magnesium, Phosphate, Potassium, Sodium, Urea nitrogen, 
serum albumin 
4. Refer to Table 2 for details on treatment administration 
 
 
 


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5. Treatment will continue until the 36 week/month 9 visit unless patients permanently discontinue from treatment at an earlier or unscheduled visit. This visit would then be 
treated as an End of Treatment visit, and the discontinuation scheduled assessments will be performed. 
6. The safety follow‐up visit should occur 4 weeks after the last dose of study treatment. 
7. This procedure is optional. 
8. This procedure is optional, and upon disease progression. 
9.   Pregnancy  test  is  required  if  patient  is  premenopausal  and  has  been  subject  to  ovarian  ablation/  suppression  at  least  3  weeks  prior  to  commencing  AI  therapy. 
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Table 2: Treatment Schedule 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Treatment 
Eribulin cycle 
11 
Eribulin cycle 
21 
Eribulin cycle 
31 
AI treatment2 
Week 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Treatment 
Eribulin cycle 
41 
Eribulin cycle 
51 
Eribulin cycle 
61 
AI treatment2 
 
1.  3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution is 1.23 mg/m2 
(equivalent to 1.4 mg/m2 eribulin mesilate), administered intravenously over 2‐5 minutes on days 1 and 
8 of every 21‐day cycle. 
2.  Type of AI to be prescribed at the clinician’s discretion. 
 
5.2.    Procedures and measurements 
 
5.2.1.            Demographic data and medical history 
 
Demographic data and other characteristics will be recorded and will include date of birth, 
race/ethnicity, height, weight and smoking history. A standard medical history will be obtained 
including details of previous and current medication, surgical history and tumour characteristics. 
 
5.2.2.            Physical examination and performance status 
 
A complete physical examination will be performed, as per local practice at the scheduled visits 
indicated in Table 1.  The following examinations should be undertaken: general appearance, skin, 
head and neck, lymph nodes, thyroid, musculoskeletal/extremities, cardiovascular, respiratory, 
abdomen and neurological.   The outcome of the examinations will be assessed as normal or 
abnormal, and whether clinically significant. 
 
5.2.3.            ECOG Performance Status 
 
Performance status will be assessed at the scheduled visits indicated in Table 1 according to ECOG 
criteria as follows: 
 
Table 3: ECOG Performance Status 
0 
Fully active, able to carry on all pre‐disease activities without restriction 
1 
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 
2 
Ambulatory and capable of all self‐care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self‐care, confined to bed or chair 50% or more of waking hours 
4 
Completely disabled. Cannot carry on any self‐care. Totally confined to bed or chair 
5 
Death 
 
 
5.2.4.            Vital signs 
 
Vital signs including weight, pulse and blood pressure will be measured at the scheduled visits 
indicated in Table 1.  Vital signs may be assessed at any time during the visit; however, supine blood 
pressure and pulse should be measured after 10 minutes rest. Height will be measured at initial 
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5.2.5.            ECG 
 
A 12‐lead ECG will be performed at the scheduled visits indicated in Table 1. A standardised ECG 
machine should be used and where possible, the patient should be examined with the same machine 
throughout the study. Details of rhythm, ECG intervals and an overall evaluation will be collected 
 
5.2.6.            Laboratory Evaluations 
 
5.2.6.1. 
Routine Evaluations 
 
Blood samples for haematology and clinical chemistry will be taken at scheduled visits and analysed 
at the local laboratory using standard methods for routine tests. 
 
The following variables will be measured: 
 
 
Clinical   Chemistry:  ALT,   AST,   Alkaline   phosphatase,  Bilirubin   (total),   Calcium   (total), 
Creatinine (total), Random glucose, Magnesium, Phosphate, Potassium, Sodium, Urea 
nitrogen, Serum Albumin 
 
Haematology: Haemoglobin, Leukocyte, Neutrophils, Lymphocytes, Platelets 
 
Laboratory values that have changed significantly from baseline and are considered to be of clinical 
concern must be recorded as an adverse event and followed up as appropriate. 
 
5.2.6.2. 
Circulating Tumour Cells (CTC) 
 
10ml peripheral blood, will be collected into CellSave tubes, and sent to the central lab (room 
temperature, in a padded envelope) for analysis using CellSearch® within 72 hours of blood sampling. 
Please refer to the Site Laboratory Manual for comprehensive instructions. 
 
 
 
5.2.6.3. 
Circulating free DNA (cfDNA) 
 
20ml venous blood samples will be collected in EDTA tubes centrifuged within 2 hours of collection at 
1000g for 10 min, and plasma will be taken from the upper phase and decanted into fresh 
polypropylene  tubes.  Tubes  will  then  be  spun  again  at  2000g  to  remove  any  contaminating 
leucocytes, and the resulting supernatant will be aliquoted into sterile tubes and stored at −80 °C. 
Plasma samples will be allowed to thaw to room temperature and will be re‐spun in a bench‐top 
centrifuge to remove any remaining cell debris. Please refer to the Site Laboratory Manual for 
comprehensive instructions. 
 
5.2.7.            Tumour assessments 
 
Tumour assessments will be performed using CT or MRI scans of the chest, abdomen and pelvis; the 
same method used for assessment at baseline must then be used at all subsequent time points. 
RECIST v1.1 criteria will be used to assess patient response to treatment by determining tumour size, 
PFS and ORR. The RECIST v1.1 (January 2009) guidelines for measurable, non‐measurable, target and 
non‐target lesions and the objective tumour response criteria (complete response, partial response, 
stable disease or progression of disease) are detailed in Appendix 1. 
 
Baseline assessment should be performed no more than 28 days before the start of study treatment 
and ideally as close as possible to the start of study treatment; it should include all areas known for 
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5.2.8.            Treatment Compliance (Patient Diary) 
 
Patients will keep a detailed record of all study medication that they take at home (i.e. AI treatment) 
in their patient diaries. Date and time of administration, drug name and drug dose will be collected. 
 
5.2.9.            Concomitant Medications 
 
All medications, with the exception of prohibited medications, that are being taken during screening 
and those taken whilst on study will be documented as a concomitant medication. The following 
details  will  be  collected: drug  name,  reason for  therapy, therapy  dosage  /  units,  frequency of 
therapy, route of administration, start and end date of therapy 
 
5.3.    Exploratory Research 
 
5.3.1.            Exploratory biomarker research 
 
Biological samples e.g. archived and study‐specific tumour samples will be collected and may be 
analysed for exploratory biomarkers to investigate possible relationships with disease status, efficacy 
of study drug and outcome. These results may be reported separately from the clinical study report 
(CSR). 
 
5.3.1.1. 
Collection of archival tumour tissue samples 
 
Where available, an archival tissue sample (either from the diagnostic tumour or a metastatic site) in 
the form of formalin fixed paraffin embedded (FFPE) tumour block will be collected for each patient. 
If it is not possible to obtain the tumour block, 10‐20 slides of freshly prepared unstained 5 micron 
sections may be provided instead. 
 
Further details on sample processing, handling and shipment are provided in the Study Manual. 
 
Archival tumour blocks will be returned to source at the end of the study or, upon request, earlier if 
required. 
 
5.3.1.2. 
Collection of paired tumour biopsies 
 
This part of the study is optional. Where patients consent to take part, tumour biopsies should be 
collected. The date and time of collection will be recorded on the case report form (CRF). 
 
These samples are classified as research samples and will be registered with the Imperial College 
Healthcare NHS Tissue Bank (ICHTB). 
 
Further details on sample processing, handling and shipment are provided in the Study Manual. 
 
5.3.2.            Chain of custody of biological samples 
 
In all cases, patients will be consented for the collection and use of their biological samples and a full 
chain of custody will be maintained for all samples throughout their lifecycle. 
 
The investigator at each site is responsible for maintaining a record of full traceability of biological 
samples collected from patients while these are in storage at the site, either until shipment or 
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Any sample receiver e.g. sub‐contracted service provider keeps full traceability of samples from 
receipt of arrival to further shipment or disposal (as appropriate). 
 
Imperial College keeps overall oversight of the entire lifecycle through internal procedures and 
monitoring of study sites 
 
Samples retained for further use will be registered with the Imperial College Healthcare NHS Tissue 
Bank (ICHTB). 
 
5.4.    Total Blood Volumes 
 
The total volume of blood that will be drawn from each patient in this study is shown in Table 4. The 
number of samples taken, and the volume required for analysis, may change during the course of the 
study as new data becomes available. 
Table 4: Volume of blood to be drawn from each patient 
Sample volume (mL) 
Number of samples 
Total volume (mL) 
Clinical chemistry 1 
8 
103 
80 
Haematology 1 
6 
103 
60 
CTC 
10 
53 
50 
cfDNA 
20 
53 
100 
Total 
2902 
1 exact volume of blood for clinical chemistry and haematology may vary depending on local practice 
2 this represents the maximum amount of blood that could be drawn during the trial. The actual amount drawn from each 
patient will depend on the duration the patient remains on treatment for. 
3 this represents the maximum number of samples, as end of treatment visit may coincide with one of the other scheduled 
visits. 
 
 
6. 
STUDY TREATMENT 
 
 
Trial treatment must begin within 1 week of the patient being enrolled into the study. Trial patients 
will be administered alternating regimes of 3 x 3 weekly cycles of intravenous eribulin over 2‐5 
minutes on days 1 and 8 of every 21 day cycle, followed by 9 weeks of AI treatment, followed again 
by 3 x 3 weekly cycles of eribulin and 9 weeks of an AI. 
 
6.1.    Non Investigational Medicinal Products 
 
AI treatment (exemestane, anastrazole or letrozole) will be dispensed from site specific hospital 
stock. Compliance to these treatments will be recorded using Patient Diary cards and all data 
transferred to the eCRFs. 
 
6.2.    Investigational Medicinal Product Details 
 
Eribulin (Halaven®) is manufactured by NerPharma according to Good Manufacturing Practice.  The 
Investigational product is provided to sites, free of charge, by Eisai Ltd. as 2mL vials for injection. 
 
In the EU, Eribulin is licenced for the treatment of patients with locally advanced or metastatic breast 
cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. 
Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic 
setting unless patients were not suitable for these treatments. It will be used outside of its marketing 
authorisation in this study as it will be administered alternately with AI treatment, and patients will 
not require prior anthracycline or taxane. 


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6.2.1.            Supply, packaging and labelling 
 
Eribulin (Halaven®) will be packaged and labelled by Catalent (UK) and distributed to sites by Catalent 
(UK). Labels will be prepared in accordance with Good Manufacturing Practice Annexe 13 
requirements and local regulatory guidelines. Eribulin will only be dispatched to sites after receipt of 
confirmation that the regulatory checklist is complete. 
 
6.2.2.            Storage and Dispensing 
 
The investigational products must be stored in a secure area with access limited to the Investigator 
and authorised site staff. Maintenance of a temperature log (manual or automated) is required. For 
further information investigators should refer to the investigator brochure. 
 
The investigational product should only be dispensed and administered as directed in the protocol, 
and only by site staff authorised to do so i.e. pharmacist / trials technician. Only subjects enrolled in 
the trial may receive investigational product. 
 
6.2.3.            Dosage and Duration 
 
The recommended dose of eribulin as the ready to use solution is 1.23 mg/m2  (equivalent to 1.4 
mg/m2  eribulin mesilate). The recommended dose of eribulin in patients with mild hepatic 
impairment (Child‐Pugh A) is 0.97 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 
and 8 of a 21‐day cycle. The recommended dose of eribulin in patients with moderate hepatic 
impairment (Child‐Pugh B) is 0.62 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 
and 8 of a 21‐day cycle. 
 
Eribulin will be administered in 3x3 weekly cycles starting at week 1 and at week 18, intravenously 
over 2‐5 minutes on days 1 and 8 of every 21‐day cycle. 
 
Eribulin should be administered in units specialised in the administration of cytotoxic chemotherapy 
and  only  under  the  supervision of  a  qualified physician experienced in  the  appropriate use  of 
cytotoxic medicinal products. 
 
6.2.4.            Dose Modifications for Eribulin 
 
6.2.4.1. 
Dose delays 
 
The administration of eribulin should be delayed, until resolved, for up to one month on Day 1 or Day 
8 for any of the following: 
 
Absolute neutrophil count (ANC) < 1 x 109/l 
 
Platelets < 75 x 109/l 
 
Grade 3 or 4 non‐haematological toxicities. 
 
6.2.4.2. 
Dose reductions 
 
Dose reduction recommendations for retreatment are shown in the following table.   Do not re‐ 
escalate the eribulin dose after it has been reduced. 
 
Table 5: Dose reduction recommendations 
Adverse reaction after previous eribulin administration  
 Recommended dose of eribulin   
Haematological: 
ANC < 0.5 x 109/l lasting more than 7 days 
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ANC < 1 x 109/l neutropenia complicated by fever or infection 
Platelets < 25 x 109/l thrombocytopenia 
Platelets < 50 x 109/l thrombocytopenia complicated by haemorrhage or 
requiring blood or platelet transfusion 
Non‐haematological: 
Any Grade 3 or 4 in the previous cycle 
0.97 mg/m2 
Recurrence of any haematological or non‐haematological adverse reactions as specified above 
Despite reduction to 0.97 mg/m2 
0.62 mg/m2 
Despite reduction to 0.62 mg/m2 
Discontinuation 
 
6.2.5.            Accountability 
Accountability for the study drug at the study site is the responsibility of the investigator. This 
responsibility may be delegated to the pharmacist, or another appropriate person. The investigator 
will ensure that the study drug is used only in accordance with this protocol. Unused eribulin may 
not be used for any purpose other than that outlined in the protocol. 
 
Drug accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each patient, and disposal of the drug will be maintained by the clinical site. Accountability records 
will include dates, quantities, batch/serial numbers, expiration dates (if applicable) and patient 
numbers. 
 
All used, unused or expired study drug will disposed of at the study site and documented following 
authorisation by the Sponsor. 
 
6.2.6.            Drug interactions/Precautions 
 
6.2.6.1. 
Restrictions 
 
The following restrictions apply while the patient is receiving study treatment and for the 10 days 
before and after: 
 
Everolimus or any other mTOR inhibitor 
 
The following should be administered with caution: 
 
Substances  which  are  inhibitors  of  hepatic  transport  proteins  such  as  organic  anion‐ 
transporting proteins (OATPS) and multidrug resistant proteins (MRPs) etc. concomitantly 
with eribulin. Inhibitors of such transporters include but are not limited to: cyclosporine, 
ritonavir, saquinavir, lopinavir and certain other protease inhibitors, efavirenz, emtricitabine, 
quinine, quinidine, disopyramide. 
 
Concomitant treatment with  inducing substances, such as  carbamazepine, phenytoin, St 
John´s wort (Hypericum perforatum) could give rise to reduced plasma concentrations of 
eribulin, and co‐administration with inducers should be carried out with caution considering 
a potential risk for reduced drug efficacy. 
 
No marked effects on eribulin exposure (AUC and Cmax) were observed during treatment with 
the CYP3A4 inducer rifampicin. However, rifampicin may due to its transporter inhibitory 
property counteract its possible inducing effect on eribulin elimination. Therefore, the effect 
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 
In vitro data indicate that eribulin is a mild inhibitor of the important drug metabolising 
enzyme CYP3A4. No in vivo data are available. Caution and monitoring for adverse effects is 
recommended with concomitant use of substances that have a narrow therapeutic window 
and that are eliminated mainly via CYP3A4‐medicated metabolism (e.g. alfentanil, 
cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus). 
 
Eribulin may cause adverse reactions such as tiredness and dizziness which may lead to a minor or 
moderate influence on the ability to drive or use machines. Patients should be advised not to drive or 
use machines if they feel tired or dizzy. 
 
6.2.6.2. 
Concomitant treatments 
 
Antiemetic prophylaxis including corticosteroids may be administered whilst patients are receiving 
eribulin, as per local policy. 
 
Information on any treatment in the 4 weeks prior to starting study treatment and all concomitant 
treatments given during the study, with reasons for the treatment, will be recorded in the CRF. 
 
6.2.7.            Overdose of IMP 
 
There is no known antidote for eribulin overdose. In the event of an overdose, the patient should be 
closely monitored.   Management of overdose should include supportive medical interventions to 
treat the presenting clinical manifestations.  If an overdose of eribulin occurs in the course of the 
study, then Investigators or other site personnel should inform the Sponsor within one day i.e. 
immediately and no later than the end of the next business day of when he or she becomes aware of 
it.   For overdoses associated with a SAE, standard reporting timelines apply. For other overdoses, 
reporting should be done within 30 days. 
 
For treatment of overdose with AI please refer to the local prescribing information.  Overdose of AI 
with associated AEs / SAEs should be recorded in the relevant AE / SAE module of the eCRF and 
reported according to the standard timelines. 
 
6.3.    Permanent discontinuation of study medication and withdrawal from study 
 
6.3.1.            Permanent discontinuation of study medication 
 
A patient may be permanently discontinued from study medication for the following reasons: 
 
Patient decision 
 
Significant adverse events or unacceptable toxicities 
 
Severe non‐compliance to this protocol as judged by the Investigator 
 
Confirmed disease progression 
 
Allergic reaction to IMP 
 
If the investigator considers that a subject's health will be compromised due to adverse events or 
concomitant illnesses that develop after entering the study. 
 
Once study medication is permanently discontinued it cannot be restarted. 
 
6.3.2.            Withdrawal from study 
 
Withdrawal  from  the  study  refers  to  discontinuation  of  both  study  medication  and  study 
assessments; this can occur at any time according to the following reasons: 


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 
Patient decision 
 
Lost to follow‐up 
 
Death 
 
6.3.3.            Procedures for withdrawal from study 
 
If the patient is withdrawn from the study the primary reason must be recorded in the CRF. If 
possible, the investigator should arrange for the post‐study assessments to be completed. Where the 
patient has withdrawn due to an AE, the investigator should follow the procedures documented in 
section 7.0 in order to assess the safety of the IMP. 
 
 
 
7.       PHARMACOVIGILANCE 
 
7.1.    Definition of an adverse event (AE) 
 
An AE is any untoward medical occurrence (including deterioration of a pre‐existing medical 
condition) in a patient or clinical trial subject administered a medicinal product, and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable 
and unintended sign including abnormal results of an investigation (e.g. laboratory finding, 
electrocardiogram), symptom(s) (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or 
disease temporally associated with the use of the trial medication. 
 
7.1.1.            Disease progression 
Disease progression is a worsening of a patient’s condition attributable to the disease for which the 
study medication is being given. This may be an increase in severity of the disease or increase in the 
symptoms of the disease. The development of new, or progression of existing metastasis to the 
primary cancer under study should be considered as disease progression and not an AE. Events that 
are unequivocally due to disease progression should not be reported as AEs during the study. 
 
7.1.2.            New cancers 
 
The development of a new cancer should be regarded as an AE and reported accordingly. Generally, 
it will also meet at least one of the serious criteria. 
 
 
 
7.2.    Recording of adverse events 
 
AEs will be collected throughout the study, from informed consent until the end of follow‐up; they 
will be followed up according to local practice until the event has stabilised or resolved, or the 
Follow‐up Visit, whichever is the sooner. SAEs will also be recorded throughout the study. 
 
Any AEs which remain unresolved at the patient’s last visit in the study should be followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF. 
 
If an Investigator learns of any SAEs, including death, at any time after a patient has completed the 
study and he/she considers there is a reasonable possibility that the event is related to eribulin, the 
Investigator should notify the trials unit. 
 
The following details will be collected in the CRF for each AE: 
 
AE description / diagnosis 


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 
Date of onset and date of resolution 
 
CTCAE grade maximum intensity 
 
Seriousness 
 
Investigator causality rating against the study medication 
 
Action taken with regard to study medication 
 
Outcome 
 
7.3.    Severity of adverse events 
 
Severity is a measure of intensity whereas seriousness is defined by the criteria in section 7.6. 
Severity will be assessed using the grading scales found in the National Cancer Institute CTCAE 
version 4.03 (June 2010) for all adverse events with an assigned CTCAE term. For those events 
without assigned CTCAE grades, the recommendation on page 1 of the CTCAE that converts mild, 
moderate and severe into CTCAE grades should be used. A copy of the CTCAE version 4.03 can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
 
7.4.    Causality of adverse events 
 
The Investigator will assess causal relationship between the investigational product and the 
combination treatment and each AE. 
 
Unrelated:     No evidence of any causal relationship 
 
Unlikely: 
There is little evidence to suggest there is a causal relationship (e.g. the event did not 
occur within a reasonable time after administration of the trial medication). There is 
another reasonable explanation for  the  event (e.g.  the  patient’s clinical condition, 
other concomitant treatment). 
 
Possible: 
There is some evidence to suggest a causal relationship (e.g. because the event occurs 
within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g. the patient’s clinical 
condition, other concomitant treatments). 
 
Probable 
There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
 
Definite: 
There is clear evidence to suggest a causal relationship and other possible contributing 
factors can be ruled out. 
 
 
 
7.5.    Abnormal laboratory test results 
 
All clinically important abnormal laboratory test results occurring during the study will be recorded as 
adverse events. The clinically important abnormal laboratory tests will be repeated at appropriate 
intervals until they return either to baseline or to a level deemed acceptable by the investigator and 
the clinical monitor, or until a diagnosis that explains them is made. 
 
7.6.    Definitions of Serious Adverse Events (SAE) 
 
An SAE is an AE occurring during any part of the study that meets one or more of the following 
criteria: 
 
Results in death; 
 
Is life‐threatening*; 
 
Requires hospitalisation or prolongation of existing inpatient’s hospitalisation**; 


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 
Results in persistent or significant disability or incapacity; 
 
Is a congenital abnormality or birth defect; 
 
* “Life‐threatening” in the definition of “serious” refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
** “Hospitalisation” means any unexpected admission to a hospital department. It does not usually 
apply to scheduled admissions that were planned before study inclusion or visits to casualty (without 
admission). 
Medical judgement should be exercised in deciding whether an adverse event/reaction is serious in 
other situations. Important adverse events/reactions that are not immediately life‐threatening, or do 
not result in death or hospitalisation but may jeopardise a subject, or may require intervention to 
prevent one of the other outcomes listed in the definition above should also be considered serious. 
 
7.7.    Reporting of SAEs 
 
Rapid reporting, within 24 hours of the Principal Investigator or designee becoming aware of the 
event, of all SAEs occurring during the study or within 28 days following the completion of the study 
treatment by the subject, must be performed as detailed in the “SAE reporting instructions”. If the 
investigator becomes aware of safety information that appears to be drug related, involving a subject 
who participated in the study, even after an individual subject has completed the study, this should 
also be reported to the Sponsor. 
 
The SAE should be reported electronically to the study team at the Imperial Clinical Trials Unit – 
Section on Cancer via the ALERT study database as detailed in the Pharmacovigilance study 
manual. 
 
All SAEs will be reviewed by the Chief Investigator or designated representative to confirm 
relatedness and expectedness. 
 
Following documented assessment by the CI, the completed SAE form will be sent by email to the 
Sponsor by the study team at CCTS within the pre‐specified timelines. 
 
7.8.    Definition of a Serious Adverse Reaction (SAR) 
 
A SAR is defined as an SAE that is judged to be related to any dose of study drug administered to the 
subject. 
 
7.9.    Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
Any SAR that is NOT consistent with the applicable product information as set out in the Investigator 
Brochure (IB) or Summary of Product Characteristics (SPC). 
 
7.10.  Reporting of SUSARs 
 
SUSARs will be notified to the appropriate regulatory authority, the relevant Independent Ethics 
Committee (IEC) / Institutional review board (IRB), Eisai Ltd, the Sponsor and the participating 
Principal Investigators by CCTS in accordance with regulatory requirements. 


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Any  Suspected  Unexpected Serious  Adverse  Reactions  (SUSARs) and  Serious  Adverse  Reactions 
(SARs) must be reported by CCTS immediately by email to  EUMedInfo@eisai.net. If unable to scan 
and email report it should be faxed to 020 8600 1486/0845 676 1401. 
 
Follow up of patients who have experienced a SUSAR should continue until recovery is complete or 
the condition has stabilised. 
 
7.11.  Annual Reporting of Serious Adverse Reactions 
 
Annual reports will be submitted to the MHRA and main REC by CCTS according to current 
requirements. 
 
7.12.  Pregnanacy 
 
Due to the possible risks associated with the treatment, all women of childbearing potential (defined 
as women who have had any menstrual bleeding in the last 24 months and who have not had a 
hysterectomy) should be informed of the potential risks to their unborn child should they fall 
pregnant  whilst  receiving  treatment.   Any  woman  who  is  pregnant  at  the  time  of  eligibility 
assessment or is unwilling to use medically approved contraception whilst receiving treatment will be 
ineligible for entry to the study.  All women of childbearing potential must use appropriate medically 
approved contraception before, during and for 28 days after the end of study treatment. 
 
Pregnancies occurring in participants of the study, or participants’ partners during the study may 
represent a safety issue and must be reported via the eCRF.  Site staff should notify CCTS of a 
pregnancy in a trial subject and the estimated due date.  Where a pregnancy is known, this will be 
followed for outcome and any adverse outcome of pregnancy assessed for causality to the treatment 
received. 
 
 
 
 
 
8.       STATISTICAL ANALYSES 
 
8.1.    Sample size and power considerations 
 
This study will be a pilot and due to feasibility constraints, we plan to recruit only 12 patients in this 
pilot proof of concept study.  This will allow us to determine the PFS rate at the relevant time points 
of 3, 6 and 9 months and to validate these in an adequately powered study in the future. 
 
8.2.    Analysis Plan 
 
The clinical data will be entered and stored in InFormTM database.   Statistical analysis will be 
conducted using R version 3.0.1 and STATA 13 SE. Analysis of the data will occur only when the study 
is complete. There is no planned interim analysis. A separate statistical analysis plan will be prepared 
and finalised prior to database lock. 
 
8.2.1.      Deviations from the statistical plan 
 
Any deviation(s) from the final statistical plan in the final analysis will be described and justification 
given in the final report. 


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8.2.2.      Efficacy analysis 
 
All efficacy data in the study will be analysed based on the Full Analysis Set (FAS) which consists of all 
patients who  receive at  least one  dose of  study  treatment. If  appropriate and  required, a  Per 
Protocol Analysis Set (PPS) will be defined prior to final analysis on which the efficacy analysis will be 
repeated. 
 
The primary endpoint of PFS at 3, 6, and 9 months will be estimated by the Kaplan‐Meier method. 
These rates estimate the proportion of patients who do not progress and are alive at a given time. 
The PFS is calculated from the start of treatment until the date of progression or death from any 
cause. Patients will be censored at the time of last follow‐up if they are withdrawn or lost to follow‐ 
up before progression or death. 
 
The secondary endpoint of CBR is defined as the proportion of patients whose best overall response, 
according to RECIST v1.1, is either a complete response (CR), partial response (PR) or stable disease 
(SD) for at least 6 months. The estimation of CBR and its 95% confidence interval will be reported. 
 
8.2.3.      Safety analysis 
 
All patients who receive at least one dose of study treatment will be included in the safety analysis 
set. The frequency of AEs will be assessed for severity (NCI‐CTCAE v4.03), expectedness, seriousness 
and causal relationship to study drugs(s). In addition, AEs will be summarised by toxicity type, impact 
on study drug(s) and by timing.  The frequency of SAEs will be summarised by SAE reason, severity 
and causal relationship to study drug. 
 
8.2.4.      Translational analysis/ Exploratory Analysis 
 
The exploratory analysis will measure alterations in CTCs and cfDNAs from baseline and at 9, 18 and 
36 weeks after start of treatment, and associate these with clinical outcomes.  Firstly, the alterations 
in CTCs and cfDNAs will be described at all time points through plots with appropriate repeated 
measures univariate tests run alongside. Subsequently, in order to determine whether CTCs and 
cfDNA, increase during hormonal therapy, levels of these biological measurements will be associated 
with timing of alternative erubulin and hormonal therapy through repeated measures ANOVA or 
another statistically appropriate repeated measures test such as its non‐parametric version, the 
Friedman test, (depending on the final distribution of the biological measurements). 
 
9.       REGULATORY, ETHICAL AND LEGAL ISSUES 
 
9.1. Declaration of Helsinki 
 
The investigator will ensure that this study is conducted in full conformity with the principles of the 
1964 Declaration of Helsinki and any subsequent revisions. 
 
9.2. Good Clinical Practice 
 
The  study  will  be  conducted in  accordance with  the  guidelines laid  down  by  the  International 
Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 guidelines). 


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9.3.    Independent Ethics Committee/Institutional Review Board Approval 
 
9.3.1.            Initial approval 
 
Prior to the shipment of IMP and the enrolment of subjects, the IEC/IRB must provide written 
approval of: the conduct of the study at named sites, the protocol and any amendments, the Subject 
Information Sheet and Consent Form, any other written information that will be provided to the 
subjects, any advertisements that will be used and details of any subject compensation. 
 
9.3.2.            Approval of amendments 
 
Proposed amendments to the protocol and aforementioned documents must be submitted to the 
IEC/IRB for approval. Amendments requiring IEC/IRB approval may be implemented only after a copy 
of the IEC/IRB’s approval letter has been obtained. 
 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented prior to receiving Sponsor or IEC/IRB approval. However, in this case, approval must be 
obtained as soon as possible after implementation. 
 
9.3.3.            Annual safety reports and end of trial notification 
 
The IEC/IRB will be sent annual safety updates in order to facilitate their continuing review of the 
study (reference. ICH GCP E6 Section 3.1.4) and will also be informed about the end of the trial, 
within the required timelines. 
 
9.4.    Regulatory authority approval 
 
The study will be performed in compliance with the regulatory requirements of the United Kingdom. 
Clinical Trial Authorisation from the appropriate Regulatory Authority must be sought/obtained prior 
to the start of the study. In addition, the Regulatory Authority must approve amendments (as 
instructed by the Sponsor), receive SUSAR reports and annual safety updates, and be notified of the 
end of the trial. 
 
9.5.    Insurance 
 
The Sponsor has civil liability insurance, which covers this study in the United Kingdom. 
 
9.6.    Informed consent 
 
The Principal Investigator at each site will: 
 
 
Ensure that each patient is given full and adequate oral and written information about the 
study including the background, purpose and risks/benefits of participation 
 
 
Ensure that each patient is notified that they are free to withdraw from the study at any time 
 
 
Ensure that each patient is given the opportunity to ask questions and allowed sufficient 
time to read and understand the information sheet 
 
 
Ensure each patient provides signed, dated informed consent before undergoing any study 
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 
Ensure  the  original  copy  of  the  signed,  dated  Informed Consent Form  is  stored  in  the 
Investigator site file and a copy is also filed in the medical records 
 
 
Ensure that each patient receives a copy of the signed, dated Informed Consent Form 
 
9.7.    Contact with General Practitioner 
 
It is the investigator’s responsibility to inform the subject’s General Practitioner by letter that the 
subject is taking part in the study provided the subject agrees to this, and information to this effect is 
included in the Subject Information Sheet and Informed Consent. A template of the GP letter should 
be filed in the Investigator Site File. 
 
9.8.    Subject confidentiality 
 
The  investigator  must  ensure  that  the  subject’s  privacy  is  maintained.  On  the  CRF  or  other 
documents submitted to the Sponsors, subjects will be identified by a trial ID number only. 
Documents that are not submitted to the Sponsor (e.g. signed informed consent form) should be 
kept in a strictly confidential file by the investigator. 
 
The investigator shall permit direct access to subjects’ records and source document for the purposes 
of monitoring, auditing, or inspection by the Sponsor, authorised representatives of the Sponsor and 
Regulatory Authorities. 
 
9.9.    Data protection 
 
Precautions will be taken to ensure that patient confidentiality is preserved at all times. The Patient 
Consent form will identify those individuals who will require access to patient data and identifiable 
details and obtain appropriate permission from the consenting patient. 
 
9.10.  End of trial 
 
The end of the trial is defined as the last visit of the last patient undergoing the study. 
 
9.11.  Study documentation and data storage 
 
The investigator must retain essential documents until notified by the Sponsor (Imperial College 
London), and at least for ten years after study completion, as per Imperial College London policy. 
Subject files and other source data (including copies of protocols, CRFs, original reports of test 
results, IMP dispensing logs, correspondence, records of informed consent, and other documents 
pertaining to the conduct of the study) must be kept for the maximum period of time permitted by 
the institution. Documents should be stored in such a way that they can be accessed/data retrieved 
at a later date. Consideration should be given to security and environmental risks. 
 
No study document will be destroyed without prior written agreement between the Sponsor and the 
investigator. Should the investigator wish to assign the study records to another party or move them 
to another location, written agreement must be obtained from the Sponsor. 


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10. 
DATA AND STUDY MANAGEMENT 
 
10.1.  Source data 
 
All original records and certified copies of original records of clinical findings, observations, or other 
activities necessary for the reconstruction and evaluation of the trial are classified as source data. 
Source data are contained in source documents; these are defined as: 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. 
 
10.2.  Language 
 
CRFs will be in English. Generic names for concomitant medications should be recorded in the CRF 
wherever possible. All written material to be used by subjects must use vocabulary that is clearly 
understood, and be in the language appropriate for the study site. 
 
10.3.  Data collection 
In compliance with Good Clinical Practice (GCP), the medical records/medical notes should be clearly 
marked and allow easy identification of a patient’s participation in the clinical trial 
 
The Investigator (or delegated member of the site study team) must record all data relating to 
protocol procedures, IMP administration, laboratory data, safety data and efficacy data into the trial 
InForm electronic data collection (EDC) system. 
 
10.4.  Electronic recording of data 
 
Full details for procedures for completion of eCRFs will be provided in the study manual. 
 
10.5.  Data management 
 
Data management will be performed by the Imperial Clinical Trials Unit – Section on Cancer using the 
InForm electronic data capture (EDC) and management system. The system allows for real time 
oversight of trial activity including adverse event reporting, rapid data validation and data 
aggregation. 
 
AE data will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class and preferred term, and CTCAE grade. 
 
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trial. 
 
10.6.  Study Management Structure 
 
10.6.1.          Trial Steering /Independent Data Monitoring Committee 
 
As there is no planned interim analysis, a joint Trial Steering (TS) and Independent Data Monitoring 
Committee (IDMC) will be convened including as a minimum an independent Chair, an independent 
Statistician, independent clinician, the  Chief  Investigator and  Trial  Coordinator. The  role  of  the 


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TS/IDMC will be to provide overall supervision of the trial progress and, as necessary, advice to the 
Trial Management Group on operational issues. 
 
10.6.2.          Trial Management Group 
 
A Trial Management Group (TMG) will be convened including the Chief Investigator, Co‐investigators 
and identified key collaborators, the Trial Statistician and Trial Coordinator. Principle Investigators 
and key study personnel may be invited to join the TMG as appropriate to ensure representation 
from a range of sites and professional groups. 
 
Notwithstanding the legal obligations of the Sponsor and Chief Investigator, the TMG will have 
operational responsibility for the conduct of the trial. 
 
Where possible, membership will also include a lay/consumer representative. 
 
10.7.  Monitoring 
 
The study will be monitored periodically by monitors in the UK to assess the progress of the study, 
verify adherence to the protocol, ICH GCP E6 guidelines and other national/international 
requirements and to review the completeness, accuracy and consistency of the data. 
 
Monitoring procedures and requirements will be documented in a Monitoring Plan. Monitoring will 
be proportionate to the objective, purpose, design, size, complexity, blinding, endpoints and risks 
associated with the clinical trial. The appropriate level and nature of monitoring required for the 
clinical trial will be assessed by undertaking a formal risk assessment analysis of the study. 
 
10.8.  Quality Control and Quality Assurance 
 
Quality Control will be performed according to Sponsor internal procedures. The study may be 
audited by a Quality Assurance representative of the Sponsor. All necessary data and documents will 
be made available for inspection. 
 
10.9.  Disclosure of data and publication 
 
Information concerning the study, patent applications, processes, scientific data or other pertinent 
information is confidential and remains the property of the Sponsor. The investigator may use this 
information for the purposes of the study only. 
 
It is understood by the investigator that the Sponsor will use information developed in this clinical 
study in connection with the development of the IMP and, therefore, may disclose it as required to 
other clinical investigators and to Regulatory Authorities. In order to allow the use of the information 
derived from this clinical study, the investigator understands that he/she has an obligation to provide 
complete test results and all data developed during this study to the Sponsor. 
 
Verbal or written discussion of results prior to study completion and full reporting, should only be 
undertaken with written consent from the Sponsor. 
 
Therefore all information obtained as a result of the study will be regarded as CONFIDENTIAL, at least 
until appropriate analysis and review by the investigator(s) is completed. 


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Investigators may only present data separately to the total data available, with the permission of the 
TMG, and not less than 6 months after the publication of the main results. 
 
Eisai has the right to review all abstracts, papers or other research communications prior to their 
submission to journals, meetings or conferences. 


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11. 
REFERENCES 
 
 
1. 
Anon., 2010. Cancer Stats Key Facts breast Cancer, s.l.: Cancer Research UK. 
 
2.  
Bidard, F. C. et al., 2014. Clinical validity of circulating tumour cells in patients with metastatic 
breast cancer: a pooled analysis of individual patient data. Lancet Oncology, Volume 15, pp. 406‐ 
414. 
 
3.  
Cortes , J. et al., 2011. Eribulin monotherapy versus treatment of physician's choice in patients 
with metastatic breast cancer (EMBRACE): a phase 3 open‐label randomised study. The Lancet, 12 
March, 377(9769), pp. 914‐923. 
 
4. 
Giordano, S. H. et al., 2004. Is breast cancer survival improving?. Cancer, 100(1), pp. 44‐52. 
 
5.  
Shaw, J. A. et al., 2011. A molecular portrait of circulating free DNA of patients with breast 
cancer: High‐resolution analysis using SNP 6.0 arrays. s.l., J Clin. Oncol.. 
 
6.  
Shaw,  J.  A.  et  al.,  2012.  Genomic  analysis  of  circulating  free  DNA  infers  breast  cancer 
dormancy. Genome Research, Volume 22, pp. 220‐31. 
 
7.  
Shaw, J. A. et al., 2000. Microsatellite alterations in plasma DNA of primary breast cancer 
patients. Clin Cancer Res., Volume 6, pp. 1119‐24. 
 
8.  
Stebbing, J. et al., 2014. The prognostic role of circulating tumour cells in heavily pre‐treated 
individuals with a low life expectancy. Future Oncology, Volume 30, pp. 1‐6. 
 
9. 
Twelves, C. et al., 2010. Phase III Trials of Eribulin Mesylate (E7389) in Extensively Pretreated 
Patients With Locally Recurrent or Metastatic Breast Cancer. Clinical Breast Cancer, 10(2), p. 160– 
163. 


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12. 
SIGNATURE PAGES 
 
 
SIGNATURE PAGE 1 (Chief Investigator) 
 
The signature below constitutes approval of this protocol by the signatory. 
 
 
 
I agree to the terms of this study protocol. I will conduct the study according to all stipulations of the 
protocol including all statements regarding confidentiality, and according to the principles of Good 
Clinical Practice (GCP) and local regulations. 
 
 
 
Study Title:                      ALERT: A phase II study of alternating eribulin and hormonal therapy in pre‐ 
treated ER+ve breast cancer. 
 
 
 
Protocol Number:          C/31/2014 
 
 
 
 
 
Signed: 
 
 Dr. Laura Kenny 
 Consultant Medical Oncologist 
Imperial College London 
 
 
 
 
Date: 


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SIGNATURE PAGE 2 (Sponsor) 
 
The signature below constitutes approval of this protocol by the signatory. 
 
 
 
Study Title: 
ALERT: A phase II study of alternating eribulin and hormonal therapy in pre‐ 
treated ER+ve breast cancer. 
 
 
 
 
Protocol Number: 
C/31/2014 
 
 
 
 
 
Signed: 
 
Gary Roper 
Head of Regulatory Compliance  
Imperial College London 
 
 
 
Date: 


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SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signature below constitutes approval of this protocol by the signatory. 
 
 
 
Study Title: 
ALERT: A phase II study of alternating eribulin and hormonal therapy in pre‐ 
treated ER+ve breast cancer. 
 
 
 
Protocol Number: 
C/31/2014 
 
 
 
 
 
Signed: 
 
Dr Xinxue Liu 
Trial Statistician 
Imperial College London 
 
 
 
Date: 


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SIGNATURE PAGE 4 (INVESTIGATOR) 
 
 
The signature of the below constitutes agreement of this protocol by the signatory and provides the 
necessary assurance that this study will be conducted at his/her investigational site according to all 
stipulations of the protocol including all statements regarding confidentiality. 
 
 
 
Study Title:                       ALERT: A phase II study of alternating eribulin and hormonal therapy in pre‐ 
treated ER+ve breast cancer. 
 
 
 
 
Protocol Number:          C/31/2014 
 
 
 
Address of Institution:                                                                                                           
 
 
 
 
 
 
 
 
 
 
 
 
Signed: 
 
 
 
Print Name and Title: 
  
 
 
 
 
Date: 


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13. 
APPENDICES 
 
 
 
Appendix A: Guidelines for Evaluation of Objective Tumour Response Using RECIST 1.1 (Response 
Evaluation Criteria in Solid Tumours) 
 
(ICTU‐Cancer guidance document v2.0 dated 17 November 2014) 
 
 
Response  and  progression  will  be  evaluated  in  this  study  using  the  new  international  criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumours (RECIST) guideline (version 
1.1) [Eur J Ca 45:228‐247, 2009]. Changes in the largest diameter (unidimensional measurement) of 
the tumour lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
Definition of Disease Parameters 
 
Measurable disease Must be accurately measured in a least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 
10mm by CT scan (CT scan slice thickness no greater than 5mm; when CT scans have slice thickness 
>5mm, the minimum size should be twice the slice thickness). 
 
10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non‐measureable). 
 
20mm by chest X‐ray. 
 
Note: Tumour lesions situated in a previously irradiated area or in an area subjected to other loco‐ 
regional therapy are usually not considered measureable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such lesions 
would be considered measurable. 
 
Malignant lymph nodes Criteria for lymph nodes given as ≥15mm short axis for target lesions and 
10mm to <15mm for non‐target lesions. Nodes under 10mm to be considered non‐pathological. 
 
Non‐measurable disease All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 to <15 mm short axis), as well as truly non‐measurable lesions. 
Lesions considered truly non‐measurable include; leptomeningeal disease, ascites, pleural/pericardial 
effusions, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal  organomegaly   identified   by   physical   exam   that   is   not   measureable   by 
reproducible imaging techniques. 
 
Note:  Lytic bone lesions or mixed lytic‐blastic lesions with identifiable soft tissue components that 
can be evaluated by cross‐sectional imaging techniques such as CT or MRI can be considered 
measurable if the soft tissue component meets the definition of measurability described above. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable if they meet 
the definition of measurability described above. However, if non‐cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
 
Target lesions All 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.  Target lesions should be selected on the basis of their size (lesions with the 
longest  diameter)  and  be  representative of  all  involved  organs,  as  well  as  their  suitability  for 


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reproducible repeated measurements. All measurements should be recorded in metric notation 
using calipers if clinically assessed. A sum of the diameters (longest for non‐nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters, 
which will be used as reference to further characterize any objective tumour regression in the 
measurable dimension of the disease. If lymph nodes are to be included in the sum, only the short 
axis will contribute. 
 
Non‐target lesions All lesions (or sites of disease) not identified as target lesions, including 
pathological lymph nodes and all non‐measurable lesions, should be identified as non‐target lesions 
and be recorded at baseline. Measurements of these lesions are not required and they should be 
followed as ‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’. 
 
Methods of Measurement 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow‐up. 
 
CT/MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. MRI is also acceptable in certain situations (e.g. for body scans but not for 
lung). 
 
Chest x‐ray Lesions on chest x‐ray may be considered measurable lesions if they are clearly defined 
and surrounded by aerated lung. However, CT is preferable. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are superficial and 
≥10mm in diameter as assessed using calipers. For the case of skin lesions, documentation by colour 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Ultrasound (US) should not be used to measure tumour lesions. 
 
Tumour markers Tumour markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete clinical 
response.   Specific guidelines for both CA‐125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer) have been published [JNCI 96:487‐488, 2004; J Clin Oncol 17, 
3461‐3467, 1999; J Clin Oncol 26:1148‐1159, 2008].  In addition, the Gynecologic Cancer Intergroup 
has developed CA‐125 progression criteria which are to be integrated with objective tumour 
assessment for use in first‐line trials in ovarian cancer [JNCI 92:1534‐1535, 2000]. 
 
Cytology, Histology Can be used in rare cases (e.g. for evaluation of residual masses to differentiate 
between Partial Response and Complete Response or evaluation of new or enlarging effusions to 
differentiate between Progressive Disease and Response/Stable Disease). 
 
Endoscopy, Laparoscopy Use of endoscopy and laparoscopy is not advised. However, they can be 
used to confirm complete pathological response. 
 
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It is sometimes reasonable to incorporate the use of FDG‐PET scanning to complement CT in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of FDG‐PET 
imaging can be identified according to the following algorithm: 
Negative FDG‐PET at baseline, with a positive FDG‐PET at follow‐up is PD based on a new lesion. 
No FDG‐PET at baseline and a positive FDG‐PET at follow up: 
 
If the positive FDG‐PET at follow‐up corresponds to a new site of disease confirmed by CT, 
this is PD. 
 
If  the  positive FDG‐PET at  follow‐up is  not  confirmed as  a  new  site  of  disease on  CT, 
additional follow‐up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG‐PET scan). 
 
If the positive FDG‐PET at follow‐up corresponds to a pre‐existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is no PD. 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non‐target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this may include the baseline sum). The sum must also 
demonstrate an absolute increase of at least 5mm. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD. 
 
Evaluation of Non‐Target Lesions 
 
Complete Response (CR): Disappearance  of  all  non‐target  lesions  and  normalization  of  tumour 
marker levels. All lymph nodes must be non‐pathological in size (<10 mm short axis) 
 
Non‐CR/Non‐PD: Persistence of one or more non‐target lesion(s) and/or maintenance of tumour 
marker level above the normal limits 
 
Progressive Disease (PD): Unequivocal progression of existing non‐target lesions. 
 
When patient has measurable disease – to achieve ‘unequivocal progression’ on the basis of 
the non‐target disease, there must be an overall level of substantial worsening in non‐target 
disease such that, even in presence of SD or PR in target disease, the overall tumour burden 
has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size 
of one or more non‐target lesions is usually not sufficient to qualify for unequivocal 
progression status. 
 
When patient has none‐measurable disease – there is no measurable disease assessment to 
factor into the interpretation of an increase in non‐measurable disease burden. Because 
worsening in non‐target disease cannot be easily quantified, a useful test that can be applied 
is to consider if the increase in overall disease burden based on change in non‐measurable 
disease is comparable in magnitude to the increase that would be required to declare PD for 


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measurable disease. Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ 
or an increase in lymphangitic disease from localised to widespread. 
 
Evaluation of Best Overall Response 
 
Summary of overall response status calculation at each time point, for patients who have measurable 
disease at baseline. 
 
Target Lesions 
Non‐Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non‐CR/Non‐PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non‐CR/Non‐ 
PD/not 
evaluated 
No 
PR 
SD 
Non‐CR/Non‐ 
PD/not 
evaluated 
No 
SD 
documented 
at 
least 
once 
>4 
wks. 
from 
baseline** 
Not 
all 
evaluated 
Non‐PD 
No 
Not evaluated 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*     See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**   Only for non‐randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non‐target lesions may be accepted as 
disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non‐Measurable Disease (i.e., Non‐Target Disease) 
 
Non‐Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non‐CR/non‐PD 
No 
Non‐CR/non‐PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non‐CR/non‐PD’ is preferred over ‘stable disease’ for non‐target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised 
 
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Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever status is recorded first) until the first date that 
recurrence or PD is objectively documented, (taking as reference for PD the smallest measurements 
recorded on study). 
 
Duration of stable disease:  SD is measured from the start of the treatment (in randomised trials, 
from the date of randomization) until the criteria for disease progression are met, taking as reference 
the smallest sum on study (if baseline sum is the smallest, this is the reference for calculation of 
PD).The clinical relevance of the duration of SD varies for different studies and diseases. This time 
interval should take into account the expected clinical benefit that such a status may bring to the 
population under study. If the proportion of patients achieving stable disease for a minimum period 
of time is an endpoint of importance in a particular trial, the protocol should specify the minimal 
time interval required between two measurements for determination of stable disease. 
 
Response Review 
For trials where the objective response (CR and PR) is the primary endpoint it is recommended that 
all responses be reviewed by an expert(s) independent of the study. Simultaneous review of the 
patients’ files and radiological images is the best approach.