Conditions: Human Cancers
Keywords: IgE antibody Folate receptor Cancer Immunotherapy First in class
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 26
Healthy volunteers: no

Brief summary:
This first in human study of the new therapeutic antibody MOv18 immunoglobulin (Ig) E, which targets a protein called folate receptor alpha (FRa), in patients with advanced cancer seeks to demonstrate the potential for the use of this IgE antibody as an example of the use of the IgE class of antibodies for the treatment of cancer.

Detailed description:
Therapeutic antibodies have significantly improved the prognosis of patients with a range of cancers. Currently available therapeutic antibodies belong to the IgG class. This study is looking at a new drug called MOv18 IgE which belongs to a different class of antibody, the IgE class. IgE antibodies may trigger a more powerful immune response to tumour cells than these available IgG antibodies and so be more effective in treating certain types of cancer. This is the first time an IgE antibody therapy will be given to patients with cancer.

The MOv18 IgE antibody is designed to recognise and attach to FRa. Scientists have found more of this protein on the surface of certain cancer cells than on the surface of normal cells, most commonly ovarian cancer but also cancers of the kidney, endometrium, lung, breast, bladder, colon and pancreas. Once attached, the MOv18 IgE antibody should trigger the body's own immune system to attack and kill the cancer cells.

Patients will be selected based on the presence of FRa on their tumour in a previous biopsy. The study is the first study of this new antibody treatment to be given to humans and will focus primarily on the assessment of safety confirming the findings of preclinical studies that exposure to MOv18 IgE will not trigger anaphylaxis. This is in addition to extensive pharmacokinetic (PK), biodistribution of the antibody and immunological response. The study will follow a dose escalation design where small groups of patients are treated at a set dose, starting with a very low dose followed by exponential increasing doses, to find a safe dose at which the drug has a good chance of effectively treating the cancer. Patients will receive a short course of treatment. Patients treated at the higher dose levels will be asked to provide a pre and post treatment biopsy to explore the effect of the treatment on the tumour.

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None

Interventions: intervention 1: MOv18 IgE intervention 2: MOv18 IgE intervention 3: MOv18 IgE intervention 4: MOv18 IgE intervention 5: MOv18 IgE intervention 6: MOv18 IgE intervention 7: MOv18 IgE
Intervention descriptions: intervention 1: The allocated dose of 70 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by an intradermal injection of 0.1 mL of a 2 µg/mL MOv18 IgE solution for safety assessment. intervention 2: The allocated dose of 250 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by either an intradermal injection of 0.1 mL of a 2 µg/mL MOv18 IgE solution or a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment. intervention 3: The allocated dose of 500 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment. intervention 4: The allocated dose of 700 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment. intervention 5: The allocated dose of 1.5 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment. intervention 6: The allocated dose of 3 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment. intervention 7: Cycle 1 - The allocated dose of 6 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 3 weeks.

Cycle 2 - The allocated dose of 12 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 3 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE.

Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment.

Protocol document:
Prot_000.pdf: 


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©Cancer Research UK 
 
 
 
CANCER RESEARCH UK 
Centre for Drug Development 
Clinical Study Protocol 
A Cancer Research UK Phase I study of MOv18 IgE, a 
first in class chimeric IgE antibody against folate 
receptor-, in patients with advanced solid tumours 
Protocol number: CRUKD/14/001 
EudraCT number: 2014-000070-19 
Version: 
13.0 
Date: 
29 April 2021 
 
 
Chief Investigator: 
Prof James Spicer 
 
 
 
 
 
 
 
 
  
 
 
 
 
Chief Scientific Investigator: 
Dr Sophia N. Karagiannis 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
Sponsor: 
Cancer Research UK 
 
Centre for Drug Development 
  
 


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PARTICIPATING INVESTIGATORS AND CENTRES: 
Details of Principal Investigators and Investigational Sites are recorded on the Participating 
Investigators and Centres list in the Sponsor’s Trial Master File. 
PROTOCOL VERSION HISTORY: 
Version No. 
Version Date 
Reason for update 
1.0 
17 September 2014 
Initial version submitted to MHRA and then withdrawn prior to 
formal response following comments from MHRA Expert Advisory 
Group.   
2.0 
17 December 2014 
CTA re-submission to MHRA and initial submission to REC.  
3.0 
22 January 2015 
Response to GNA submission to MHRA. Exclusion of 
bisphosphonates (MHRA request)  
4.0 
03 December 2015 
Minor amendment to Appendix 8. 
5.0 
23 February 2017 
Change from intradermal to skin prick testing, refinement of 
criteria for dose-limiting toxicity and associated changes 
6.0 
19 October 2017 
• Clarification of additional samples to be taken in response to 
positive skin prick tests and infusion reactions 
• Medications to be available at bedside 
• Skin prick test training 
• 
 
• Updates to Appendix 4: Treatment of Anaphylaxis. 
7.0 
19 December 2017 
• Anaphylaxis no longer a DLT but considered a ‘dose 
independent significant toxicity’ (added as a primary 
endpoint). 
• Assessment of anaphylaxis – frequency to be considered 
across whole study. Assessment triggered by Grade 2 
events. 
• Update to trial specific grading of anaphylaxis. 
• Add positive basophil activation test (BAT) as an exclusion 
criterion 
• Revise timepoints for skin prick response assessment 
8.0 
08 August 2018 
• Grade 4 Fatigue has been removed from the DLT criteria  
• A positive skin prick test is no longer considered to be a 
‘medically important event’. This is now an ‘event of 
interest’ 
• Wording clarifications and consistencies 
• Clarification regarding the Trial Steering Group (TSG) and 
their involvement.  
• Updates as per new Sponsor protocol template version. 
9.0 
14 January 2019 
• Removal of an eligibility implication of FRα expression in 
the ‘Optional’ pre-treatment tumour biopsy. Eligibility is 
reliant on archival sample result only.  
• Clarification of wording in Section 7.2.5 relating to 
additional samples which need to be taken following 
infusion reactions/anaphylaxis.  


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Version No. 
Version Date 
Reason for update 
• Corrections made to Schedule of Events and Blood 
Volumes 
• Clarification of wheal diameters measured in Skin Prick 
Test assessment.  
• Other minor non-substantial changes and corrections.  
10 
13 September 2019 
• Changes to mandate the paired pre-treatment and on 
treatment PD biopsies. 
• Addition of optional skin punch biopsies in the event of 
Urticaria (any grade) – to be completed for research 
purposes only.  
• 
 
 
• Wording added to allow additional PK timepoints if 
emerging data suggested that this would be beneficial.  
• 
 
 
 
• Addition of (+/-5 mins) window for Drug administration by 
infusion 
• Additional clarification and updates to wording in Section 
7.2.5 relating to additional samples which need to be taken 
following infusion reactions/anaphylaxis.  
• Updates to the PK/PD Assessments methodology 
• Other minor non-substantial changes and corrections 
11 
07 January 2020 
• 
 
 
• Removal of requirement for 28 day and 70 day follow-up 
PK samples. 
• Addition of (+/- 4 hr) window for pre-dose bloods. 
• Updated 60-minute drug admin infusion window to (+/-10 
mins) and 90 minute drug admin infusion window (+/-15 
mins). 
• Clarification regarding patient evaluability, should their 
infusion be interrupted. 
• Extension of window during which the on-treatment tumour 
biopsy can be conducted.   
• Change of Sponsor Address 
• Other minor non-substantial changes and corrections 
 
12 
03 December 2020 
• Addition to allow the possibility of Intra-patient dose 
escalation from Cohort 7 onwards.  
• Primary prophylaxis (premedication) will be allowed prior to 
the first infusion of MOv18 IgE based on emerging safety 
information.  
• Longer infusion times may be allowed in order to better 
manage infusion related cutaneous toxicity 


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Version No. 
Version Date 
Reason for update 
• Correction to timepoints for clinical laboratory tests in Table 
7 
• Other minor non-substantial changes and corrections 
13 
29 April 2021 
• Update to include a 1 week washout period following the 1st 
and 2nd dose of any COVID-19 Vaccination and prior to 
infusion with MOv18 IgE 
• Other non-substantial change (correction) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
TITLE PAGE 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
PROTOCOL SIGNATURES 
 
1 
PROTOCOL SYNOPSIS ..................................................................................................... 13 
2 
INTRODUCTION ................................................................................................................. 15 
2.1 
Background ......................................................................................................................... 15 
2.2 
Investigational medicinal product ........................................................................................ 15 
2.2.1 
Structure of MOv18 IgE .................................................................................................. 15 
2.2.2 
Mechanism of action of MOv18 IgE ............................................................................... 16 
2.2.3 
Folate receptor in Human Cancer .................................................................................. 17 
2.2.4 
Non-clinical efficacy ........................................................................................................ 17 
2.2.5 
Non-clinical pharmacokinetics ........................................................................................ 19 
2.2.6 
Non-clinical toxicology .................................................................................................... 19 
2.3 
Clinical experience .............................................................................................................. 21 
2.3.1 
Clinical trials using antibodies and antibody derivatives targeting the folate receptor ... 21 
2.3.2 
Mouse MOv18 IgG ......................................................................................................... 21 
2.3.3 
Chimeric MOv18 IgG ...................................................................................................... 22 
2.3.4 
Farletuzumab.................................................................................................................. 22 
2.3.5 
Other approaches ........................................................................................................... 23 
2.4 
Rationale for the clinical study ............................................................................................. 24 
2.4.1 
Rationale for using IgE therapeutically ........................................................................... 24 
2.4.2 
Rationale for folate receptor alpha as a target ............................................................... 24 
3 
STUDY DESIGN .................................................................................................................. 26 
3.1 
Study objectives and endpoints ........................................................................................... 26 
3.2 
Design of the Study ............................................................................................................. 26 
3.3 
Definition of dose limiting toxicity ........................................................................................ 27 
3.3.1 
Dose limiting toxicity (DLT) ............................................................................................. 27 
3.3.2 
Dose-independent significant toxicity ............................................................................. 29 
3.4 
Definition of maximum tolerated dose ................................................................................. 29 
3.4.1 
Maximum tolerated dose (MTD) ..................................................................................... 29 
3.4.2 
Acceptable frequency of dose-independent significant toxicity (anaphylaxis) ............... 29 
3.5 
Patient evaluability ............................................................................................................... 29 
3.6 
Trial Steering Group ............................................................................................................ 30 
4 
PATIENT SELECTION ........................................................................................................ 31 
4.1 
Eligibility criteria ................................................................................................................... 31 
4.1.1 
Inclusion criteria.............................................................................................................. 31 
4.1.2 
Exclusion criteria ............................................................................................................ 31 
4.2 
Patient enrolment ................................................................................................................ 32 
5 
TREATMENT ...................................................................................................................... 33 
5.1 
Selection of the Phase I starting dose ................................................................................. 33 
5.2 
Selection of the maximum dose .......................................................................................... 34 
5.3 
Dosing schedule/treatment schedule .................................................................................. 34 
5.3.1 
Study drug administration ............................................................................................... 35 
5.4 
Dose escalation scheme ..................................................................................................... 36 
5.4.1 
Intra-patient dose escalations ........................................................................................ 38 
5.4.2 
Expansion of dose level(s) ............................................................................................. 41 
5.4.3 
Patients enrolled in the intra-patient escalation cohorts ................................................ 41 
5.5 
Dose modifications .............................................................................................................. 41 
5.5.1 
Dose reductions.............................................................................................................. 41 
5.5.2 
Dose delays .................................................................................................................... 42 
5.5.3 
Dose interruptions .......................................................................................................... 42 
5.5.4 
Dose discontinuations following positive skin prick tests ............................................... 42 
5.6 
Duration of treatment ........................................................................................................... 42 
5.6.1 
Replacement of patients ................................................................................................. 43 
5.7 
Concomitant medication and treatment ............................................................................... 43 


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6 
PHARMACEUTICAL INFORMATION ................................................................................ 45 
6.1 
Supply of MOV18 IGE ......................................................................................................... 45 
6.2 
Pharmaceutical data ............................................................................................................ 45 
6.2.1 
Formulation of MOv18 IgE ............................................................................................. 45 
6.2.2 
Storage conditions .......................................................................................................... 45 
6.2.3 
Method of reconstitution ................................................................................................. 45 
6.2.3.1 
Solution for intravenous (IV) infusion ......................................................... 45 
6.2.3.2 
Solution for skin prick testing ...................................................................... 46 
6.2.4 
Stability and labelling of the diluted MOv18 IgE ............................................................. 46 
6.2.5 
MOv18 IgE administration .............................................................................................. 46 
6.2.6 
Vein extravasation/accidental spillages ......................................................................... 46 
6.3 
MOv18 IgE accountability .................................................................................................... 46 
7 
INVESTIGATIONS SCHEDULE ......................................................................................... 47 
7.1 
Pre-treatment evaluations ................................................................................................... 47 
7.1.1 
Archival tumour testing for FR ..................................................................................... 47 
7.1.2 
Obtaining written informed consent ................................................................................ 47 
7.1.3 
Evaluations within 28 days (Day -28 to Pre-dose on Day 1) .......................................... 48 
7.1.4 
Evaluations within seven days (Day -7 to Pre-dose on Day 1) ...................................... 48 
7.2 
Evaluations during the study ............................................................................................... 49 
7.2.1 
Safety evaluations with EVERY administration of MOv18 IgE ....................................... 49 
7.2.2 
Additional evaluations for the first administration of MOv18 IgE on Cycle 1 Day 1 ....... 50 
7.2.3 
Weekly and fortnightly clinic visits .................................................................................. 50 
7.2.4 
Prior to the start of a new cycle of MOv18 IgE treatment (within 24 h before start of 
infusion on Day 1) .......................................................................................................... 51 
7.2.5 
Infusion reactions and anaphylaxis ................................................................................ 51 
7.3 
Evaluations at First Post-treatment Safety Assessment (28 ±7 days after final dose) ....... 52 
7.4 
Evaluations at Second Post-treatment Safety Assessment (70 ±14 days after final dose) 53 
7.5 
Follow-up of drug-related AEs ............................................................................................. 53 
7.6 
Schedule of events .............................................................................................................. 54 
8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............................ 60 
8.1 
Summary of assessments ................................................................................................... 60 
8.2 
Secondary assessment - Pharmacokinetics of MOV18 IgE ................................................ 60 
8.3 
Tertiary/research assessments - pharmacodynamics ......................................................... 61 
9 
ASSESSMENT OF SAFETY............................................................................................... 67 
9.1 
Investigator Responsibilities ................................................................................................ 67 
9.1.1 
Medical Cover................................................................................................................. 67 
9.2 
Adverse event definitions .................................................................................................... 68 
9.2.1 
Adverse event................................................................................................................. 68 
9.2.2 
Serious adverse events .................................................................................................. 68 
9.2.3 
Suspected, unexpected, serious, adverse reactions...................................................... 69 
9.2.4 
Causality ......................................................................................................................... 69 
9.2.5 
Expectedness ................................................................................................................. 70 
9.3 
Collection of safety information ........................................................................................... 70 
9.3.1 
Screening failures ........................................................................................................... 70 
9.3.2 
Eligible patients .............................................................................................................. 70 
9.3.3 
Follow-up of AEs and SAEs ........................................................................................... 70 
9.3.4 
Other safety information of interest ................................................................................ 71 
9.4 
Reporting of SAEs to the Pharmacovigilance Department, CDD........................................ 71 
9.4.1 
Events exempt from being reported as SAEs to the Pharmacovigilance Department ... 71 
9.5 
Recording of adverse events and serious adverse events in eCRFs ................................. 71 
9.6 
Urgent safety measures ...................................................................................................... 72 
9.7 
Pregnancy............................................................................................................................ 72 
10 
ASSESSMENT OF EFFICACY ........................................................................................... 74 
10.1 
Measurement of disease ..................................................................................................... 74 
10.2 
Timing and type of tumour assessments ............................................................................. 74 
10.2.1 
Baseline evaluations ...................................................................................................... 74 
10.2.2 
Evaluations during the study and at ‘First Post-treatment Safety Assessment’ 28 ±7 
days after final dose) ...................................................................................................... 74 
10.3 
Tumour response ................................................................................................................ 75 


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10.3.1 
Recording of response in the eCRF ............................................................................... 75 
10.3.2 
Other definitions of outcome .......................................................................................... 75 
11 
PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT ............................ 76 
12 
DEFINING THE END OF TRIAL ......................................................................................... 77 
13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................ 78 
13.1 
Presentation of data ............................................................................................................ 78 
13.2 
Safety ................................................................................................................................... 78 
13.3 
Pharmacokinetics ................................................................................................................ 78 
13.4 
Pharmacodynamics ............................................................................................................. 79 
13.5 
Anti-tumour activity .............................................................................................................. 79 
14 
ADMINISTRATION ............................................................................................................. 80 
14.1 
Protocol deviations and amendments ................................................................................. 80 
14.2 
Completion of the electronic case report form (eCRF) ........................................................ 80 
14.3 
Study performance and monitoring ..................................................................................... 81 
14.4 
Source document verification .............................................................................................. 81 
14.5 
Clinical study report ............................................................................................................. 81 
14.6 
Record retention .................................................................................................................. 82 
14.7 
Ethical considerations .......................................................................................................... 82 
14.8 
Indemnity ............................................................................................................................. 82 
14.9 
Publication policy and press releases ................................................................................. 82 
15 
REFERENCES .................................................................................................................... 83 
16 
APPENDICES ..................................................................................................................... 88 
16.1 
Appendix 1: WHO Performance Scale ................................................................................ 88 
16.2 
Appendix 2: Declaration Of Helsinki .................................................................................... 89 
16.3 
Appendix 3: Assessment of Disease Response ................................................................. 93 
16.4 
Appendix 4: Treatment of Anaphylaxis .............................................................................. 102 
16.5 
Appendix 5: Trial-specific Grading of IgE-associated Mast Cell Degranulation (anaphylaxis)
 
103 
16.6 
Appendix 6: NCI-CTCAE v.4.02 Grading of Cytokine Release Syndrome ....................... 104 
16.7 
Appendix 7: Levels of Asthma Control (GINA Guidelines 2012$) ..................................... 105 
16.8 
Appendix 8: Skin Prick testing to evaluate sensitivity to MOv18 IgE ................................ 106 
 
 
 
 
 


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List of Tables and Figures  
Table 1: Planned dose escalation scheme (Flat Dosing) ................................................................ 37 
Table 2: Dose escalation decision-making ....................................................................................... 38 
Table 3: Planned intra-patient dose escalation scheme ................................................................. 39 
Table 4: Schedule for Initial Dosing Period ...................................................................................... 54 
Table 5: Schedule for Maintenance Dosing Period .......................................................................... 58 
Table 6: Summary of PK and PD Assessments ............................................................................... 62 
Table 7: Approximate volume of blood required for study-specific tests (mL) ............................ 65 
Figure 1: 
 
 
). ..................................................................................................... 16 
Figure 2: IgE versus IgG ..................................................................................................................... 17 
Figure 3: MOv18 IgE Dosing Schedule .............................................................................................. 35 
Figure 4 Intra-patient dose escalation: Example of planned escalation ....................................... 40 
 
 






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PROTOCOL SIGNATURES 
Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities 
as an Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice 
(GCP)2, the Declaration of Helsinki3 (Appendix 2), the applicable regulations of the relevant NHS Trusts 
and the trial protocol.  I agree to conduct the study according to these regulations and guidelines and to 
appropriately direct and assist the staff under my control, who will be involved in the study, and ensure 
that all staff members are aware of their clinical study responsibilities. 
 
Investigator's Name: 
 
 
 
 
 
Name of site: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, adopted by 
CPMP July 1996. 
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 


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PROTOCOL SIGNATURES 
SPONSOR SIGNATURE 
The Sponsor has read and agrees to the protocol, as detailed in this document.  I am aware of my 
responsibilities as the Sponsor under the UK Clinical Trials Regulations1, the guidelines of Good Clinical 
Practice (GCP)2, the Declaration of Helsinki3 (Appendix 2), the applicable regulations of UK law and the 
trial protocol.  The Sponsor agrees to conduct the trial according to these regulations and guidelines 
and to appropriately direct and assist sponsor’s staff who will be involved in the trial, and ensure that all 
staff members are aware of their clinical trial responsibilities. 
 
Name: 
 
 
 
 
 
Title: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, adopted by 
CPMP July 1996. 
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 




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Study treatment: MOv18 IgE will be administered as an IV infusion.  Patients in all cohorts will receive 
a total of six doses of MOv18 IgE at 1-week intervals over a 6 week ‘Initial Treatment Period’. 
Should additional drug supply become available during the study (for example if dose escalation does 
not proceed through all the planned dose levels), patients in any cohort who appear to be benefitting 
from MOv18 IgE may be given up to three further doses of MOv18 IgE at fortnightly intervals called the 
‘Maintenance Period’.  The maximum number of doses for patients, i.e. those completing the ‘Initial 
Treatment Period’ and the ‘Maintenance Period’, would be 9 doses over a total treatment period of 12 
weeks. 
It is planned that all patients will receive a flat dose of MOv18 IgE without adjustment for body weight or 
surface area. The starting dose will be 70 µg and dose escalation will be carried out through defined 
dose levels up to a maximum dose of 50 mg (see Section 5.4 Dose Escalation Scheme). However, a 
switch to weight-based dosing, and/or intra-patient escalation will be considered during the course of 
the trial, if emerging data suggest that this could be beneficial, for example by reducing any large inter-
patient variations in PK.  


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2 
INTRODUCTION 
2.1 Background 
Therapeutic antibodies have significantly improved the prognosis of patients with a range of 
malignancies.  Currently available therapeutic antibodies belong to the IgG class, the most prevalent 
antibody class in human blood.  IgE antibodies are known to exert natural immune surveillance in tissues 
and are engaged locally by the high-affinity IgE receptor, FcɛRI, which is present on effector cells such 
as mast cells, macrophages, basophils and, possibly, eosinophils. IgE antibodies may trigger a more 
powerful immune response to tumour cells than IgGs, resulting in better anti-tumour efficacy.   
MOv18 IgE is a chimeric IgE monoclonal antibody specific for the alpha-folate receptor (FRα), which is 
expressed on the cell surface of a range of tumour types. 
2.2 Investigational medicinal product 
2.2.1 
Structure of MOv18 IgE 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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phagocytosis (ADCP).  ADCC appears to have been mediated by the high affinity FcεRI, and ADCP by 
the lower affinity FcεRII (CD23) (Coney et al., 1994; Gould et al., 1999). 
In vivo efficacy studies have been performed in two mouse models of ovarian cancer, one using the 
IGROV1 cell line in SCID mice and one using a HUA ascites cells (a xenograft model of ovarian cancer 
was established from human primary tumour cells, produced from ascites from a patient with Stage III 
ovarian carcinoma – these are termed HUA cells) passaged in nude mice.  In both models anti-tumour 
efficacy was observed when MOv18 IgE (at 100 μg/mouse) was co-administered with human peripheral 
blood mononuclear cells (PBMCs); this efficacy was statistically significantly greater that that after 
administration of PBMCs alone or after co-administration of PBMCs and MOv18 IgE IgG1.  In the HUA 
model the anti-tumour activity of MOv18 IgE could be abolished by depleting PBMCs of monocytes, and 
recovered by adding monocytes back to the depleted PBMCs.  Co-administration of MOv18 IgE and a 
monocyte cell line in the HUA model also demonstrated anti-tumour efficacy, and this could be 
enhanced by stimulation of CD23 expression on the monocyte cell line using IL4.  The in vitro anti-
tumour activity of MOv18 IgE could therefore be replicated in vivo (Gould et al., 1999; Karagiannis et 
al., 2008; Karagiannis et al., 2007; Karagiannis et al., 2003). 
The in vivo studies in mouse required administration of both human target and human effector cells. 
This limited the duration of efficacy studies and prevented involvement of the host immune system (since 
mouse effector cells and human IgE Fc do not interact).  Further in vivo efficacy studies were therefore 
performed in a syngeneic rat model using a surrogate rat MOv18 IgE (rMOv18 IgE).  Using a fortnightly 
dosing schedule, anti-tumour efficacy was observed at rMOv18 IgE doses of 5 mg/kg or greater (but not 
at lower doses including 1 and 3 mg/kg).  After a fortnightly dose of 5 mg/kg the anti-tumour efficacies 
of rMOv18 IgE and rMOv18 IgG2b were similar, while at 10 mg/kg the IgE was statistically significantly 
more efficacious.  With a weekly administration schedule, a dose of 3 mg/kg rMOv18 IgE demonstrated 
efficacy that was statistically significantly greater than the same dose of rMOv18 IgG2b.  The in vivo 
anti-tumour efficacy of rMOv18 IgE was therefore maintained in an immunocompetent model (Josephs 
D et al, manuscript in preparation). 
The anti-tumour efficacy of rMOv18 IgE in the rat model was associated with increased tumour necrosis 
and infiltration of tumour associated macrophages (TAMs).  The IgE-associated macrophages had a 
distinct phenotype that was neither M1 (predominantly expressing killer phenotype) or M2 (involved in 
tissue repair).  The TAMs in rats administered rMOv18 IgE were found to express high levels of 
intracellular TNF and IL-10, and high levels of these cytokines were also found in bronchoalveolar 
lavage together with increased levels of the chemokine MCP-1 and the cytokine IL-1α.  The association 
between these chemo/cytokines and rMOv18 IgE activity is not unique to the rat model.  Similarly, 
elevated levels of MCP-1, IL-10 and TNF were associated with target cell cytotoxicity in cell killing 
assays using MOv18 IgE, IGROV1 target cells, and human monocytes.  Individual blockade of the action 
of these cytokines all reduced the cytotoxicity induced by the IgE to some extent (Josephs D et al, 
manuscript in preparation). 
MCP-1 is a chemokine produced by tumour cells and may be responsible for the chemotaxis of 
monocytes, mast cells and CD8+ T cells into the tumour (Negus et al., 1998; Soucek et al., 2007).  IL-1 
is a pro-inflammatory cytokine generated by macrophages on inflammatory stimulus.  It induces the 
expression of pro-inflammatory genes in diverse stromal/inflammatory cells, which ultimately act to 
propagate and sustain inflammation.  Taken together, these studies suggest that both rMOv18 IgE and 
MOv18 IgE may be able to produce anti-tumour efficacy by recruiting macrophages to the tumour, and 
promoting these TAMs to adopt an IgE-associated phenotype distinct from both the M1 and M2 
phenotypes.  These IgE induced phenotype TAMs then appear to promote the release of pro-
inflammatory cytokines and recruitment of further immune cells to the tumour (Josephs D et al, 
manuscript in preparation). 
In the context of the very high affinity of IgE for its FcεRI (approximately 1 x 10-11 M), the mg/kg doses 
of rMOv18 IgE required for anti-tumour efficacy initially appear higher than might be expected.  An 
efficacious dose of 5 mg/kg rMOv18 IgE is estimated to produce a plasma level of approximately 1 x 10-
7M, which is four orders of magnitude greater than the antibody’s affinity for FcεRI.  The doses required 
for efficacy of MOv18 IgE in mouse models are also estimated to produce plasma levels of the same 
order of magnitude.  This unexpected finding is thought to be due to competition between exogenously 
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Free IgE is released into the vascular compartment where it binds effector cells and then enters the 
extravascular compartment bound to FcεRI.  This binding step is essential for IgE to reach its target 
antigens in tissues.  Therapeutic MOv18 IgE must compete with endogenous IgE which is already 
present at steady state levels of around 5 x 10-9M.  Administration of MOv18 IgE at doses producing 
levels of 5 x 10-11M would therefore be outcompeted by the 100 fold higher concentration of endogenous 
IgE for binding to effector cells.  In the absence of effector cell binding MOv18 IgE will not be carried 
into tissues and may not be expected to have anti-tumour efficacy at these low doses (Josephs D et al, 
manuscript in preparation). 
In both mouse and rat model systems the dose of rMOv18 IgE required for efficacy was adequate to 
produce concentrations of intravascular IgE significantly greater than endogenous IgE levels for several 
days post-administration.  Such doses would be expected to produce significant tissue levels of rMOv18 
IgE-bound effector cells throughout this period. 
2.2.5 
Non-clinical pharmacokinetics 
IgE is present at much lower concentrations and is turned over much more rapidly in blood than IgG.  
However, IgE in blood is extensively and stably bound to effector cells via FcεRI before entering the 
extravascular compartment as part of normal immunosurveillance.  As a result, the plasma 
pharmacokinetics of IgE are of limited relevance to the activity of the antibody and are independent of 
antigen binding. As distribution is largely a consequence of non-selective binding to effector cell FcεRI, 
the pharmacokinetics of IgE in blood should therefore be independent of the antigen target, with all IgEs 
competing equally for effector cell binding (Waldmann et al., 1969; Waldmann et al., 1975). 
Published data suggest that the half-life of serum IgE in man is 1 to 2 days (Dreskin et al., 1987; Iio et 
al., 1978) and in rodents approximately 12 hours (Hirano et al., 1983; Vieira et al., 1988).  In two 
separate studies using different detection methods, the half-life of rMOv18 IgE was found to be between 
6 and 36 hours.  However, the study indicating a longer half-life involved the use of indium-111 
radiolabelled antibody, with pharmacokinetics calculated using total radioactivity rather than rMOv18 
IgE itself (which could result in an over-estimate of half-life).  Therefore, based on existing data on the 
pharmacokinetics of IgE in rodents and the discussion above, the half-life of rMOv18 IgE in rat serum is 
estimated to be approximately 12 hours. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Accordingly the clinical trial starting dose and dose escalation plan have been based around competition 
between the administered MOv18 IgE and endogenous IgE, rather than FcεRI occupancy in an isolated 
system lacking such competition for binding (see Section 5.1). 
2.2.6 
Non-clinical toxicology 
 
 
 
  
 


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For additional information concerning MOv18 IgE, refer to the Investigator Brochure. 
2.3 Clinical experience  
2.3.1 
Clinical trials using antibodies and antibody derivatives targeting the folate receptor 
This is the first clinical study of a therapeutic IgE antibody targeting the FR in patients with cancer. 
However, trials have been conducted using IgGs directed against the FR, including trials of ‘naked’ 
and/or radiolabelled mouse and chimeric IgG versions of MOv18. A humanised version of MOv18 IgG 
does not appear to have been evaluated in humans, although another humanised IgG targeting the FR 
(farletuzumab) is currently in phase III. Overall, MOv18 IgGs and related agents targeting the FR have 
been well tolerated in these studies with few side effects reported other than mild-moderate infusion-
related events (such as nausea, vomiting, headache, chills, flu’-like symptoms, arthralgia and myalgia) 
in some patients. 
2.3.2 
Mouse MOv18 IgG 
Two clinical studies involving the administration of mouse MOv18 IgG have been published, both 
involving radiolabelled antibody. In the first study, a single dose of 0.25 to 1.2 mg mouse [131I]-MOv18 
was administered intravenously (n = 20) or intraperitoneally (n = 10) to patients with ovarian carcinoma. 
A higher tumour uptake and a better tumour/background ratio was seen following intraperitoneal (IP) 
administration than after IV injection (Crippa et al., 1991). In a subsequent study, 16 ovarian cancer 
patients with minimal residual disease were administered 8 to 21 mg of mouse [131I]-MOv18 by IP 
injection (Crippa et al., 1995).  Five patients achieved a complete response, six patients no change and 
five patients had disease progression. In both studies, radiolabelled antibody was well tolerated, apart 
from mild transient bone marrow suppression attributable to the radioisotope. However, 15 of the 16 
patients in the second study (94%) developed human anti-mouse antibodies (HAMA). 
Mouse MOv18 IgG1 has also been evaluated as a potential diagnostic and/or therapeutic 
radiopharmaceutical agent as part of a staged process using biotinylated MOv18 IgG.  In the first study, 
15 patients with ovarian carcinoma were injected intraperitoneally with 2 mg of biotinylated mouse 
MOv18 IgG1, followed 3-5 days later by 100-150 µg of indium-111 streptavidin in 500 mL of normal 
saline (Paganelli et al., 1992).  Tumours were imaged 2 to 48 h after the radioactive streptavidin 
administration and then patients underwent surgery 1 to 8 days later.  Results of the trial suggested that 
this two-step strategy might be superior to the conventional approach (radiolabelled antibodies) for 
intraperitoneal radioimmunolocalization and radioimmunotherapy of ovarian cancer.  No toxicity was 
observed.  
In a subsequent study, a three-step approach was used.  Four patients with metastatic ovarian cancer 
were administered 2 mg of biotinylated MOv18 IgG by intravenous injection (first step), followed 


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36 hours later by a double injection of 2 mg of avidin (chase) plus 5 mg streptavidin (second step), 
followed 24 hours later by a third injection of 111In-labeled biotin (third step) (Casalini et al., 1997).  The 
majority of tumours were successfully imaged by immunoscintigraphy following this stage, but the 
tumour-to-background ratio was relatively low.  Toxicity (if it occurred) was not reported.  In another 
study using the three-step approach, 30 patients with ovarian cancer underwent surgery 3 to 4 days 
after immunoscintigraphy (Magnani et al., 2000).  In this study 1 mg of biotinylated MOv18 IgG1 was 
administered intravenously, followed 24 to 36 hours later with 2 mg of avidin, 5 mg of streptavidin 
15 minutes later and then, 24 hours later, by an injection of indium-111 labelled biotin.  The presence of 
tumour in the area of immunoscintigraphic uptake was evaluated in the biopsied material.  Twenty-one 
patients studied were true-positive, five were true-negative, four were false-positive and none was false-
negative.  On the basis of these data, the authors considered immunoscintigraphy based on MOv18 to 
be a potentially cost-effective procedure for following up patients after surgery for ovarian carcinoma, 
since it could potentially identify patients who do not require surgical re-exploration, and guide biopsies 
when they are indicated.  No toxicity was seen in this study although two of the 15 patients tested (13%) 
developed HAMA. 
In the most recent publication on this technique, 38 advanced ovarian cancer patients were treated 
therapeutically with a three-step protocol (on a compassionate basis). Biotinylated MOv18 IgG (first 
step) and avidin (second step) were injected intraperitoneally, and 12-18 h later 90Y-labeled biotin was 
injected either intravenously or intraperitoneally (third step) (Grana et al., 2004).  Both regimens (IP, and 
IP/IV) were well tolerated and no acute side effects were observed although two patients (5%) 
experienced temporary Grade 3-4 haematological toxicity.  In the intraperitoneal group, 6% of patients 
had objective tumour reduction and 31% had stable disease.  In the combined treatment group, 9% of 
patients achieved objective responses and 32% had stable disease. 
2.3.3 
Chimeric MOv18 IgG 
A single IV infusion of increasing doses of chimeric MOv18 IgG was evaluated in 15 ovarian carcinoma 
patients (Molthoff et al., 1997).  Administration of chimeric MOv18 IgG was described as uneventful with 
no significant changes in haematological, biochemical, or urine profiles noted at any time following 
injection.  At doses of 50 mg or more, however, all patients experienced infusion-associated side effects 
such as fever, headache, and nausea/vomiting (Grade 1-2 on the World Health Organization Toxicity 
Scale).  In a subsequent study, five ovarian cancer patients received weekly IV injections (50 mg) for 4 
weeks (van Zanten-Przybysz et al., 2002).  Administration was described as well tolerated and 
uneventful in all patients, although infusion-associated Grade 1 nausea, vomiting, headache, chills, flu’-
like symptoms, arthralgia and myalgia were reported.  Three patients achieved stable disease for up to 
4 months, 9 months and 14 months, respectively.  Immunological effects of treatment were evaluated 
in this study but only minor changes were noted (increased antibody-dependent cell-mediated 
cytotoxicity [ADCC] associated with an increase in CD4+ and CD8+ fractions).  
The use of radiolabelled MOv18 IgG1 as a radiotherapeutic agent has also been evaluated.  In 
24 patients with ovarian cancer the distribution of 1 mg of iodine radiolabelled MOv18 IgG was 
compared with that of the labelled IgG F(ab')2 fragments (Buist et al., 1993).  In a separate study, iodine-
131 radiolabelled MOv18 IgG1 was administered to eight patients intraperitoneally at doses of 
equivalent to 15, 20, 50 or 80 mg or intravenously to four patients at doses of 30, 50 or 75 mg (Buijs et 
al., 1998).  Three patients with ovarian cancer were also administered 10 mg of iodine-131 radiolabelled 
chimeric MOv18 IgG (van Zanten-Przybysz et al., 2000).  The dosimetry of iodine radiolabelled MOv18 
IgG1 administered via the IP or IV route has also been examined.  Fifteen patients with recurrent 
epithelial ovarian cancer received a total of 2 to 3 mg of iodine radiolabelled MOv18 IgG1 by a mixture 
of IP and IV injections (van Zanten-Przybysz et al., 2001). No toxicity attributable to FR targeting was 
reported in any of these studies. 
No human anti-chimeric antibodies were detected in these studies. 
2.3.4 
Farletuzumab 
Farletuzumab (MORAb-003), a humanised IgG antibody directed against the FR has been evaluated in 
the phase III setting.  In a phase I study in platinum-resistant epithelial ovarian carcinoma, farletuzumab 
was well tolerated at doses ranging from 12 mg/m2 to 40 mg/m2 (Konner et al., 2010).  No treatment-


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related serious adverse events (SAEs) occurred and no dose-limiting toxicity (DLT) was encountered.  
The most common treatment-related adverse events were hypersensitivity reactions (15 patients; 60%), 
fatigue (12 patients; 48%), and diarrhoea (4 patients; 16%).  There were no clinically significant changes 
in cardiac, pulmonary or renal function and no evidence of human anti-human antibody formation.  The 
most common hypersensitivity reactions were pyrexia and chills, which were mostly Grade 1 in severity 
and occurred during the first infusion.  Pharmacokinetic analysis demonstrated a half-life of 5-11 days, 
consistent with other humanized monoclonal IgG antibodies (this finding was supported by a subsequent 
population PK analysis (Farrell et al., 2012).  Anti-tumour activity was also seen, with four patients 
achieving a response according to CA125 tumour markers, and seven patients achieving stable disease 
on imaging.  There were no objective responses but nine patients (36%) had stable disease and four 
patients had a CA125 reduction. 
Preliminary data have been published from a phase II study of farletuzumab, conducted in patients with 
platinum-sensitive epithelial ovarian cancer after an initial remission period of 6-18 months (Armstrong 
et al., 2008).  Twenty-eight asymptomatic patients were given single agent farletuzumab at a dose of 
100 mg/m2 until progressive disease occurred.  After nine weeks of treatment, one patient showed a 
measured reduction in CA125 tumour marker by >75% and a further patient by >25%.  Eight patients 
had stable disease and five patients remained on study for 15-25 weeks.  Patients with symptomatic 
relapse were given standard chemotherapy with carboplatin and paclitaxel combined with farletuzumab.  
In total, results from forty-one patients were evaluated and amongst these patients, CA125 resolved to 
normal levels in thirty-seven patients.  Six patients remained in remission for longer than their first 
remission.  Although independent radiological reviews were not complete, a 70% response rate was 
seen.  The drug combination was well tolerated, although with infrequent mild infusion reactions noted.  
Grade 3 toxicity was reported for single agent treatment (headache and abdominal disease secondary 
to progressive disease), and for farletuzumab in combination with chemotherapy (diarrhoea and 
neutropenia). 
In December 2011, in a company press release, Morphotek, a subsidiary of Eisai Inc., announced the 
termination of FAR122 (NIH Clinical Trials identifier NCT00738699), a Phase III study of farletuzumab 
in platinum-resistant ovarian cancer.  This decision was based on the results of an interim analysis 
indicating the study was unlikely to meet its statistically defined endpoints of progression-free survival 
and overall survival.  Safety issues did not play a part in this decision.  In January 2013, the company 
announced that a second phase III trial of farletuzumab (NCT00849667), in platinum-sensitive ovarian 
cancer, had failed to achieve its primary objective (improved progression-free survival).  Overall, these 
phase I/II/III data suggest that farletuzumab has, at best, modest efficacy in patients with ovarian cancer.  
However, farletuzumab is well tolerated and adverse effects reported to date do not appear to be related 
to targeting of the FR in normal tissues.  
2.3.5 
Other approaches 
Other therapeutic approaches targeting the FR include folate-targeted liposomes e.g. (Watanabe et al., 
2012), folate-targeted nanoparticles and other novel delivery methods e.g. (Wang et al., 2012), bispecific 
antibodies (Canevari et al., 1995; Luiten et al., 1997), immunoconjugates of single chain antibodies 
(Melani et al., 1998), adoptive T-cell therapy using genetically modified T-cells expressing a chimeric 
anti-FR single-chain antibody (Kershaw et al., 2006), and dendritic cell vaccines transfected with mRNA 
encoding FR (Hernando et al., 2007).  
Vintafolide, a conjugate of folic acid (the ligand for FR) and a vinca alkaloid is in clinical development 
for ovarian, lung and triple-negative breast cancer. In a phase I study, constipation, nausea, fatigue, and 
vomiting were the most commonly reported adverse events and constipation was dose-limiting (Lorusso 
et al., 2012).  One partial response to therapy was observed in a patient with metastatic ovarian cancer.  
A subsequent randomised phase II study of vintafolide in combination with pegylated liposomal 
doxorubicin (the PRECEDENT study) showed a significant improvement in progression-free survival in 
patients with platinum-resistant ovarian cancer (Naumann et al., 2010) and this was the basis of an 
initial EU recommendation for conditional approval.  However, an interim analysis of a confirmatory 
Phase III trial in platinum-resistant ovarian cancer (NIH Clinical Trials identifier NCT01170650; 
PROCEED trial) was negative and the application for conditional approval was withdrawn.  However, 
evidence of anti-tumour activity has also been reported in a randomised phase II trial of vintafolide in 
FR-positive adenocarcinoma of the lung (Edelman et al., 2012).  Importantly, in relation to the MOv18 


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IgE CRUKD/14/001 study, the adverse events reported to date for vintafolide do not suggest that 
toxicities are due to targeting of FR in normal tissues (consistent with clinical data for MOv18 IgG and 
farletuzumab). 
For additional information concerning MOv18 IgE, refer to the Investigator’s Brochure. 
2.4 Rationale for the clinical study 
2.4.1 
Rationale for using IgE therapeutically  
Monoclonal antibodies directed against tumour antigens have become an important treatment modality 
in the clinical management of both haematological and solid malignancies in the last 25 years.  Several 
antibodies are now licensed and these humanised or chimeric antibodies behave in a manner similar to 
naturally occurring immunoglobulins (Reichert et al., 2007).  All therapeutic antibodies licensed to date 
have been IgG antibodies (mainly IgG1).  Although they have been shown to be efficacious in the clinical 
management of some cancers it is possible that other antibody classes - namely IgE - may have superior 
anti-tumour efficacy because of differences in tissue retention, higher receptor affinity, natural tissue 
surveillance activities, as well as activation and recruitment of a different spectrum of immune effector 
and inflammatory cells to the tumour site.  
IgE antibodies are primarily known for their role in the immediate hypersensitivity reactions – the basis 
of conditions such as allergic rhinitis and asthma.  IgE antibodies against allergens remain permanently 
bound to IgE receptors on the surface of IgE receptor-expressing cells such as mast cells, basophils 
and Langerhans cells.  The cross-linking of FcεRI on mast cells by allergen, leads to the release of 
histamine and cytokines which increases circulation to the tissue and the influx and activation of 
inflammatory and potentially cytotoxic cells at the site of allergen provocation.  These activated cells 
may also migrate to local lymph nodes to stimulate T cells which in turn migrate to the tissue (Gould et 
al., 2003).  Overall, nonclinical data suggest that the efficacy of immunotherapy for solid tumours may 
be improved by the use of IgE antibodies in place of the conventional IgG. Nonclinical data and ex vivo 
data using clinical samples also indicate that MOv18 IgE will not trigger anaphylaxis when administered 
intravenously to humans, regardless of the presence of FRα-expressing tumours, circulating FRα or 
FRα-expressing cells.  
2.4.2 
Rationale for folate receptor alpha as a target 
MOv18 IgE is a chimeric antibody raised against an epitope of the human FRα. The significance of this 
receptor as a tumour marker was discovered in 1991 when amino acid sequence analysis of a protein 
enriched on the surface of a human ovarian carcinoma cell line showed it to be FRα (Coney et al., 1991).  
Monoclonal antibodies that recognise FRα revealed that it was expressed on the majority of non-
mucinous ovarian carcinomas.  However, little to no reactivity was detected on non-epithelial tumours 
and normal tissues (Miotti et al., 1987).  Subsequent publications have reported elevated FRα 
expression in up to 100% of ovarian carcinomas and lower but elevated expression levels in subsets of 
other cancers, including endometrial, kidney, lung, mesothelioma, breast, brain, and myeloid leukaemia 
(Franklin et al., 1994; Garin-Chesa et al., 1993; Holm et al., 1995; Holm et al., 1997; Holm et al., 1994; 
Parker et al., 2005; Ross et al., 1994; Weitman et al., 1992).  Using the immunohistochemical technique 
planned for this study FRα overexpression is expected to be detectable in around 30-40% of ovarian 
and endometrial cancers, with less frequent expression in other tumour types (Lawson et al., 2010). The 
presence of elevated circulating concentrations of FRα has additionally been correlated with biologically 
more aggressive ovarian cancers (O'Shannessy et al., 2013; Toffoli et al., 1998).  
A few normal tissues have been found to express FRα, although most express the protein at lower levels 
than that detected in FRα-positive carcinomas.  Significant FRα expression has been reported in the 
proximal tubules of the kidney (luminal surface), the choroid plexus, intestinal brush-border membranes, 
type 1 and type 2 pneumocytes of the lung and placental tissue (Antony et al., 1981; Birn et al., 1997; 
Birn et al., 1993; Holm et al., 1991; Morshed et al., 1997; Zimmerman, 1990).  Expression of FRα in 
these tissues is generally not accessible to circulating antibodies and so FRα is effectively a tumour-
specific antigen.   


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In clinical trials to date, FRα has been targeted with IgG antibodies.  These antibodies have been well 
tolerated with no evidence of toxicity secondary to FRα binding in normal tissues.  However, anti-tumour 
efficacy has been disappointing.  
 
 
 
 
This study will be a proof of principle study, primarily demonstrating the safety of an alternative antibody 
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to reach a threshold frequency of dose-independent significant toxicity (Section 3.3.2) or to reach the 
maximum planned dose level (50 mg). 
It is expected that the study will take about 4 to 5 years depending upon the number of cohorts explored 
during dose escalation.   
MOv18 IgE will be administered as an IV infusion. Patients in all cohorts will receive a total of six doses 
of MOv18 IgE at 1-week intervals (over an initial dosing period of 6 weeks). This dosing period, called 
the ‘Initial Treatment Period’, is considered a loading phase. During this period, three weeks of treatment 
is considered one cycle.  
Should additional drug supply become available during the study (for example if dose escalation does 
not proceed through all the planned dose levels), patients in any cohort who appear to be benefitting 
from MOv18 IgE may be given up to three further doses of MOv18 IgE at fortnightly intervals, starting 
two weeks after the sixth dose of MOv18 IgE, and continuing at the same dose level as the last dose 
received.  This additional period is considered a maintenance phase. The total number of doses for 
patients completing the ‘Initial Treatment Period’ and the ‘Maintenance Period’ would be 9 over a 
treatment period of 12 weeks.      
Please refer to Figure 3: MOv18 IgE Dosing Schedule in Section 5.3.   
It is planned that all patients will receive a flat dose of MOv18 IgE, without adjustment for body weight 
or surface area. The starting dose will be 70 µg and dose escalation will be carried out through defined 
dose levels up to a maximum dose of 50 mg (see Section 5.4 Dose Escalation Scheme). However, a 
switch to weight-based dosing and/or intra-patient escalation will be considered during the course of the 
trial, if emerging clinical data suggest that this could be beneficial, for example by reducing any large 
inter-patient variations in PK.  
3.3 Definition of dose limiting toxicity 
Therapeutic IgGs such as trastuzumab, alemtuzumab or rituximab, and related proteins commonly 
cause infusion-related reactions.  These reactions are thought to be due to cytokine release and typically 
are most frequent and severe with the first infusion, declining in incidence and severity thereafter. Such 
reactions are generally managed by slowing or interrupting the infusion.  It is possible that MOv18 IgE 
will cause these non-specific infusion-related reactions, which are biologically distinct from anaphylaxis, 
although it can be difficult to distinguish them clinically.  
Despite pre-clinical evidence suggesting otherwise, it is possible that MOv18 IgE may also cause 
anaphylaxis due to basophil and/or mast cell degranulation.  Such a reaction would be predicted to 
persist and probably worsen with subsequent infusions.  Slowing or interrupting the infusion would 
typically be insufficient to control such a reaction and systemic therapy, including administration of 
adrenaline, might be needed. 
Clinically, the symptoms, signs and onset of typical cytokine release-type infusion reactions are very 
similar to those associated with IgE-mediated basophil and/or mast cell degranulation/anaphylaxis and 
it may be difficult to distinguish these different types of acute reaction in a patient receiving their first 
dose.  However, the presence of urticaria is almost universal in reactions due to mast cell degranulation, 
but is not typical of infusion reactions seen with protein-based therapeutics such as IgGs (although it 
can occur).  Importantly, emerging data from the CRUKD14001 study indicate that urticaria without 
systemic symptoms is common with MOv18 IgE and does not necessarily indicate the onset of 
anaphylaxis. Serum tryptase elevation (a marker of mast cell degranulation) would not be expected to 
occur with cytokine release-type infusion reactions (Cheifetz et al., 2003), and for this study is 
considered critical in distinguishing these two types of reactions clinically.  
3.3.1 
Dose limiting toxicity (DLT) 
Dose limiting toxicity is defined as any of the following events occurring in the first 3 weeks of IMP 
administration that are considered to be probably or highly probably related to MOv18 IgE: 


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(For dose-independent significant toxicity, see Section 3.3.2) 
Non-haematological toxicity 
• 
Any other drug-related non-haematological Grade 3 or 4 toxicity EXCLUDING: 
➢ Grade 3 or 4 nausea or vomiting, in patients who have not received optimal 
treatment with anti-emetics 
➢ Grade 3 or 4 diarrhoea in patients who have not received optimal treatment with 
anti-diarrhoeals e.g. loperamide and/or codeine 
➢ Transient Grade 3 biochemical abnormalities that are asymptomatic and 
considered not to be clinically significant 
➢ Grade 3 fatigue 
• Fatal event 
Haematological toxicity 
• 
Grade 4 neutropenia (ANC < 0.5 x 109/L) for  5 days duration *see note 
• 
Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection with Grade 3 or 4 neutropenia [ANC <1.0 x 109/L] and fever  38.5ºC) 
• 
infection (documented clinically or microbiologically) with Grade 3 or 4 neutropenia (ANC 
<1.0 x 109/L); 
• 
Grade 4 thrombocytopenia (platelets < 25 x 109/L)  
a) for  5 days *see note, or  
b) associated with active bleeding, or  
c) requiring platelet transfusion. 
* In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full blood count must be 
performed at least five days after the onset of the event to determine if a DLT has occurred.  Continue 
to monitor the patient closely until resolution to Grade 3 or less. 
Note that: 
• 
Isolated cutaneous toxicity (urticaria or other skin symptoms/signs) without any associated 
systemic symptoms or signs and without serum tryptase elevation may not be considered a 
DLT, if agreed by the Trial Steering Group (TSG) (see Section 3.6 for information regarding the 
Trial Steering Group). Such patients require premedication (at least for the first subsequent 
dose) and very close observation if they are given further doses of MOv18 IgE;   
• 
A positive skin prick test is not considered a DLT in this study unless it is associated with 
systemic symptoms or signs, or an elevated serum tryptase. However, a positive skin prick test 
is considered an indicator that anaphylaxis might occur if MOv18 IgE were to be given 
intravenously.  Accordingly, positive skin prick tests are an event of interest and must be taken 
into consideration by the TSG (see Section 3.6) when decisions on dose escalation and/or 
cohort expansion are made (see also Section 5.5.4). 
The dose limiting toxicity (DLT) and maximum tolerated dose (MTD) are defined using the National 
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Should any change be made to the grade or causality of an AE during the study that may alter its DLT 
status, the Centre for Drug Development (CDD) must be informed immediately as this may affect dose 
escalation decisions. 
3.3.2 
Dose-independent significant toxicity 
Any event judged to be due to systemic IgE-mediated mast cell degranulation (anaphylaxis; see 
Appendix 5) is considered to be a dose-independent significant toxicity that may have an impact on the 
future safe use of IgE therapy. Grade 2 or worse anaphylaxis that is probably or highly probably related 
to MOv18 IgE is considered clinically important and could lead to temporary suspension of recruitment 
into the trial and/or other restrictions to patient entry (see Section 3.4.2). Observation of Grade 2 or 
worse anaphylaxis at a frequency above a pre-determined threshold will lead to permanent cessation 
of the trial. 
3.4 Definition of maximum tolerated dose  
3.4.1 
Maximum tolerated dose (MTD) 
The maximum tolerated dose will be defined as a dose level below the dose level associated with DLT 
in two out of three patients (or two out of six patients in an expanded cohort).  All decisions on dose 
escalation/de-escalation and cohort expansion/termination will be made by the Trial Steering Group. 
(see Section 3.6). 
It is possible that the MTD will not be reached in this study.   
The RP2D will be determined following discussion of all relevant toxicity and efficacy data by the TSG.  
All significant toxicities (including those occurring after the first three doses of MOv18 IgE) will be 
considered in the determination of the RP2D. 
3.4.2 
Acceptable frequency of dose-independent significant toxicity (anaphylaxis) 
Anaphylaxis is an unwanted event driven by effector cell degranulation that is usually triggered by 
exposure to an allergen. Emerging data from the CRUKD14001 trial indicate that anaphylaxis following 
exposure to Mov18 IgE can occur, but this is unlikely to be dose-related. Patient-specific factors in an 
affected patient (such as the presence of pre-existing antibodies to IgE) may be involved. Anaphylaxis 
is reported following exposure to many other medications, although the frequency of such events is 
generally low. Therefore, the occurrence of anaphylaxis in a single patient in the CRUK14001 trial does 
not necessarily indicate that a maximum tolerated dose has been reached, or that recruitment overall, 
cohort expansion, and/or dose escalation should cease in the CRUKD14001 trial.  
Accordingly, for anaphylaxis >Grade 1 within this trial (defined according to Appendix 5), an assessment 
will be made as to the frequency of these events (taking into account events seen in all patients who 
received MOv18 IgE). An anaphylaxis frequency of 1% or less is likely to be acceptable, but a frequency 
of 20% or more unacceptable, based on experience with other medications used in routine oncology 
practice. Therefore, if any patient experiences >Grade 1 anaphylaxis, recruitment will be suspended 
and a dose review meeting will take place. Taking into consideration the relatively small numbers of 
patients that are enrolled in a Phase I trial, the TSG will decide whether further patients should be 
enrolled, whether the dose escalation and/or cohort expansion may continue and whether there should 
be further restrictions to patient eligibility (if clear risk factors for anaphylaxis can be identified). The TSG 
will also take into consideration any equivocal or Grade 1 events, should these occur. 
3.5 Patient evaluability 
All patients who receive any amount of MOv18 IgE, either by IV infusion or as a skin prick test, will be 
evaluable for safety.  However, dose escalation decisions require at least one or three patients 
(depending on the cohort) to receive 3 doses of IV MOv18 IgE without DLT (see Section 5.4).  


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All eligible patients who receive at least one dose of IV MOv18 IgE and have a baseline and at least 
one post-baseline disease assessment will be evaluable for response according to RECIST version 1.1 
(see Appendix 3).  For this study, to be assigned a status of complete response (CR) or partial response 
(PR), changes in tumour measurements do not need to be confirmed by repeat measurements four 
weeks later.  To be assigned a status of stable disease (SD), follow-up measurements must have met 
the SD criteria at least once and at least six weeks after the initial dose of MOv18 IgE is given. 
3.6 Trial Steering Group 
The TSG is composed of relevant members of the CDD Study Team (including at least one CDD 
member with the appropriate expertise in the area being discussed), the Chief Investigator (CI), the 
Chief Scientific Investigator and Principal Investigators (PIs) (a nominated sub- or co-investigator may 
attend in the PI or CI’s place if necessary).  The TSG is responsible for reviewing safety and efficacy 
data on a regular basis and for making decisions on dose escalation, cohort expansion/termination and 
other aspects of the study. Members should attend dose review meetings (in person or by telephone) 
and other relevant meetings. Clinical and preclinical immunology/allergy experts are involved, as 
needed. 
Within this protocol there are various examples of when the TSG will be consulted – their involvement 
is not limited to these situations.  




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6. 
Female patients who are able to become pregnant (or already pregnant or lactating).  However, 
those female patients who have a negative serum or urine pregnancy test before enrolment and 
agree to either sexual abstinence* or to use two highly effective forms of contraception (oral, 
injected or implanted hormonal contraception and condom; have an intra-uterine device and 
condom; diaphragm with spermicidal gel and condom) effective at the first administration of IMP, 
throughout the study and for six months afterwards are considered eligible.  
7. 
Male patients with partners of child-bearing potential (unless they agree to take measures not to 
father children by using one form of highly effective contraception at the first administration of IMP, 
throughout the study and for six months afterwards) or agree to sexual abstinence*.  Men with 
pregnant or lactating partners should be advised to use barrier method contraception (for example, 
condom plus spermicidal gel) to prevent exposure to the foetus or neonate. 
8. 
Major thoracic or abdominal surgery from which the patient has not yet recovered. 
9. 
At high risk from the effects of anaphylaxis because of non-malignant systemic disease including 
active 
uncontrolled 
infection, 
cardiac 
failure, 
peripheral 
vascular 
disease, 
previous 
cerebrovascular accident (CVA), dyspnoea due to heart failure, extensive lung metastases, 
significant pleural effusions or other conditions. 
10. History of laryngeal oedema, uncontrolled or high-risk asthma (according to Global Initiative for 
Asthma (GINA) guidelines – see Appendix 7), or anaphylaxis. Patients with a history of 
hypersensitivity to carboplatin, taxanes, or contrast media may enter the study at the investigator’s 
discretion. 
11. Patients with any congenital or acquired immunodeficiency syndrome or receiving 
immunosuppressive therapy (including any dose of systemic corticosteroids), or who are 
immunosuppressed post organ transplant.  However, patients receiving inhaled corticosteroids 
and patients with a history of allergy (other than anaphylaxis) are eligible, as are patients with a 
history of auto-immune disease. 
12. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus 
(HIV). 
13. Patients with baseline elevation in serum tryptase (indicating possible mastocytosis) or a positive 
baseline basophil activation test (indicating a hypothetical potential for anaphylaxis with MOv18 
IgE). 
14. Participating or planning to participate in another interventional clinical trial, whilst taking part in 
this study.  Participation in an observational study or in the follow-up phase of a previous 
interventional trial is acceptable. 
15. Any other condition which in the Investigator’s opinion would not make the patient a good 
candidate for the clinical study. 
16. Patients unwilling or unable to interrupt antihistamines (which may interfere with skin prick 
testing).  Antihistamines should be discontinued at least 4 half-lives before the first skin prick test 
(see Section 5.7 for further information). 
* Abstinence is only considered to be an acceptable method of contraception when this is in line with 
the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
4.2 Patient enrolment 
Before enrolling the patient in the trial, the Investigator or designated representative should determine 
the eligibility of the patient.  Please ensure that CDD are notified of any eligibility concerns at least four 
working days before treatment is planned.  Importantly, for this trial, paired pre-treatment and 
on-treatment tumour biopsies are required for all patients.  
Eligible patients must be enrolled in the EDC system by site staff and then registered at the CDD before 
they start treatment with MOv18 IgE.  If the patient is eligible the patient number will be automatically 
allocated by the EDC system during the enrolment process.  The CDD will send confirmation of the 
patient registration and the assigned dose level to the Investigator following enrolment of the patient. 
Study treatment may only be administered after confirmation has been received. 


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5 
TREATMENT 
5.1 Selection of the Phase I starting dose  
In selecting the starting dose and dose escalation scheme for this trial the needs of patient safety were 
balanced with the desire for anti-tumour efficacy.  The starting dose of MOv18 IgE was based on data 
from a range of sources. 
• 
Non-clinical studies of rMOv18 IgE 
 
  
 
 
  
 
 
 
 
 
 
• 
The affinity of MOv18 IgE for the FRα 
 
 
 
 
 
 
 
• 
The affinity of MOv18 IgE for the FcεRI 
 
 
 
 
  
 
 
  
 
 
• 
Normal levels of circulating IgE in healthy humans 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Based on previous human experience 
 
 
Based on these data the starting dose for this clinical trial could lie in the range 10 µg to 500 mg/kg.  
However, the pharmacology of IgE suggests that adverse events are most likely to result from the 
interaction of IgE with effector cells rather than the free antibody or antibody-antigen complex.  
Therefore, an appropriate starting dose should consider the interaction of the IgE with FcεRI rather than 
its antigen interactions.  As the administered IgE will have to compete with endogenous IgE for effector 
cell binding, the relative concentration of the two IgEs in serum is considered critical in determining the 


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effect of MOv18 IgE doses.  Accordingly, the clinical starting dose for this study is based on the normal 
range of circulating IgE. A starting dose of 70 µg or one tenth of the normal circulating IgE level has 
been selected.  A dose of 70 µg of MOv18 IgE is expected to produce a pulse of binding to effector cells 
before the unbound MOv18 IgE is cleared (IgE has a plasma half-life of 2 days in human).  In contrast, 
endogenous IgEs will continuously be replenished and quickly out-compete MOv18 IgE for effector cell 
binding. 
The 70 μg starting dose is considered to be scientifically justified based on the known pharmacology of 
IgE in humans.  This starting dose is approximately half that estimated based on the affinity of MOv18 
IgE for its target antigen, 50 fold higher than that based on its affinity for FcεRI, and six fold greater than 
the existing human experience of exogenously administered IgE.  However, exceeding these lower 
estimates for the starting dose of MOv18 IgE is considered justified for MOv18 IgE based on existing 
knowledge of the biology of IgE. 
5.2 Selection of the maximum dose  
A maximum evaluated dose of 50 mg is proposed.  While this dose is lower than that for most IgGs used 
therapeutically in oncology (e.g., trastuzumab, rituximab, bevacizumab and pertuzumab), the 
pharmacology of IgE indicates that these doses are sufficient to overwhelm endogenous IgE and 
produce pharmacodynamic effects.   
5.3 Dosing schedule/treatment schedule 
Please refer to Figure 3 later in this section for details of the MOv18 IgE dosing schedule.   
It is planned that all patients will receive flat doses of MOv18 IgE, without adjustment for body weight or 
surface area (based on the expected pharmacokinetics and toxicity of an IgE, there is no reason to 
adjust dosing for body weight or surface area). However, a switch to weight-based dosing, and/or intra- 
patient escalation will be considered during the course of the trial, if emerging clinical data suggest that 
this could be beneficial, for example by reducing any large inter-patient variations in PK.  
Initial Treatment Period 
Patients in all cohorts will receive a total of six doses of MOv18 IgE at 1-week intervals unless 
dose-limiting toxicity is encountered or the patient develops progressive disease. During this period, 
three weekly doses will be considered one cycle of treatment.  
A weekly dosing schedule has been selected for initial dosing of MOv18 IgE due to the relatively short 
plasma half-life of IgE (2 days) but relatively long tissue half-life (2 weeks).  In addition, weekly dosing 
appeared to be efficacious in the rat model.  Weekly administration should result in plasma levels 
sufficient to maintain occupancy of effector cell FcεRI by MOv18 IgE at higher doses.   
Maintenance Period 
Should additional drug supply become available during the study (for example, if dose escalation does 
not proceed through all the planned dose levels), patients in any cohort who appear to be benefitting 
from MOv18 IgE may be given up to three further doses of MOv18 IgE at fortnightly intervals continuing 
at the same dose level as the last administered dose (unless dose-limiting toxicity is encountered or the 
patient develops progressive disease).  Ideally, the first maintenance dose of MOv18 IgE will be given 
two weeks after the sixth dose of MOv18 IgE.  However, a gap of up to 4 weeks will be allowed.    
A two-weekly dosing schedule has been selected for ‘maintenance’ dosing (which will only take place if 
drug supply permits). This choice is based on the expected long tissue half-life of MOv18 IgE which 
suggests that six weekly doses will have effectively ‘loaded’ the patient with MOv18 IgE-bound to 
effector cells in the tissues.  


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Figure 3: MOv18 IgE Dosing Schedule 
 
5.3.1 
Study drug administration 
All patients will receive their first two doses of MOv18 IgE as an IV infusion over 90 minutes (+/-15 mins).  
A shorter infusion time for subsequent doses of 60 minutes (+/-10 mins) will be allowed if no infusion-
related reactions or other allergic reactions are encountered after two doses have been administered. 
A longer infusion time for subsequent infusions will also be allowed if required in order to manage 
infusion related cutaneous toxicity. Patients should remain in the clinic for observation for at least one 
hour after every dose of MOv18 IgE. 
The study will be undertaken at investigational centres staffed and equipped to manage medical 
emergencies and with intensive care facilities. If the patient experiences an event related to study drug 
that requires intensive clinical care, the Sponsor must be notified immediately. 
Patients will be admitted overnight after the first two doses to facilitate intensive safety monitoring 
procedures.  At the investigator’s discretion, the requirement for admission may be waived for the 
second dose if the patient experiences no clinically important adverse events related to MOv18 IgE 
during the infusion and observation period. 


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Pre-medication will be administered prior to the first dose in later cohorts if deemed medically 
appropriate. See Section 5.4  
The patient will be intensively monitored during their first two infusions, with measurement of vital signs 
(blood pressure, pulse rate and temperature) every 15 minutes from the start of the infusion until 
30 minutes after completion of the infusion.  If no changes are seen, during the first two infusions, then 
for subsequent infusions vital signs will be assessed 15 minutes and 30 minutes after completion of the 
infusion. Continuous monitoring with a pulse oximeter is required throughout each infusion until 
30 minutes after completion. 
If the patient experiences symptoms suggestive of an infusion-related reaction or cytokine release (such 
as fever, chills, and myalgia), the infusion must be slowed or interrupted and the patient must be treated 
with oxygen, paracetamol, antihistamines, fluid resuscitation and/or steroids, as clinically indicated. If 
the reaction does not respond to these conservative measures or is > Grade 2 in severity, the algorithm 
for the treatment of anaphylaxis must be followed (Appendix 4). Note that for the purposes of this 
protocol, infusion-related symptoms and signs (such as fever, myalgia, and hypotension) will be 
recorded and graded individually according to NCI-CTCAE Version 4.02.  Grading of systemic mast cell 
degranulation (anaphylaxis) is defined in Appendix 5 and grading of cytokine release syndrome is 
defined in Appendix 6, but the distinction between these two events and grading of these events will be 
performed only in retrospect when results of serum tryptase assays are available, and will thus not be 
relevant for the management of acute events at the time of infusion.  A blood test for measurement of 
serum tryptase will be taken on completion of all infusions.  Additional blood samples for serum tryptase 
levels should be taken in patients who experience a suspected anaphylactic reaction, such as urticaria 
and/or severe infusion-related symptoms necessitating interruption or discontinuation of the infusion. 
Additional samples for serum tryptase should also be taken for patients with a positive skin prick test 
(see study lab manual and protocol section 7.2 for time points).  For details on grading and reporting of 
infusion-related events and anaphylaxis see Section 7.2.5. 
The following medications must be available at the bedside for use in case of an immune-mediated 
reaction: epinephrine (0.5-1mL IM injection 1:1000), chlorphenamine 10 mg IV/IM injection, paracetamol 
1 g orally, hydrocortisone 200 mg IM or IV; oxygen (see 16.4 Appendix 4: Treatment of Anaphylaxis). 
For patients who are enrolled in an intra-patient escalation cohort, and receive a higher dose in Cycle 2, 
the following additional measures will apply:  
• 
In Cycle 1 and in Cycle 2 all patients will receive their first two doses of MOv18 IgE as an IV 
infusion over 90 minutes (+/-15 mins). A shorter infusion time for subsequent doses of 
60 minutes (+/-10 mins) will be allowed if no infusion-related reactions or other allergic reactions 
are encountered after two doses at each dose level have been administered. A longer infusion 
time for subsequent infusions will also be allowed if required in order to manage infusion related 
cutaneous toxicity.  
• 
Patients will be admitted overnight after the first two doses in Cycle 1, and the first two doses in 
Cycle 2 to facilitate intensive safety monitoring procedures.  The requirement for admission may 
be waived for the second dose in each cycle at the investigator’s discretion. 
• 
Patients will be intensively monitored during their first two infusions (Cycle 1 doses 1 and 2) and 
in Cycle 2 (doses 4 and 5 at the increased dose level), the same monitoring will be performed 
as for Cycle 1. 
5.4 Dose escalation scheme 
The planned dose escalation scheme is summarised in Table 1.  Additional cohorts may be added to 
evaluate intermediate dose levels or to evaluate alternative dosing schedules, depending on emerging 
safety information and/or pharmacokinetic data if available.  Non-clinical studies have indicated that 
efficacy in rat xenograft models occurs at 5 to 10 mg/kg.  This equates to a surface-area scaled human 
dose of approximately 50 to 100 mg.  However, the plasma half-life of IgE in rat is considerably shorter 
than in human (12 hours versus 2 days) (Hanashiro et al., 2001, 2002).  Efficacious doses in the rat 
were associated with plasma rMOv18 IgE levels sufficient to represent at least 50% of total plasma IgE 




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Decisions on dose escalation will be based primarily on toxicities encountered after the first two doses 
of MOv18 IgE in each cohort (see Table 2),or the first two doses of cycle 2 for patients undergoing intra-
patient dose escalation. However, if available, data on toxicities occurring after later doses will also be 
taken into consideration.  The decision to start a new cohort, and selection of the MOv18 IgE dose for 
each cohort, will be agreed by investigators and sponsor on review of the toxicities experienced by the 
preceding cohort during the three-week period from first dosing of each patient. The availability of paired 
pre-treatment and on-treatment tumour biopsies will also be taken into consideration in decisions on 
starting a new cohort since paired tumour biopsies are required for all patients.  
Based on emerging safety information, prophylactic medication (antihistamine, antipyretic and/or 
corticosteroid), will be given ahead of the patient’s first and subsequent infusions if considered 
medically appropriate by the PI and Sponsor. Under these circumstances, the prophylactic medication 
should be given after the skin prick test (before IV administration of MOv18 IgE). Any prophylactic 
medication will be used within its marketing authorisation. 
Table 2: Dose escalation decision-making 
No. Patients with DLT 
Action 
0/1 (Cohorts 1-4 only) 
Increase to next level 
0/3 
Increase to next level 
1/3 
Accrue 3 more pts at same dose level 
1/3 + 0/3 
Increase to next dose level 
1/3 +1/3* 
Stop: recommend previous dose level 
1/3 + 2/3* 
Stop: recommend a lower dose level 
1/3 + 3/3* 
Stop: recommend a lower dose level 
2/3* 
Stop: recommend previous dose level 
3/3* 
Stop: recommend a lower dose level 
*No additional patients will be added to a cohort after a second DLT is observed.  Should DLT occur in 
more than 2/3 or 2/6 patients in a cohort, the previous dose level may not be the most appropriate RP2D. 
Note: Dose-independent significant toxicity (anaphylaxis) is not counted as a DLT as shown in Table 2 
(above) but may limit recruitment to the trial as a whole as outlined in Section 3.4.2.  
5.4.1 
Intra-patient dose escalations  
The established pattern of predictable and tolerable adverse events in Cohorts 1-6 provides 
reassurance that accelerated dose escalation could proceed subsequently. Intra-patient dose escalation 
may be initiated from Cohort 7 onwards in order to evaluate alternative doses, depending on emerging 
safety information and/or pharmacokinetic data if available. An intra-patient dosing schedule has been 
proposed as per Table 3.  
A dose review meeting will be held following completion of Cycle 1 in Cohorts 7 and above, prior to 
confirming the intra-patient dose escalation for Cycle 2. Should a patient experience any IMP-related 
AEs of Grade 2* or higher in Cycle 1, then intra-patient dose escalation will not occur, and the patient 
will continue to be dosed in Cycle 2 based on the flat dose received in Cycle 1 (See Figure 4). 
An additional dose review meeting will be held following completion of Cycle 2 prior to confirming the 
opening of the next cohort. Should a patient experience any IMP-related AEs of Grade 2* or higher in 


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Cycle 2, then the decision will be made by TSG based on safety data available to either: expand the 
Cohort by one patient and repeat Cycle 1 and 2 dose levels, OR recruit to the next cohort.  
Note: Depending on the outcome of the TSG review where patients have experienced a Grade 2 MOv18 
related AE, it may be deemed appropriate to move to the next dose level.  Assessment for this will be 
made on a case by case basis. Grade ≥2 rash will generally not preclude intra-patient dose escalation 
or opening of the next cohort. 
If a DLT is experienced in Cycle 1 or Cycle 2, treatment will be withheld until toxicity resolves to baseline 
or Grade 1. Upon resolution, if appropriate, MOv18 IgE may be recommenced at a lower dose, or the 
patient may withdraw from study treatment. The cohort will be expanded, and a decision will be made 
by the TSG whether to expand the cohort by 1 or 2 patients, depending on the nature of the DLT 
observed (e.g. its nature, grade, expectedness and clinical significance).  
Table 3: Planned intra-patient dose escalation scheme 
Cohort 
Cycle 1 Dose level 
Cycle 2 Dose level 
No. planned 
patients/cohort 
7(i) 
6 mg 
*12mg 
1** 
8(i) 
12 mg 
*20mg 
1 
9(i) 
20mg 
*40mg 
1 
* If required, intermediate dose levels may be explored for the starting dose in Cycle 2, this will be discussed at the 
dose review meeting and is dependent on the emerging safety profile.  
**A minimum of 1 patient will be dosed in each cohort, the final number will be dependent on review of safety data 
from that dose level. 
(i) indicates this is an intra-patient escalation cohort 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 4: Intra-patient dose escalation: Example of planned escalation 
The TSG to review all data and pay careful consideration to the safety of any current or future 
patient before making any decisions. Planned escalation may vary from the below based on TSG 
review of emerging safety data.  
 


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5.4.2 
Expansion of dose level(s) 
If one instance of DLT (as defined in Section 3.3) is observed in up to three patients, then up to six 
patients will be treated at that dose.  If one out of six patients experience a DLT, dose escalation will 
continue.  If two out of up to six (i.e. between two and six) patients experience a DLT, dose escalation 
will stop, and this dose will be defined as the maximum administered dose (MAD).  At least three more 
patients will be treated at a dose below the MAD to define the MTD. 
If any dose-independent significant toxicities (i.e. Grade >1 anaphylaxis, see Sections 3.3.2 and 3.4.2) 
occur, then the TSG must meet to discuss whether any further patients can be enrolled. See 
Section 3.4.2. 
In case of uncertainty (e.g. patients with a history of immunological reactions to other agents), one or 
more additional patients with no apparent predisposing factors may be recruited to a dose level to better 
evaluate toxicity, if agreed by the TSG. 
The MAD could also equal the MTD in the event that dose escalation is stopped before two DLTs are 
observed at a given dose level, due to the expectation that higher dose levels would be too toxic to 
administer to patients. 
5.4.3 
Patients enrolled in the intra-patient escalation cohorts 
A patient must receive 3 doses of MOv18 IgE without experiencing a DLT in Cycle 1 before they are 
eligible for intra-patient escalation at a higher dose for Cycle 2. The patient must complete all three 
doses in Cycle 2 before consideration is given to opening another cohort at a higher dose.   
If a patient receives less than 80% of Cycle 1 Dose 1, but tolerates 100% of Doses 2 & 3, the patient 
will need to receive a full fourth Cycle 1 dose to make them evaluable before consideration of intra-
patient dose escalation in Cycle 2. In this situation the treatment course may consist of more than 6 
doses. 
If a patient has received at least one dose in Cycle 2 but is then withdrawn due to disease progression 
or other non-clinical reasons prior to completion of treatment, then the TSG will decide whether to 
expand the current cohort or proceed to the next cohort. This decision will be based on a review of the 
clinical safety data. 
[See Figure 4 “Intra-patient dose escalation” schema for decision making]. 
5.5 Dose modifications  
5.5.1 
Dose reductions 
Patients experiencing a DLT at any time will have their MOv18 IgE treatment withheld until toxicity 
resolves to baseline or Grade 1.  After resolution, MOv18 IgE may be recommenced at the same dose.  
Dose reduction is not generally envisaged but if required (for DLT or other toxicities, other than Grade ≥ 
2 anaphylaxis) will be to the next lowest dose according to the dose escalation scheme (Table 1).  Only 
one dose reduction is allowed per patient. Individual patient dose reductions should be discussed and 
agreed with the CDD. 
Patients experiencing Grade ≥ 2 anaphylaxis (see Appendix 5) must discontinue study medication (see 
Section 3.3.2 and 3.4.2). As per Section 3.4.2, the TSG will also take into consideration any equivocal 
or Grade 1 events, should these occur.  For other infusion reactions (see Appendix 6), continuation of 
study drug at the same dose level may be appropriate but must be discussed with the TSG. 


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5.5.2 
Dose delays 
If at the time of the next planned administration, any drug-related toxicities are still present and have not 
resolved to Grade ≤ 1 or returned to baseline, the infusion should be delayed for up to two weeks until 
these toxicities have resolved to Grade ≤ 1 or returned to baseline.  If there is no recovery after a two 
week delay (i.e. the time between doses is three weeks or more), the patient should be withdrawn from 
the study.  Dose delay for reasons other than toxicity should be avoided if possible, but delays resulting 
from intercurrent illness will not necessarily mandate discontinuation of study treatment.  
5.5.3 
Dose interruptions 
Interrupting or slowing the rate of the infusion may help control infusion-related symptoms (other than 
anaphylaxis). The infusion may be resumed when symptoms abate.  Should repeated infusion 
interruptions be required, the infusion may be interrupted overnight and resumed the following day. 
However, this is expected to be a rare occurrence. If a patient receives less than 80% of the planned 
infusion, then they will be evaluable for safety, but they will not be evaluable for dose review decisions. 
A patient must have received >80% of 3 infusions before being evaluable for dose review decisions 
unless otherwise agreed with the TSG.  
5.5.4 
Dose discontinuations following positive skin prick tests 
In general, patients experiencing a positive skin prick test will be withdrawn immediately from study 
treatment (i.e. they will receive no further IV MOv18 IgE and will undergo no further skin prick testing). 
However, IgEs have never been administered into the skin before and it is possible that they may be 
more likely to provoke a positive reaction than other agents. They may also be more likely to provoke 
cutaneous reactions (without systemic symptoms) when administered IV. The clinical implications of a 
wheal and flare reaction following skin prick testing of MOv18 IgE is therefore not clear. Accordingly, it 
is possible that patients may be able to safely receive IV MOv18 IgE (with prophylactic medication and 
very careful medical supervision) despite a positive skin prick test.  
Prior to Protocol Version 5.0, all patients underwent intradermal testing before IV MOv18 IgE 
administration. Since Protocol Version 5.0, all patients will undergo skin prick testing (instead of 
intradermal testing) prior to IV MOv18 IgE administration. It is expected that skin prick testing will avoid 
“false-positive” tests due to non-specific mast cell reactivity (which may be the cause of positive 
intradermal tests). A decision on whether to allow IV MOv18 IgE administration despite a positive skin 
prick test will be made by the TSG following a review of patient data from at least 6 patients who have 
undergone at least two skin prick tests using MOv18 IgE (assuming the first test is negative). A patient 
experiencing a positive skin prick test on first administration can also be included in this assessment. If 
50% or more of 6 patients experience a positive skin prick test (on first or subsequent exposure), without 
systemic symptoms or signs or serum tryptase elevation, IV dosing in the presence of a positive skin 
prick test may be explored with the TSG.  
The possibility of IV dosing in the presence of a positive skin prick test may be considered by the TSG 
again at a later date following enrolment of further patients, depending on emerging data (for example, 
if positive tests without systemic symptoms or signs or tryptase elevation prevent patients receiving 
further IV MOv18 IgE despite evidence of anti-tumour activity).    
5.6 Duration of treatment 
A finite number of doses will be administered to each patient. All patients should receive six weekly 
infusions (two cycles of three weeks) unless (a) the patient asks to be withdrawn, (b) there is evidence 
of disease progression, or (c) the patient experiences unacceptable toxicity, or (d) for any other of the 
reasons for withdrawal from the study listed in Section 11.  Patients who receive all six infusions in the 
Initial Dosing Period are considered to have completed study treatment.  The duration of treatment will 
be approximately six weeks followed by a 70-day (+/- 14 days) follow-up period.   
As outlined in Section 3.2, drug supply permitting, patients may continue on treatment into the 
Maintenance Period.  These patients may receive an additional three fortnightly infusions of MOv18 IgE.  


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For these patients, the total treatment duration would be 12 weeks unless treatment stops early because 
(a) the patient asks to be withdrawn, (b) there is evidence of disease progression, or (c) the patient 
experiences unacceptable toxicity, or (d) for any other of the reasons for withdrawal from the study listed 
in Section 11.  Treatment will be followed by a 70 day (+/- 14 days) safety follow-up period.   
5.6.1 
Replacement of patients 
If a patient is withdrawn from the study for reasons other than drug-related toxicity or a positive skin 
prick test and has received less than three infusions of MOv18 IgE during Cycle 1, then this patient can 
be replaced. The withdrawn patient will be replaced by another patient who will be treated at the same 
dose level.  
5.7 Concomitant medication and treatment 
Concomitant medication may be given as medically indicated.  Details (including doses, frequency, route 
and start and stop dates) of the concomitant medication given must be recorded in the patient’s medical 
records and relevant details entered into the electronic case report form (eCRF). Prophylactic 
medication (antihistamine, antipyretic and/or corticosteroid), will be given ahead of the patient’s first 
and subsequent infusions if considered medically appropriate by the PI and Sponsor (See Section 5.4). 
Palliative radiotherapy may be given concomitantly for the control of bone pain or other symptoms.  
Irradiated lesions will not be evaluable for response.  
The patient must not receive other anti-cancer therapy or investigational medicinal products during the 
study. 
The following medications are not allowed and must be discontinued before starting study treatment 
and throughout therapy: 
• 
Beta-blockers (which may counteract the therapeutic effects of adrenaline)  
• 
Tricyclic anti-depressants or monoamine oxidase inhibitors (MAOIs) (which can dangerously 
augment the effects of adrenaline) 
• 
Systemic immunosuppressive therapy (including any dose of systemic corticosteroids except 
when prescribed for prevention or treatment of infusion reactions to MOv18 IgE; inhaled 
corticosteroids are generally allowed) 
• 
Bisphosphonates  
• 
Herbal products, which may have an immunomodulatory effect (e.g. green tea), should 
generally be avoided but food supplements and homeopathic products are allowed 
• 
Antihistamines (eg. hydroxyzine, cetirizine, loratadine, ketotifen), may interfere with skin prick 
testing and are not allowed before skin prick testing (see below for washout period). They may 
be used after a skin prick test when prescribed for prevention or treatment of infusion 
reactions to MOv18 IgE. 
• 
Omalizumab, topical steroids or topical calcineurin inhibitors in the region used for skin prick 
testing. These may all interfere with skin prick testing  
A washout period of at least four half-lives is required for beta-blockers, tricyclics and MAOIs before 
starting study medication.  An appropriate washout period should be implemented for corticosteroids 
(e.g. a few days may be sufficient for low doses given for a short period for appetite stimulation). Patients 
who have been treated with bisphosphonates in the 18 months before starting study medication are 
excluded from the trial. Antihistamines should be stopped for at least four half-lives before each MOv18 
IgE skin prick test. If required for prevention of infusion reactions, antihistamines must be given after the 


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skin prick test results are known. If needed to ensure adequate washout of an antihistamine, the MOV18 
IgE dose may be delayed. 
COVID-19 Vaccinations: Due to the lack of interaction studies with the COVID-19 vaccines and 
Immunotherapy IMPs, an appropriate wash our period of 1 week has been implemented following any 
COVID-19 vaccine and infusion with MOv18. This will be a 1-week washout following both the 1st and 
2nd vaccine doses. Therefore, MOv18 infusions could take place in between the 2 vaccine doses if 
necessary, but MOv18 dosing would need to be delayed by 1 week after each vaccination. This 
washout period will be applicable to any COVID-19 vaccine approved for use by the MHRA.  
 


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6 
PHARMACEUTICAL INFORMATION 
6.1 Supply of MOV18 IGE 
A complete certificate of analysis and a Qualified Person (QP) certification must be provided with each 
batch of MOv18 IgE (IMP) and be retained in the Pharmacy File. 
For information on MOv18 IgE and re-ordering of supplies, contact the Clinical Research Associate 
(CRA)/Clinical Study Manager (CSM) responsible for the study who will arrange further supplies.  
MOv18 IgE will be supplied by: 
 
 
 
 
 
 
 
 
  
 
 
 
The primary and secondary packaging for the IMP will be labelled according to Eudralex Volume 4: 
Annex 13 ‘Investigational Medicinal Products’ of the European Union guide to Good Manufacturing 
Practice (GMP).  Prior to despatch of IMP to the clinical trial site a label detailing the investigator name 
and investigator site name will be added to the secondary packaging at the MIA (IMP) licensed 
manufacturer in accordance with GMP.  An example of the labels can be found in the Pharmacy File. 
6.2 Pharmaceutical data 
6.2.1 
Formulation of MOv18 IgE 
MOv18 IgE will be supplied in glass vials as a sterile, pyrogen and particle-free clear colourless solution 
for dilution prior to infusion.
 
 
  
 
 
6.2.2 
Storage conditions 
All supplies must be stored in a secure, limited access storage area. 
MOv18 IgE must be stored at 2-8C and protected from light.   
6.2.3 
Method of reconstitution 
6.2.3.1 
Solution for intravenous (IV) infusion 
Good aseptic practice must be employed when preparing MOv18 IgE solution for infusion. 
The MOv18 IgE solution will be drawn from the supplied vial and injected into a bag for IV infusion 
containing 250 mL of saline.  Please refer to the IMP Handling Guidelines for instructions on the 
preparation of solution for infusion.  


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6.2.3.2 
Solution for skin prick testing  
Solution for skin prick testing will be prepared for each patient from the supplied vial.  The target 
concentration for skin prick testing is 2 µg/mL. Please refer to the IMP Handling Guidelines for 
instructions on the preparation of solution for skin prick testing.  
As of Protocol Version 5.0, patients will only undergo skin prick testing prior to IV MOv18 IgE 
administration (prior to this, patients received a MOv18 IgE intradermal test dose).  
6.2.4 
Stability and labelling of the diluted MOv18 IgE 
The prepared infusion bag must be stored at 2-8C and used within 24 hours. 
Labelling requirements for the diluted MOv18 IgE can be found in the IMP Handling Guidelines.  
6.2.5 
MOv18 IgE administration 
Before administering MOv18 IgE, the exact dosage must always be double-checked by a second 
suitably qualified person.  All checks and double-checks must be documented (signed and dated) and 
the documentation must be available for the CRA/CSM to verify. 
6.2.6 
Vein extravasation/accidental spillages 
MOv18 IgE is not a vesicant.  Extravasation and accidental spillages should be dealt with according to 
hospital policy.   
6.3 MOv18 IgE accountability 
Accurate records of all IMP (MOv18 IgE) shipments, vials dispensed, and all IMP returned must be 
maintained.  This inventory record must be available for inspection at any time by CRAs or CSMs of the 
Centre for Drug Development (CDD).  IMP supplies are to be used only in accordance with this protocol 
and under the supervision of the Investigator.  
The Investigator undertakes not to destroy any unused IMP unless authorised to do so by the CDD. Any 
unused IMP must be destroyed according to hospital procedures (refer to the study IMP Handling 
Guidelines for exceptions to this) and properly accounted for using the IMP Destruction Form and also 
on the IMP Accountability Record.  During the course of the study the CRA will check the numbers of 
vials of MOv18 IgE shipped to the centre, the number used and the number destroyed or returned.  The 
pharmacy will give an account of any discrepancy. 
The MOv18 IMP Handling Guidelines will describe any appropriate procedures relating to retention of 
IMP for investigations. If applicable, the retained IMP and vial should be fully accounted for, and any 
relabelling fully documented. Where the retained IMP is transferred to an analysing lab, this transfer 
should be documented appropriately. 


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7 
INVESTIGATIONS SCHEDULE 
In cases where a patient has investigations at a different hospital, for example weekly blood samples, 
then it is the Investigator’s responsibility to ensure he/she receives and reviews the reported results.  
These results must be available for source data verification.  Laboratory reference ranges, including 
effective dates, and evidence of laboratory accreditation must be obtained from all laboratories used. 
7.1 Pre-treatment evaluations 
Details of all evaluations/investigations for enrolled patients, including relevant dates, required by the 
protocol must be recorded in the medical records so that the eCRF can be checked against the source 
data. 
Please also refer to the tabulated Schedule of Assessments in Section 7.6. 
7.1.1 
Archival tumour testing for FR 
An archival tumour specimen must be sent to the central analysing laboratory for assessment of FR 
expression by immunohistochemistry (IHC) prior to enrolment on the study.  Otherwise, there is no time 
limit for this assessment.  A separate ‘FR testing on stored tumour sample informed consent’ is 
required. 1+, 2+ or 3+ membrane staining on at least 5% of tumour cells is required for inclusion of the 
patient in the study.  For patients with no archival specimen available, a pre-treatment tumour biopsy is 
mandatory. Such patients will need to consent using section B of the ‘Alpha Folate Receptor’ informed 
consent’ form.  
7.1.2 
Obtaining written informed consent 
Written informed consent must be obtained from the patient using the ‘Main study consent’ form before 
any protocol-specific procedures are carried out, other than archival tumour testing for FR expression 
which may be performed prior to obtaining written informed consent for the main study (see Section 
7.1.1).  The patient must be given adequate time to think about their commitment to the study.  If more 
than 28 days has passed since informed consent was obtained before the start of MOv18 IgE dosing 
then the Investigator should consider whether repeat consent should be obtained from a patient. 
Only the Principal Investigator (PI) and those Sub-Investigator(s) delegated responsibility by the PI, and 
have signed the Delegation Log, are permitted to gain informed consent from patients and sign the 
consent form.  All signatures must be obtained before the occurrence of any medical intervention 
required by the protocol (ICH GCP 4.8.8 and 8.3.1.2).  The patient should sign in the presence of the 
PI/Sub-Investigator, therefore the date of the signatures of both the patient and the PI/Sub-Investigator 
should be the same. 
The PI or the Sub-Investigator must inform the patient about the background to, and ensure that the 
patient is aware of, the following points: 
• The known toxicity of the IMP and the possibility of experiencing side-effects. 
• That IMP is new and that the exact degree of activity is at present unknown, but that treating 
him/her will contribute to further knowledge. 
• The potential dangers of becoming pregnant (or the patient’s partner becoming pregnant) and 
he/she has been given information about appropriate medically approved contraception (refer 
to Section 9.7). 
• That he/she may refuse treatment either before or at any time during the study and that refusal 
to participate will involve no penalty or loss of benefits to which they are otherwise entitled. 


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• The options for routine management of their cancer. 
• Whom to contact for answers to pertinent questions about the research and their rights, and 
also who to contact in the event of a research-related injury. 
A copy of the consent form and patient information sheet must be given to the patient to keep and the 
original consent form and patient information sheet, must be filed in the Investigator Study File (ITF) 
(unless otherwise agreed that the original consent form will be filed in the medical records and the copies 
kept in the ITF). 
7.1.3 
Evaluations within 28 days (Day -28 to Pre-dose on Day 1)  
The following must be performed/obtained within the 28 days before the patient receives the first 
infusion of MOv18 IgE.  Existing results may be used even where these investigations were performed 
prior to the patient’s provision of informed consent for the study if they were performed within the 
required time window. 
• 
Demographic details 
• 
Medical history including prior diagnosis, prior treatment, concomitant diseases and baseline 
signs and symptoms, concomitant treatment 
• 
Radiological disease assessment per RECIST 1.1 (see Appendix 3) including a computerised 
tomography (CT) scan or magnetic resonance imaging (MRI) scan of the chest, abdomen and 
pelvis, with additional investigations as clinically indicated 
• 
Tumour marker, if applicable for tumour type 
• 
Full physical examination, including clinical examination and measurement of palpable or 
visible tumour lesions per RECIST 1.1 (see Appendix 3) 
• 
WHO performance status 
• 
Height and weight 
• 
Vital signs (blood pressure (BP), pulse rate and temperature) 
• 
Electrocardiogram (ECG)   
• 
Urine sample for urinalysis - glucose, protein and blood 
• 
 
 
  
 
   
 
  
Note that all adverse events (AEs), including serious adverse events (SAEs), must be monitored and 
recorded in the eCRF from the time the patient consents to any protocol-specific procedure (see Section 
9 for further details).  
7.1.4 
Evaluations within seven days (Day -7 to Pre-dose on Day 1)  
The following must be performed within seven days before the patient receives the first dose and 
results must be confirmed prior to the patient receiving IMP: 
• 
Blood sample for clinical laboratory tests: 
➢ Haematology – haemoglobin (Hb), white blood cells (WBC) with differential count 
(neutrophils and lymphocytes) and platelets 


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➢ Coagulation screen (international normalised ratio (INR), and activated partial 
thromboplastin time (APTT) value or ratio) 
➢ Biochemistry – sodium, potassium, corrected calcium, phosphate, urea, creatinine, total 
protein, albumin, bilirubin, alkaline phosphatase (alk phos), alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST), uric acid 
• Female patients able to have children must have a negative result on a human chorionic 
gonadotropin (HCG) pregnancy test (serum or urine test is acceptable) 
• Blood sample for serum tryptase and basophil activation test (BAT) 
• Research blood samples – as described in Table 6 Summary of PK and PD Assessments. 
7.2 Evaluations during the study 
Please refer to Table 6 Summary of PK and PD Assessments and Table 7 Volume of blood required for 
study-specific tests (see Section 8.3) and to the Study Laboratory Manual for the details of the timing 
and handling instructions for research blood and tumour biopsy samples. 
7.2.1 
Safety evaluations with EVERY administration of MOv18 IgE 
• Adverse events and concomitant treatments: 
Before each MOv18 IgE administration, an assessment of any AE experienced or changes in 
concomitant treatment since the previous visit must be made by the Investigator or Research 
Nurse.  The start and stop dates of an AE together with the Investigator’s assessment of the 
relationship of the event to treatment with MOv18 IgE and details of concomitant treatments 
must be recorded in the medical records.  All AEs must be graded according to NCI-CTCAE 
Version 4.02.  
• Skin prick testing with MOv18 IgE 
As of Protocol Version 5.0, skin prick testing has been selected for optimal detection of potential 
anaphylaxis to MOv18 IgE. Site staff performing the skin prick test doses will first be trained in 
this technique by an Allergy nurse experienced in skin prick testing for sensitivity to allergens 
(once staff are trained, with the site Principal Investigator’s approval, they may train other 
colleagues in the technique).   
For this test, one drop of a 2 µg/mL solution of MOv18 IgE will be placed on onto the forearm 
skin.  Please refer to the IMP Handling Guidelines for instructions on the preparation of the 
solution for administration.  Alongside this test dose, a positive histamine control and a negative 
saline control will be required.  Please refer to Skin Prick Testing Method in Appendix 8 for 
detailed guidance on the method of administration and interpretation of results.  Response to 
the skin prick test should be checked at 15, 30 and 60 minutes post initiation of the skin prick 
test, prior to the start of every infusion of MOv18 IgE. If the skin prick test is positive at ANY of 
the three time points, that will constitute a positive result. Absence of a weal and flare reaction 
will allow the IV dose to be administered with the expectation that the risk of anaphylaxis is very 
low.   
• 
In case of a positive reaction, no further MOv18 IgE will be given and the patient will be 
followed up for safety and then withdrawn from the trial (see Section 11; and Section 5.5.4 
for possible exceptions to this rule).  In case of a positive skin test, the following additional 
samples should be taken: 
➢ Serum tryptase (immediately*, 2 and 6 hours post onset),  
➢ BAT assay (immediately* post onset),  


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➢ PK (immediately*, 2 and 6 hours post onset),  
➢ 
 
  
*or as soon as possible after onset.  
Additional exploratory tests may be performed on these existing samples to elucidate the 
cause of the reaction on the day of the reaction. Further blood draws may be collected at 
other time points, as deemed appropriate by the TSG, with the patients documented 
consent in the patient notes. Approximately 45 mL of additional blood may be collected.  
In case of uncertainty as to whether a skin prick test is positive or negative, advice will be sought 
from the Clinical Immunology team. 
• Vital signs (BP, pulse rate and temperature) should be performed as clinically indicated and 
➢ Within the 30 minutes pre-dose 
➢ Every 15 minutes during the infusion for the first two infusions at least (see Section 
5.3.1) and for those patients enrolled in the intra-patient dose escalation part of the 
trial, monitoring will be performed on Cycle 2 (doses 1 and 2) as per Cycle 1. 
➢ 15 minutes and 30 minutes after completion of the infusion 
➢ Before discharge from the clinic. 
• Monitoring with a pulse oximeter continuously throughout the infusion until 30 minutes after 
completion of the infusion. 
• ECG after completion of the infusion. 
• Blood sample for serum tryptase test – taken on completion of the infusion.  
Patients should remain in the clinic for observation for at least one hour after every dose of MOv18 IgE 
(6 hours for a positive skin prick test). 
7.2.2 
Additional evaluations for the first administration of MOv18 IgE on Cycle 1 Day 1 
• Vital signs (BP, pulse rate and temperature) should be performed as described in Section 7.2.1 
and additionally 
➢ 1h, 2h, 4h, 8h, 12h (±1 hour), 18h (±2 hour) and 24h (±2 hours) after completion of 
the infusion 
• Blood sampling for PK assessment of circulating MOv18 IgE in serum: 3.5 mL blood sample 
at 6 time points: Pre-dose, and 30 min (5 min), 2 h ( 30 min), 4 h ( 30 min), 6 h ( 30 min), 
24 h ( 2 h). It is possible that the 30 min sample may be substituted for a 48 h ( 2 h) time point 
in later cohorts – see study lab manual) post-dose.  If a time point has been missed, a sample 
should be taken as soon as possible and the time recorded.  
For patients enrolled in the intra-patient dose escalation, these additional evaluations will also 
be performed on Cycle 2 Day 1. 
7.2.3 
Weekly and fortnightly clinic visits  
Patients will be reviewed weekly (±2 days) prior to each dose of MOv18 IgE (fortnightly ±2 days during 
maintenance MOv18 IgE, if given) and the following tests and procedures will be performed: 
• Symptom-directed physical examination 


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• Assessment of adverse events and concomitant medication 
• WHO performance status 
• Blood sample for clinical laboratory tests: Haematology and biochemistry must be 
performed within 24 hours ( 4 h) before each dose of MOv18 IgE and until 4 weeks after the 
last dose.  At a minimum: 
➢ 
Haematology – haemoglobin (Hb), white blood cells (WBC) with differential count 
(neutrophils and lymphocytes) and platelets 
➢ 
Biochemistry - sodium, potassium, calcium, phosphate, urea, creatinine, total 
protein, albumin, bilirubin, alk phos, ALT or AST, uric acid.  
• Research blood samples – as described in Table 6 Summary of PK and PD Assessments. 
• 
 
 
  
• 
 
 
 
7.2.4 
Prior to the start of a new cycle of MOv18 IgE treatment (within 24 h before start of 
infusion on Day 1) 
• Urinalysis –glucose, protein and blood 
• Tumour marker, if appropriate for tumour type 
• Assessment of disease response: required every 2 cycles (6-weekly) based on clinical 
examination, tumour marker, and CT/MRI for patients with measurable disease.  Response will 
be assessed by RECIST 1.1 criteria (see Appendix 3), as well as by CA125 or other tumour 
marker (Rustin, 2003) if applicable. 
For patients receiving maintenance MOv18 IgE, these tests/assessments should be repeated after 
6 weeks (i.e. after the third maintenance dose, if given). 
7.2.5 
Infusion reactions and anaphylaxis 
Patients should be assessed carefully for infusion-related reactions.  Since it may not be apparent at 
the time whether a patient is having a reaction due to cytokine release or mast cell degranulation, and 
since NCI-CTCAE Version 4.02 criteria overlap for cytokine release syndrome, allergic reaction and 
anaphylaxis, it is proposed that:  
• All infusion-related events are reported as individual AEs (e.g. fever, nausea, myalgia or 
hypotension).  Time of onset and worst grade (according to NCI-CTCAE Version 4.02) should 
be noted for each event. 
• Subsequently, infusion-related events associated with an elevation in serum tryptase will be 
categorised according to the grading criteria outlined in Appendix 5 for IgE-associated mast cell 
degranulation (anaphylaxis).  
• Urticaria is a characteristic feature of anaphylaxis and is to be regarded with suspicion. Patients 
who experience any of the following events should have additional samples taken as outlined 
below:  


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- 
Urticaria; symptoms/signs suggestive of mast cell degranulation; a suspected anaphylactic 
reaction; signs and symptoms suggestive of a severe allergic-type reaction; severe 
infusion-related symptoms necessitating interruption or discontinuation of the infusion. 
Additional Samples:  
NB: the additional samples outlined below can replace the existing samples in the Schedule of 
assessments, if the timepoints overlap. Please take all other samples as per schedule in 
section 7.6.  
➢ Serum tryptase (immediately*, 2 and 6** hours post onset),   
➢ BAT assay (immediately* post onset, in replacement of existing 2 hour timepoint in 
schedule),  
➢ PK (immediately*, 2 and 6** hours post onset),  
➢ 
 
 
*Or as soon as possible post onset.  
**6 hour samples may be omitted if impracticable and clinical suspicion of systemic toxicity is low. This is 
at the discretion of the treating clinician. 
• 
If a patient clearly shows a pattern of simple urticaria with two separate infusions, with no other 
systemic signs or symptoms and no other features of anaphylaxis (including normal tryptase 
results and normal BAT assay results) then, following discussion and confirmation with Sponsor, 
there may be no requirement for additional samples. 
• 
 
 
 
 
• 
 
 
 
  
• Infusion-related events without an elevation in serum tryptase will be categorised as cytokine 
release syndrome according to NCI-CTCAE Version 4.02 (Appendix 6). 
7.3 Evaluations at First Post-treatment Safety Assessment (28 ±7 days after final dose) 
Evaluations at the First Post-treatment Safety Assessment must be performed 28 ±7 days after the final 
infusion of MOv18 IgE.  The following investigations should be done: 
• 
Symptom-directed physical examination  
• 
WHO performance status  
• 
Weight  
• 
Vital signs, if clinically indicated 
• 
ECG 


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• 
Blood sample for clinical laboratory tests – Haematology and Biochemistry parameters as 
detailed in Section 7.1.4 
• 
Urine sample for urinalysis – glucose, protein and blood 
• 
Assessment of AEs and concomitant treatments  
• 
Assessment of disease response: if not performed within previous 28 days per RECIST 
based on clinical examination, tumour marker, and CT/MRI for patients with measurable 
disease.  Response will be assessed by RECIST 1.1 criteria (see Appendix 3),as well as by 
CA125 or other tumour marker (Rustin, 2003) if applicable. 
• 
Tumour marker, if appropriate for tumour type 
• 
Research blood samples as described in Table 6 Summary of PK and PD Assessments (see 
Section 8.3). 
Patients who receive MOv18 IgE as a skin prick test only should be followed for safety until resolution 
or stabilisation of any AEs/SAEs associated with MOv18 IgE. 
7.4 Evaluations at Second Post-treatment Safety Assessment (70 ±14 days after final 
dose) 
• Symptom-directed physical examination 
• Assessment of AEs 
For patients who are unable to attend in person for this visit due to concurrent illness, progressive 
disease or other reasons, the safety assessment may be made by telephone and the sample for PK 
assessment omitted. 
7.5 Follow-up of drug-related AEs 
Patients who receive any dose of IV MOv18 IgE will be followed for safety reporting until the Second 
Post-treatment Safety Assessment.  If any drug-related AEs and SAEs (i.e. those considered to have a 
highly probable, probable or possible causal relationship to MOv18 IgE) are present at this assessment, 
the patient will be followed up at least monthly afterwards until resolution to baseline or stabilisation of 
these events, unless the patient starts another anti-tumour treatment.  If the patient is experiencing no 
drug-related AEs at the Second Post-treatment Safety Assessment then no follow-up is required. 
Patients who receive MOv18 IgE as a skin prick test only should also be followed for safety at least 
monthly until resolution or stabilisation of any treatment-related AEs/SAEs. 






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(c) Blood sample for clinical laboratory tests: Haematology, biochemistry and coagulation screens should be performed for the assessment of eligibility during Screening 
(Day -7 to pre-dose on Day 1).  Measurements performed before Day -14 may be accepted by the CDD to demonstrate eligibility if repeat testing is logistically difficult for 
the patient and is not considered necessary medically in the opinion of the Investigator or CDD.   
Haematology and biochemistry should be performed within the 24 h ( 4 h) prior to each dose.   
In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full blood count must be performed at least five days after the onset of the event to determine if a 
DLT has occurred.  Continue to monitor the patient closely until resolution to Grade 3 or less (see Section 3.3 Dose Limiting Toxicity). 
(d) Pregnancy test for female patients of child bearing potential. 
(e) 1 mL blood sample for assessment of serum IgE will be taken at baseline only. 
(f) 
MOv18 IgE skin prick test on inner forearm with positive histamine control and negative saline control to be performed at the bedside by a specifically trained nurse. 
Response to the skin prick test should be assessed at 15, 30 and 60 mins post initiation of the skin prick test, prior to the start of every infusion of MOv18 IgE (see 
Appendix 8 for test method and instructions on interpretation of results). 
(g) 
Vital signs (BP, pulse rate and temperature) should be performed for each infusion of MOv18 IgE within the 30 min (5min) pre-dose, every 15 min (5min) during the 
first and second infusions, 15 min (5min) and 30 min (5min) after completion of each infusion, and before discharge from the clinic.  For the first infusion only, vital 
signs are additionally required (10min) at 1h, 2h, 4h, 8h, 12h, 18h and 24h after completion of the infusion, and as clinically indicated.  Monitoring with a pulse oximeter 
is required continuously throughout each infusion until 30 min after completion of the infusion. For intra-patient dose escalation cohorts, these assessments are to also 
be performed on Cycle 2 Day 1.    
(h) 1 mL blood sample for 200 µL serum for measurement of serum tryptase at baseline and on completion of every infusion of MOv18 IgE. Additional samples may be 
taken in response to a positive skin prick test or in patients who experience a suspected anaphylactic reaction, such as urticaria or severe or infusion-related symptoms 
necessitating interruption or discontinuation of the infusion (see protocol section 7.2.1 and 7.2.5 for details of when to take these samples).  Samples will be analysed and 
reported prior to next dose for 2nd and 3rd doses.  Subsequent samples can be analysed on request of the Investigator in response to clinical symptoms and reported 
prior to next dose. 
(i) 
3.5 mL blood sample for 1-2 mL serum for PK assessment of circulating MOv18 IgE at 7 time points: Pre-dose on Cycle 1 Day 1 (within 24 h of infusion), 30 min (5 
min)*, 2 h ( 30 min), 4 h ( 30 min), 6 h ( 30 min), 24 h ( 2 h), and possibly* at 48 h ( 2 h) post-dose; Cycle 1 Day 8 Pre-dose;  (total blood volume ~25mL).  If a time 
point has been missed, a sample should be taken as soon as possible and the time recorded. *The 30 min (5 min) sample may be replaced by the 48h ( 2 h) post-dose 
sample at higher dose cohort levels (refer to the study laboratory manual for which sample to take). Additional samples should be taken at 0, 2 and 6 hours following a 
suspected anaphylactic/urticarial reaction or positive skin prick test (see protocol section 7.2.1 and 7.2.5 for details). 
(j) 
 
 
 
(k) 6 mL blood sample for basophil activation test (BAT) at Day -7 to Pre dose Cycle 1 Day 1 and 2 h ( 30 min) after the end of infusion of MOv18 IgE at the first and third 
infusions (Cycle 1 Day 1 and Cycle 1 Day 15) (total blood volume 18 mL). Additional samples should be taken immediately (0 hours) following a suspected anaphylactic 
reaction, urticarial, or severe infusion-related symptoms necessitating interruption or discontinuation of the infusion or positive skin prick test (see protocol section 7.2.1 
and 7.2.5 for details). For intra-patient dose escalation cohorts, a sample will also be taken on Cycle 2 Day 1, 2 h ( 30 min) after the end of infusion of the higher dose 
of MOv18 IgE. 


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(l) 
 
 
(m) 
 
 
 
 
(n) 
 
 
(o) 
 
 
    
(p) 
Monthly follow-up required ONLY for those AEs and SAEs considered drug-related (highly probable, probable or possible) and present at the Second Post-treatment 
Safety Assessment.  Monthly follow-up to continue until resolution, return to baseline, stabilisation or patient starts another anti-cancer treatment. 
(q) 
All patients, who are removed from the study for reasons other than progressive disease, must be re-evaluated at the time of treatment discontinuation, unless a tumour 
assessment was performed within the previous four weeks. 
(r) 
For patients unable to attend in person for the Second Post-treatment Safety Assessment due to concurrent illness, progressive disease or other reasons, the safety 
assessment may be made by telephone and the sample for PK assessment omitted.  
(s) 
ECG to be performed after completion of the infusion.  
(t) 
For intra-patient dose escalation cohorts, these assessments are to also be performed on Cycle 2 Day 1. 
(u) 
For intra-patient dose escalation cohorts, the post dose biopsy should be performed following at least the first dose in Cycle 2 where possible.  
 
 




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(d) 5 mL blood sample for 200 µL serum for measurement of serum tryptase at baseline and on completion of every infusion of MOv18 IgE. Additional 
samples may be taken in response to a positive skin prick test or in patients who experience a suspected anaphylactic reaction, urticarial, or severe 
infusion-related symptoms necessitating interruption or discontinuation of the infusion (see protocol section 7.2.1 and 7.2.5 for details of when to take 
these samples). Samples can be analysed on request of the Investigator in response to clinical symptoms and reported prior to next dose.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS  
Please refer to the Study Laboratory Manual for the names of the analysing laboratories and for detailed 
instructions for sampling. 
Sample collection schemes and frequency of analysis may be reconsidered during the study in response 
to the reported PK, PD or safety data. 
Patients will be asked to consent to the use of leftover blood, ascitic or pleural fluid and tumour tissue 
for future research into the treatment of cancer using IgE and similar immunotherapies. 
8.1 Summary of assessments 
See Table 6 Summary of PK and PD assessments and Table 7 Volume of Blood required. 
8.2 Secondary assessment - Pharmacokinetics of MOV18 IgE 
The t½ of IgE in the circulation is known to be approximately two days in man but much longer in the 
tissues (Gould et al., 2003).  The PK sampling time points have therefore been chosen to confirm the 
hypothesis that MOv18 IgE is cleared from the blood over a timescale that is expected for this antibody 
class, and to obtain preliminary data to guide further dosing schedules. 
3.5 mL of blood will be collected at the following time points on and following Cycle 1 Day 1: 
• 
Within the 24 h pre-dose 
• 
30 min ±5 min after completion of the infusion (Refer to lab manual whether this or the 48h 
sample should be taken) 
• 
2 h ±30 min after completion of the infusion  
• 
4 h ±30 min after completion of the infusion 
• 
6 h ±30 min after completion of the infusion 
• 
24 h ±2 h after completion of the infusion 
• 
48 h ±2 h after completion of the infusion (Refer to lab manual whether this or the 30min sample 
should be taken) 
• 
7 days ±1 day after commencement of the infusion (i.e. Pre-dose Cycle 1 Day 8)  
The approximate volume of blood withdrawn from each patient for pharmacokinetic analysis will be 
24.5mL. This volume may increase if additional samples are needed as per section 7.2.5. 
Additional PK timepoints may be implemented if emerging data suggested that this would be beneficial 
following discussion between the TSG. The additional timepoints will be on C1D15 and the total blood 
volume taken will not exceed 17.5 mL. 
Serum samples will be prepared at each centre and then frozen on site.  They will be shipped to the 
analysing laboratory on dry ice.  MOv18 IgE serum levels will be assayed using an anti-idiotypic enzyme-
linked immunosorbent assay (ELISA).  
The plasma concentration/time data will be analysed using non-compartmental methods.  The PK 
parameters to be determined for MOv18 IgE include the maximum observed plasma concentration 
(Cmax), time to reach Cmax (Tmax), the area under the plasma concentration time curve (AUC), and the 
terminal elimination half-life (T1/2). 


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8.3 Tertiary/research assessments - pharmacodynamics 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6: Summary of PK and PD Assessments 
Biomarker 
Method 
Sample/ 
Quantity per Time 
point 
Rationale 
Time points3 
Timing of analysis 
Tumour FRα 
expression 
IHC  
Archival tumour 
tissue  
To demonstrate target 
expression in tumour; required 
for patient eligibility 
Screening 
3-5 day turnaround from receipt of 
sample at laboratory 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Serum tryptase ELISA  
1mL blood for 200 µl 
serum to allow for 
re-test.  
To distinguish between non-
specific infusion reaction and 
anaphylaxis. Validated routine 
NHS test with normal value 2-14 
µg/L. 
Day -7 to Pre dose Cycle 1 Day 1; on 
completion of infusion at each dose. 
Additional samples in response to clinical 
symptoms (0, 2 and 6 hours after onset 
of the reaction). (see Table 4 footnotes). 
Analysed and reported prior to next 
dose for 1st and 2nd doses.  
Subsequent samples may be reported 
prior to the next dose on request. 
Otherwise, batched and analysed at 
the end of each cohort.  
Circulating 
MOv18 IgE 
(PK)   
ELISA 
3.5mL blood for 1-
2mL serum 
Exposure in plasma and to look 
at adaptive immunity – FR 
specific IgE 
Cycle 1 Day 1 Pre dose (within 24 h of 
infusion) and 2h, 4h, 6h, 24h, and either 
30min or 48h Post dose (see lab 
manual); Pre dose Cycle 1 Day 85 
For Intra-patient escalation cohorts only, 
as above plus: 
Cycle 2 Day 1 Pre-dose (within 24 h of 
infusion) and 2h, 4h, 6h, 24h, and either 
30min or 48h Post dose (see lab 
manual) 
Flexible timing; in response to toxicity, 
to inform dose review decisions or in 
batches. 


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Biomarker 
Method 
Sample/ 
Quantity per Time 
point 
Rationale 
Time points3 
Timing of analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Basophil 
activation test 
(BAT test) 
In vitro 
followed by 
FACS 
6mL whole blood 
Measures functional IgE capable 
of binding to and stimulating 
basophils 
Day -7 to Pre dose Cycle 1 Day 1; 2 h 
after end of infusion at 1st and 3rd doses 5 
For Intra-patient escalation cohorts only, 
as above plus: 
Cycle 2 Day 1; 2 h after end of infusion 
Within a day of sample being taken 
(See current lab manual).  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Biomarker 
Method 
Sample/ 
Quantity per Time 
point 
Rationale 
Time points3 
Timing of analysis 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
2 
 
   
3 Unless specifically stated otherwise, blood sample timings have a window of +/- 30 minutes for samples taken within 24 hours of an infusion, +/- 2 hours for samples 
taken at 24 or 48 hours, +/- 1 day for samples up to 28 days after the last dose and then +/- 7 days thereafter (see Section 8.2 for example). 
4 Some assays may be done (in batches) before the end of study. 
5 Additional samples may be taken following a positive skin prick test (see Section 7.2.1) or a suspected anaphylactic reaction (see Section 7.2.5). 
6 
 
  




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Patients who complete the Maintenance Period will have additional fortnightly clinical laboratory tests (10 mL per time point) and a serum tryptase assay after each of the three doses 
(5mL blood for 200µL serum, per assay), increasing the approximate total volume of blood drawn for study-specific tests to 365.5 mL. 


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9 
ASSESSMENT OF SAFETY 
Potential risks of MOv18 IgE therapy based on mechanistic and preclinical data for MOv18 IgE, and 
clinical data for other therapies directed against the FRα include: 
• 
Anaphylaxis 
• 
Infusion reactions/cytokine release 
• 
Risks related to FRα targeting  
• 
Anti-drug antibody (ADA) formation 
Monitoring and management of infusion reactions and anaphylaxis are described in Sections 7.2.1 and 
7.2.5, and Appendix 4.  
Side effects due to FRα–targeting in normal tissues are not anticipated with MOv18 IgE since FRα 
expression is generally low in normal tissues and likely to be inaccessible to MOv18 IgE in many organs 
(for example, expression in renal tubules is endoluminal). Moreover, no unequivocal reports of such 
side effects have been found in the literature for other FRa-targeted agents. However, should it occur, 
FRα–targeting in normal tissues could result in renal, pulmonary, intestinal or CNS toxicity (manifest for 
example, as glomerulonephritis, interstitial pneumonitis, gastro-enteritis or neuro-inflammatory 
symptoms).  Such side effects should be detected by routine clinical monitoring for AEs and laboratory 
abnormalities within the trial. If identified, treatment should be symptomatic/supportive along with 
cessation of MOv18 IgE therapy, if clinically indicated. Immunosuppressive medication (for example 
corticosteroids) could potentially be required for severe normal tissue toxicity Supportive treatment could 
include analgesics and/or anti-inflammatory medication, oxygen, antibiotics, fluid replacement therapy, 
anti-diarrhoeals, histamine (H2) antagonists etc, depending on the organ(s) affected. 
In theory, inflammation, pain or tenderness at sites of bulky disease could also occur. Treatment should 
be with conventional analgesia, as needed.  
Anti-drug antibody (ADA) formation is not expected with MOv18 IgE since it was not reported in clinical 
studies of MOv18 IgG.  Nevertheless, it could occur since ADA formation has been reported with other 
chimeric IgGs, such as rituximab.  ADA formation following MOv18 IgE exposure could potentially result 
in worsening of infusion reactions with subsequent MOv18 IgE infusions, loss of efficacy of MOv18 IgE 
resulting in clinical deterioration, or hypersensitivity reactions when treated with other diagnostic or 
therapeutic monoclonal antibodies. 
 
 
 
Tumour lysis syndrome is not expected to occur with MOv18 IgE but all patients will be monitored with 
regular serum uric acid levels (additional assessments of uric acid levels will be made if clinically 
indicated). Treatment with hydration, allopurinol and/or rasburicase should be initiated if clinically 
indicated.    
9.1 Investigator Responsibilities 
The investigator is responsible for monitoring the safety of patients who have enrolled in the study and 
for accurately documenting and reporting information as described in the following sections. 
9.1.1 
Medical Cover 
The Chief/Principal Investigator is also responsible for ensuring patients have access to 24 hour advice 
and/or care.  Patients will be provided with the necessary contact numbers for both normal working and 
out of hours care.  A copy of the protocol must be made available out of hours to ward staff and clinicians 


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on call so that the appropriate advice may be given to the patient, the patient’s relative or other care 
giver (for example GP).  The Chief/Principal Investigator must ensure that should the on call clinician or 
ward staff require more advice than is in this protocol, that they have access to the Investigator or 
delegated members of the investigator’s team who can answer any questions. 
9.2 Adverse event definitions 
9.2.1 
Adverse event 
An adverse event (AE) is any untoward, undesired or unplanned occurrence in a patient administered 
an IMP, a comparator product or an approved drug.  An AE can be a sign, symptom, disease, and/or 
laboratory or physiological observation that may or may not be related to the IMP or comparator.   
An AE includes but is not limited to those in the following list.  
• 
A clinically significant worsening of a pre-existing condition.  This includes conditions that 
may resolve completely and then become abnormal again.  
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional. 
• 
AEs occurring from lack of efficacy of an IMP, for example, if the Investigator suspects that a 
drug batch is not efficacious or if the Investigator suspects that the IMP has contributed to 
disease progression. 
9.2.2 
Serious adverse events 
A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 
• 
is life-threatening*; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation (some 
hospitalisations are exempt from SAE reporting – e.g. hospital admissions planned prior to the 
patient entering the trial; overnight stays for planned procedures such a blood transfusion (see 
Section 9.4.1); 
• 
results in persistent or significant incapacity or disability; 
• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event**. 
* A life-threatening event is defined as an event when the patient was at substantial risk of dying at the 
time of the adverse event, or use or continued use of the device or other medical product might have 
resulted in the death of the patient. 
**A medically important event is defined as any event that may jeopardise the patient or may require 
intervention to prevent one of the outcomes listed above. Examples include allergic bronchospasm (a 
serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias 
(blood disorders) or seizures/convulsions that do not result in hospitalisation. The development of drug 
dependence or drug abuse would also be examples of important medical events. 
For fatal SAEs, wherever possible report the cause of death as an SAE with a fatal outcome rather than 
reporting death as the SAE term.  When available the autopsy report will be provided to the Sponsor. 
If during the course of the study, other medically important events are identified and there is a 
requirement to report specific events outside of the standard criteria, this will be communicated to site 
and the protocol will be updated to reflect this. 
Trial–specific medically important events: Anaphylaxis is considered to be a dose-independent 
significant toxicity that may have an impact on the further conduct of this trial.  Therefore, all events of 
anaphylaxis, regardless of severity, must be reported as SAEs.   


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Any dose limiting toxicity (DLT) must be reported to the CDD Clinical Study Manager (CSM) and CRA 
within 24 hours of site staff becoming aware of the DLT. The CDD Pharmacovigilance Department must 
be copied into any initial email notification. (See Section 3.3.1) 
Other reportable events that must be treated as SAEs are listed below.   
• 
Pregnancy exposure to the IMP.  Any pregnancy occurring in a patient or a patient’s partner 
during treatment with an IMP or occurring within six months of the last IMP administration, must 
be reported to the Pharmacovigilance Department in the same timelines as an SAE.  These 
should be reported even if the patient is withdrawn from the trial. 
• 
Overdose with or without an AE (any dose above that specified in the protocol, not necessarily 
intentional). 
• 
Inadvertent or accidental exposure to an IMP with or without an AE, including for example, 
spillage of the IMP that contaminates staff.   
• 
Any AE that could be related to the protocol procedures, and which could modify the conduct 
of the trial. 
• 
A positive skin prick test is considered an event of interest in this trial since it indicates that 
anaphylaxis might occur if MOv18 IgE were to be administered IV. Therefore, all positive skin 
prick tests must be reported to PV as an SAE within 24 hours.  
9.2.3 
Suspected, unexpected, serious, adverse reactions 
A SUSAR is a suspected, unexpected, serious adverse reaction. 
All AEs and SAEs will be assessed by CDD for seriousness, causality and expectedness.  The 
Pharmacovigilance Department will expedite all SUSARs to the relevant competent authority/authorities 
and the relevant Ethics Committee(s) within the timelines specified in legislation (SI 2004/1031 as 
amended).  
9.2.4 
Causality 
The relationship of an AE to the IMP is determined as follows. 
Highly probable 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible 
• 
Starts within a time related to the IMP administration and 
• 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the trial drug is not likely to 
have had an association with the observed effect. 
Not related 
• 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 


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The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness, progressive malignancy etc) and must provide his/her opinion of the causal 
relationship between each AE and IMP.  This may require instituting supplementary investigations of 
significant AEs based on their clinical judgement of the likely causative factors and/or include seeking a 
further opinion from a specialist in the field of the AE. 
The following guidance should be taken in to account when assessing causality of an AE: 
• 
Previous experience with the IMP and whether the AE is known to have occurred with the IMP. 
• 
Alternative explanations for the AE such as concomitant medications, concurrent illness, 
non-medicinal therapies, diagnostic tests, procedures or other confounding effects. 
• 
Timing of the events between administration of the IMP and the AE. 
• 
IMP blood levels and evidence, if any, of overdose. 
• 
De-challenge, that is, if the IMP was discontinued or the dosage reduced, what happened to the 
adverse reaction? 
• 
Re-challenge, that is, what happened if the IMP was restarted after the AE had resolved? 
9.2.5 
Expectedness 
Assessment of expectedness will be made by the Pharmacovigilance Department against the current 
version of the MOv18 IgE Investigator’s Brochure.  
9.3 Collection of safety information 
9.3.1 
Screening failures 
For screening failures, SAEs must be reported to the Pharmacovigilance Department, CDD from the 
date of consent until the date the patient is confirmed as ineligible. 
9.3.2 
Eligible patients 
For eligible patients, SAE and AE collection and monitoring will commence at the time the patient gives 
their written consent to participate in the trial and will continue until the Second Post-treatment Safety 
Assessment 70 ±14 days after the last administration of MOv18 IgE or until the patient starts another 
anti-cancer therapy.   
Should an Investigator become aware of any drug-related SAEs after the patient’s final study visit, these 
must also be reported to the CDD within the expedited timelines stated above. 
9.3.3 
Follow-up of AEs and SAEs 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events 
resolve, stabilise or the patient starts another anti-cancer therapy.   
The Pharmacovigilance Department will make requests for further information on SAEs to the trial site 
at regular intervals.  Requested follow-up information should be reported to the Pharmacovigilance 
Department in a timely manner and as soon as possible after receipt of the follow-up request.  For fatal 
or life-threatening cases, follow-up information should be reported to the Pharmacovigilance Department 
as soon as possible. 


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9.3.4 
Other safety information of interest 
We are also interested in collecting information on the following situations, whether they are associated 
with an AE or not: 
• 
Abuse or misuse 
• 
Occupational exposure (to a person other than the patient, for example spilling of IMP on hands 
of nurse or splashing in the eye). 
Any occurrences of these should be reported in the same manner as SAEs (Section 9.4). 
9.4 Reporting of SAEs to the Pharmacovigilance Department, CDD 
All SAEs, regardless of causality, must be reported to the Pharmacovigilance Department in an 
expedited manner.  SAEs should be documented on an SAE report form, using the completion 
guidelines provided.  
The SAE report form should be emailed to Pharmacovigilance Department within 24 hours of 
site staff becoming aware of the SAE. 
 
Each episode of an SAE must be recorded on a separate SAE report form.  The NCI-CTCAE 
Version 4.02 must be used to grade each SAE, and the worst grade recorded.  If new or amended 
information on a previously reported SAE becomes available, the Investigator should report this to the 
Pharmacovigilance Department on a new SAE report form. 
If the SAE has not been reported within the specified timeframes, a reason for lateness must be added 
on the form when sending the SAE report to the Pharmacovigilance Department. 
Should the investigator become aware of any drug-related SAEs after the patient has withdrawn from 
the study, these must also be reported to the PV Department within the timelines specified above. 
9.4.1 
Events exempt from being reported as SAEs to the Pharmacovigilance Department 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed.  The events must still be recorded 
in the appropriate section of the electronic case report form (eCRF). 
Elective admissions to hospital for procedures which were planned prior to entering the trial are not 
SAEs. Hospitalisation for administration of the IMP according to the trial protocol is also exempt from 
being reported as an SAE, unless the patient experiences an event during the admission which would 
normally qualify as an SAE.   
Death due to disease progression does not require expedited reporting unless considered related to 
the IMP. 
9.5 Recording of adverse events and serious adverse events in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients.  All concomitant 
medications, including herbal medications and supplements must be recorded.  Any therapy used to 
treat the event must be recorded.  The eCRF will be reconciled with the safety database regularly during 
the trial and at the end of the trial.  Therefore, the sites should ensure the data entered on the SAE 
report form and the data entered into the eCRF are consistent.  The CDD Medical Advisor and the 
Investigator(s) will regularly review the safety data from both the safety and the clinical database. 


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9.6 Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical trial against any immediate hazard to their health or safety.  This includes 
procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health.  
USMs may be taken without prior authorisation from the competent authority. 
The Medicines and Healthcare products Regulatory Agency (MHRA) and the Main Research Ethics 
Committee (REC) must be notified within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
• 
 
• 
   
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
why action was taken. 
The Sponsor will then notify the MHRA and the Main REC within three days of USM initiation.   
9.7 Pregnancy 
Female patients who become pregnant during the trial must stop study treatment immediately. 
The Investigator must make every effort to try and ensure that a clinical trial patient or a partner of a 
clinical trial patient does not become pregnant during the trial or for six months afterwards.  This should 
be done as part of the consent process by explaining clearly to the patient the potential dangers of 
becoming pregnant and also providing each patient with information about appropriate medically 
approved contraception.  Two forms of medically approved contraception should be used, such as:   
• 
oral contraceptives and condom; 
• 
intra-uterine device (IUD) and condom; 
• 
diaphragms with spermicidal gel and condom. 
Contraception should be effective before the patient is enrolled on the trial, throughout the trial and for 
six months after completing the trial. 
Alternatively, the patient may agree to sexual abstinence, effective from the first administration of IMP, 
throughout the trial and for six months afterwards. Abstinence is only considered to be an acceptable 
method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
For male patients, it should be explained to the patient that if his partner is pregnant or breast-feeding 
when he is enrolled on the trial, the patient should use barrier method contraception (condom plus 
spermicidal gel) to prevent the unborn baby or the baby being exposed to MOv18 IgE.  


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However, if a patient or a partner of a patient does become pregnant, the reporting procedures below 
must be followed. 
Any pregnancy occurring in a patient or a patient’s partner during treatment with an IMP or occurring 
within six months of last IMP administration must be reported to the Pharmacovigilance Department 
within 24 hours of the site staff becoming aware of it using a Pregnancy Report Form (provided in the 
ITF). It is the Investigator’s responsibility to obtain consent for follow-up from the patient or patient’s 
partner.  In addition, the Investigator must be made aware of the need to obtain contact details for the 
patient’s partner’s General Practitioner. The Pharmacovigilance Department will follow-up all 
pregnancies for the pregnancy outcome via the Investigator, using a Pregnancy Report Form.  
The Investigator must ensure that all patients are aware at the start of a clinical trial of the importance 
of reporting all pregnancies (in themselves and their partners) that occur whilst being treated with the 
IMP and occurring up to six months after the last IMP administration.  The Investigator should offer 
counselling to the patient and/or the partner, and discuss the risks of continuing with the pregnancy and 
the possible effects on the foetus.  Monitoring of the patient should continue until the conclusion of the 
pregnancy, if the patient or patient’s partner has consented to this. Monitoring of the baby should 
continue until 12 months after birth, if the patient or patient’s partner has consented to this. 


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10 ASSESSMENT OF EFFICACY 
10.1 Measurement of disease 
Disease must be measured according to the RECIST 1.1 criteria given in Appendix 3. 
Patients must have measurable disease or disease evaluable by assessment of tumour marker to be 
eligible for participation in the study (see Section 4.1).  Previously irradiated lesions clearly progressing 
at the baseline disease assessment can be considered measurable disease.  
10.2 Timing and type of tumour assessments 
A thorough clinical and radiological evaluation of malignancy, as judged appropriate by the Investigator, 
and in line with the protocol, must be performed before starting the investigational medicinal product 
(IMP).  The same methods that detect evaluable lesions at baseline must be used to follow these lesions 
throughout the study.  To ensure compatibility, the radiological assessments used to assess response 
must be performed using identical techniques.  Imaging based evaluation is preferred to evaluation by 
clinical examination when both methods have been used to assess the anti-tumour effect of a treatment. 
All radiological assessments and clinical measurements to assess response must be performed within 
28 days before starting treatment.  The interval between the last anti-cancer therapy and these 
measurements must be at least four weeks (28 days).   
For this study, due to the limited duration of study treatment, complete (CR) and partial responses (PR) 
do not need to be confirmed by a subsequent assessment at least 4 weeks later.  Stable disease criteria 
must be met at least once after study entry at a minimum interval of six weeks to be defined as stable 
disease (SD).  Possible contribution of inflammatory cell infiltration to transient enlargement of tumours 
may be considered when assessing response and considering discontinuation of study treatment.  
Evaluation by tumour marker such as CA125 may be used for patients without measurable disease. 
Copies of the scans must be available for external independent review if requested by the CDD. 
10.2.1 Baseline evaluations 
These must include radiological measurements of lesions in the chest and abdomen by CT scan or MRI 
scan and/or other radiological measurements as clinically indicated or clinical measurements as 
appropriate e.g. assessment of palpable lesions or measurement of tumour markers.  All areas of 
disease present must be documented (even if specific lesions are not going to be followed for response) 
and the measurements of all measurable lesions must be recorded clearly on the scan reports.  Any 
non-measurable lesions must be stated as being present.  For clinical measurements, documentation 
by colour photography including a ruler to estimate the size of the lesion is strongly recommended, as 
this aids external independent review of responses. (See Appendix 3 Section 1.2.1 of RECIST criteria) 
10.2.2 Evaluations during the study and at ‘First Post-treatment Safety Assessment’ 28 ±7 
days after final dose) 
Tumour assessments must be repeated every six weeks (i.e. after the first 6 doses during the Initial 
Dosing Period and again after 3 doses in the Maintenance Period) or more frequently, if clinically 
indicated.  All lesions measured at baseline must be measured at every subsequent disease 
assessment and recorded clearly on the scan reports.  All non-measurable lesions noted at baseline 
must be noted on the scan report as present or absent. 
All patients, who are removed from the study for reasons other than progressive disease, must be 
re-evaluated at the time of treatment discontinuation, unless a tumour assessment was performed within 
the previous four weeks. 


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It is the responsibility of the Principal Investigator to ensure that the radiologists are aware of 
the requirement to follow-up and measure every target lesion mentioned at baseline and 
comment on the non-target lesions in accordance with RECIST criteria. 
10.3 Tumour response 
All patients who meet the eligibility criteria, receive at least one dose of study drug and have a baseline 
and at least one post-baseline assessment of disease will be evaluable for response.  Patients who 
develop clear evidence of progressive disease (PD) without a formal disease assessment will be 
considered non-responders.  There is no requirement for repeat assessments to be performed in order 
for a patient to be assigned a status of CR or PR in this study.  To be assigned a status of stable disease 
(SD), tumour response measurements must have met the SD criteria at least once and at least six 
weeks after the first dose of the investigational medicinal product (IMP) MOv18 IgE is given. 
Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it 
under another response category, for example, when baseline and/or follow-up assessment is not 
performed or not performed appropriately.  
Expert reviewers appointed by CDD may undertake an independent review of all the Investigator’s 
assessed objective responses (CR and PR).  The expert reviewers will include at least one specialist 
who is not an Investigator in the study.  The independent reviewer’s assessment will also be documented 
in the final clinical study report (CSR) along with the assessment made by the Investigator.  The eCRF 
will reflect the Investigator’s opinion. 
10.3.1 Recording of response in the eCRF 
The applicable overall response category for each visit that includes disease assessment must be 
recorded in the eCRF. 
10.3.2 Other definitions of outcome 
Toxic death:   
Any death to which drug toxicity is thought to have a major contribution. 


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11 PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT 
The Investigator must make every reasonable effort to keep each patient on study for the whole duration 
of the study (i.e. until 70 days ±14 days after last MOv18 IgE administration).  However, if the Investigator 
removes a patient from the study or if the patient declines further participation, the Post-treatment Safety 
Assessments should ideally be performed before any subsequent therapeutic intervention.  All the 
results of the evaluations and observations, together with a description of the reasons for withdrawal 
from the study, must be recorded in the medical records and in the eCRF. 
Patients who are removed from the study due to adverse events (clinical or laboratory) will be treated 
and followed according to accepted medical practice.  All pertinent information concerning the outcome 
of such treatment must be recorded in the eCRF and on the serious adverse event (SAE) report form 
where necessary. 
The following are justifiable reasons for the Investigator to withdraw a patient from study: 
• 
AE/SAE (including a positive skin prick test or anaphylaxis) 
• 
Withdrawal of consent (note that a patient can withdraw consent to treatment but remain on 
study for follow-up of safety)  
• 
Serious deviation of the study protocol (including persistent patient attendance failure and 
persistent non-compliance) 
• 
Sponsor’s decision to terminate the study 
• 
Withdrawal by the Investigator for clinical reasons not related to the IMP (MOv18 IgE) 
• 
Evidence of disease progression 
• 
Pregnancy (for female patients during the study). 


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


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13 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The final analysis will be conducted after one of the following conditions is met: 
• 
The study is terminated early (for example, due to toxicity). 
• 
All patients have had the opportunity to receive two cycles of treatment (six doses) and have 
completed their final Post-treatment Safety Assessment. 
Once one of the conditions is met, a data cut-off date will be established.  All patient visits occurring on 
or before this date will be analysed and summarised in the final clinical study report.  Any data collected 
after this date will be summarised in a supplemental report. 
13.1 Presentation of data 
Data will be presented in a descriptive fashion.  Variables will be analysed to determine whether the 
criteria for the study conduct are met.  This will include a description of patients who did not meet all the 
eligibility criteria, an assessment of protocol deviations, IMP accountability and other data that impact 
on the general conduct of the study. 
Baseline characteristics will be summarised for all enrolled patients.  Patients who died or withdrew 
before treatment started or did not complete the required safety observations will be described and 
evaluated separately. 
Treatment administration will be described for all cycles.  Dose administration, dose modifications or 
delays and the duration of therapy will be described. 
13.2 Safety 
Safety data will be collected from the date of written consent.  Safety variables will be summarised by 
descriptive statistics.  Laboratory variables will be described using the NCI-CTCAE Version 4.02. 
Adverse events (AEs) will be reported for each dose level and presented as summary tables presenting 
frequency of AEs by body system and by worst severity grade observed as well as total frequency of 
related and unrelated AEs.  All patients who receive any amount of MOv18 IgE, either by IV infusion or 
as a skin prick test, will be evaluable for safety. However, dose escalation decisions require at least one 
or three patients (depending on the cohort) to receive 3 doses of IV MOv18 IgE without DLT (see Section 
5.4). 
13.3 Pharmacokinetics 
Please refer to Table 6 in Section 8.3 for the timing of analyses of the PK assay. 
Note that for patients in the lowest cohort at least, the dose of IV MOv18 IgE is so low that MOv18 IgE 
is expected to be undetectable on PK analysis.   
The serum concentration/time data will be analysed using non-compartmental methods.  The 
pharmacokinetic (PK) parameters to be determined for MOv18 IgE include the maximum observed 
plasma concentration (Cmax), time to reach Cmax (Tmax), and the area under the plasma concentration 
time curve (AUC), and the terminal elimination half-life (T1/2), mean residence time (MRT), total body 
clearance (CLT) and steady/state volume of distribution (VSS).   


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13.4 Pharmacodynamics 
Please refer to Table 6 in Section 8.3 for the timing of analyses of the Pharmacodynamic assays. 
 
 
  
 
  No formal statistical analyses will be 
performed.  The results of all pharmacodynamic assays will be reported and may be published but only 
those results available at the time of reporting will be included in the clinical study report.   
13.5 Anti-tumour activity 
Evaluating anti-tumour activity of MOv18 IgE is a secondary study objective. Eligible patients must 
receive at least one dose of the study drug to be evaluable for best overall response assessed according 
to RECIST version 1.1 (see Appendix 3).  Best overall response will be presented in the data listings. 


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14 ADMINISTRATION 
This study is conducted under a clinical trial authorisation (CTA) and approval from the Medicines and 
Healthcare products Regulatory Agency (MHRA) and the relevant Research Ethics Committee(s) will 
be obtained before the start of this study.  This study is sponsored and managed by the Cancer 
Research UK, Centre for Drug Development (CDD).  Applicable regulatory requirements are described 
in this section. 
14.1 Protocol deviations and amendments 
The protocol should be adhered to throughout the conduct of the study.  If a situation arises where the 
conduct of the study may not be in line with the protocol, the site should discuss the suitable course of 
action with the CSM/CRA at the CDD. 
A serious breach is a breach which is likely to effect to a significant degree: the safety or physical or 
mental integrity of the subjects of the trial, or the scientific value of the trial.  In order that the Sponsor 
can fulfil their obligations in terms of reporting serious breaches of GCP to the MHRA within seven 
calendar days of identification, site staff must inform the Sponsor of any unplanned deviations to the 
trial protocol (or GCP principles) as soon as possible after the deviation occurs to allow prompt 
evaluation by the Sponsor. 
Amendments to the protocol may only be made with the approval of the CDD.  A protocol amendment 
may be subject to review by the assigned Ethics Committee, Health Research Authority (HRA) and the 
MHRA. Written documentation of the Ethics Committee and HRA (and if appropriate the MHRA) 
‘favourable opinion’ (i.e. approval) must be received before the amendment can be implemented and 
incorporated into the protocol if necessary. 
14.2 Completion of the electronic case report form (eCRF) 
Electronic CRFs approved by the CDD will be used to collect the data. The Investigator is responsible 
for ensuring the accuracy, completeness, clarity and timeliness of the data reported in the eCRFs. 
Only the Investigator and those personnel who have signed the Study Team Responsibilities Delegation 
Log provided by the CDD and have been authorised by the Investigator should enter or change data in 
the eCRFs.  Authorised users will be included on a Master User List in order to be provided access to 
the eCRF.  All protocol required investigations must be reported in the eCRF.    The Investigators must 
retain all original reports, traces and images from these investigations for future reference.   
Data will be entered directly into electronic screens by authorised site personnel.  Amendments to eCRF 
data will be made directly to the system and the system audit trail will retain details of the original 
value(s), who made the change, a date and time, and a reason for the change. 
Once an eCRF form has been entered by the site personnel, the data are cleaned using manual and 
automated checks.  Queries will be issued electronically to the site.  Authorised personnel must answer 
the queries by making relevant amendments to data or providing a response.  Answered queries will be 
closed or reissued as appropriate. 
Once the patient has completed their participation in the study and the eCRF has been fully completed, 
the Investigator must provide an electronic signature to authorise the complete subject casebook. 
At the end of the study all eCRFs are retained and archived by the CDD and a PDF copy provided to 
the Investigator who is responsible for archiving at site. 


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14.3 Study performance and monitoring 
Before the study can be initiated, the prerequisites for conducting the study must be clarified and the 
organisational preparations made with the study centre.  CDD must be informed immediately of any 
change in the personnel involved in the conduct of the study. 
During the study the CDD Clinical Research Associate (CRA) is responsible for monitoring data quality 
in accordance with CDD’s standard operating procedures (SOPs).  A strategic monitoring approach, 
including targeted source data verification, will be implemented where appropriate. 
Before the study start, the Investigator will be advised of the anticipated frequency of the monitoring 
visits.  The Investigator will receive reasonable notification before each monitoring visit. 
It is the responsibility of the CRA to: 
• 
review study records and compare them with source documents; 
• 
check pharmacokinetic and pharmacodynamic samples and storage; 
• 
discuss the conduct of the study and any emerging problems with the Investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; and 
• 
verify that the investigational site facilities and staff remain acceptable. 
It is the responsibility of the Sponsor to inform the Main REC within 90 days of the ‘end of the trial’ that 
the study has closed.  (See definition in Section 12) 
During the course of the trial, the Quality Assurance Department of the CDD, or external auditors 
contracted by the CDD, may conduct an on-site audit visit (ICH Topic E6 (R2) Guideline for Good Clinical 
Practice Sections 1.6). 
Principal Investigators conducting this trial will accept the potential for inspection by the MHRA 
14.4 Source document verification 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source data.  Therefore, 
it is the Investigator’s responsibility to ensure that both he/she and his/her study team records all relevant 
data in the medical records.  The Investigator must allow the CRA direct access to relevant source 
documentation for verification of data entered into the eCRF, taking into account data protection 
regulations.  Entries in the eCRF will be compared with patients’ medical records and the verification 
will be recorded in the eCRF and the monitoring report.   
Some source data may exist only electronically and be entered, or loaded directly into the eCRF.  The 
patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the CDD appointed to audit the study, and by regulatory authorities.  Details 
will remain confidential and patients’ names will not be recorded outside the hospital. 
14.5 Clinical study report 
At appropriate intervals, interim data listings will be prepared to give the Investigators the opportunity to 
review the data and check the completeness of information collected.  All clinical data will be presented 
at the end of the study on final data listings and summary tables.  CDD will prepare a clinical study report 
based on the final data.  The report will be submitted to the Investigator(s) for review and confirmation 
it accurately represents the data collected during the course of the study.  Summary results of the trial 
will be provided by the CDD to the MHRA and to the Research Ethics Committee. 


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14.6 Record retention 
During the clinical study and after study closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical study and the quality of the data produced to be evaluated 
and verified.  These essential documents (as detailed in Chapter V of Volume 10 (Clinical Trials) of The 
Rules Governing Medicinal Products in the European Union based upon Section 9 of the ICH GCP 
Guidelines), including source documents such as scans, study related documents and copies of the 
eCRFs, associated audit trail and serious adverse event (SAE) report forms, shall show whether the 
Investigator has complied with the principles and guidelines of Good Clinical Practice (GCP). 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for the 
minimum period required by national legislation or for longer if needed by the CDD.  Records must not 
be destroyed without prior written approval from the CDD. 
The medical files of study subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
14.7 Ethical considerations 
Before starting the study, the protocol, patient information sheets and consent forms will go through the 
CDD’s independent peer review and PSRB review process, and receive the favourable opinion of the 
Research Ethics Committee. 
It is the Chief/Principal Investigator’s responsibility to update patients (or their authorised 
representatives, if applicable) whenever new information (in nature or severity) becomes available that 
might affect the patient’s willingness to continue in the study.  The Chief/Principal Investigator must 
ensure this is documented in the patient’s medical notes and the patient is re-consented. 
The Sponsor and Chief/Principal Investigator must ensure that the study is carried out in accordance 
with the GCP principles and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 
2006/1928 as amended), the ICH GCP guidelines and the Declaration of Helsinki (Appendix 2). 
14.8 Indemnity 
This study is being carried out under the auspices of Cancer Research UK and therefore injury to a 
patient caused by the compounds under study will not carry with it the right to seek compensation from 
the pharmaceutical industry.  Cancer Research UK will provide patients with compensation for adverse 
side effects, in accordance with the principles set out in the Association of the British Pharmaceutical 
Industry (ABPI) guidelines on compensation for medicine-induced injury. 
14.9 Publication policy and press releases 
Results of this study must be submitted for publication.  The CDD must be involved in reviewing all 
drafts of the manuscripts, abstracts, press releases and any other publications.  Manuscripts must be 
submitted to the CDD at least 28 days in advance of being submitted for publication to allow time for 
CDD to schedule a review and resolve any outstanding issues.  Abstracts and press releases must be 
submitted to the CDD at least 14 days in advance of being released.  Authors must acknowledge that 
the study was sponsored by and performed with the support of the CDD. 
The contribution of the CDD should be recognised by at least one member of staff being included as an 
author on the publication.  The Biotherapeutics Development Unit (BDU) have developed and 
manufactured MOv18 IgE and so a member of the BDU staff should be included as an author. 


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15 REFERENCES 
Note for Guidance on Good Clinical Practice.  ICH Topic E6.  CSMP/ICH/135/95.  EMEA, May 1996, 
updated September 1997 with post Step 4 errata included  
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 
on the approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. Official Journal of the European Communities L121/34-44 
Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human 
use to the competent authorities, notification of substantial amendments and declaration of the end of 
the trial. October 2005.  ENTR/F2/BL D(2003) CT 1 (Revision 2) 
Detailed guidance on the application format and documentation to be submitted in an application for an 
Ethics Committee opinion on the clinical trial on medicinal products for human use. February 2006. 
ENTR/CT 2 (Revision 1) 
Detailed guidance on the collection, verification and presentation of adverse reaction reports arising 
from clinical trials on medicinal products for human use. April 2006.  ENTR/CT 3 (Revision 2) 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 1031) 
COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines 
for good clinical practice as regards investigational medicinal products for human use, as well as the 
requirements for authorisation of the manufacturing or importation of such products.  Official Journal of 
the European Union L 91/13 
The Medicines for Human use (Clinical Trials) Amendment Regulations 2006 (Statutory Instrument 
2006/1928). 
Antony, A. C., C. Utley, K. C. Van Horne and J. F. Kolhouse (1981). "Isolation and characterization of a 
folate receptor from human placenta." J Biol Chem. 256(18): 9684-9692. 
Armstrong, D., A. Bicher, R. Coleman, D. Gibbon, D. Glenn, et al. (2008). "Exploratory phase II efficacy 
study of MORAb-003, a monoclonal antibody against folate receptor alpha, in platinum-sensitive ovarian 
cancer in first relapse." J Clin Oncol 26(18S): 5500. 
Birn, H., S. Nielsen and E. I. Christensen (1997). "Internalization and apical-to-basolateral transport of 
folate in rat kidney proximal tubule." American Journal of Physiology - Renal Physiology. 272(1): F70-
F78. 
Birn, H., J. Selhub and E. I. Christensen (1993). "Internalization and intracellular transport of folate-
binding protein in rat kidney proximal tubule." American Journal of Physiology - Cell Physiology. 264(2): 
C302-C310. 
Bottero, F., A. Tomassetti, S. Canevari, S. Miotti, S. Menard, et al. (1993). "Gene transfection and 
expression of the ovarian carcinoma marker folate binding protein on NIH/3T3 cells increases cell 
growth in vitro and in vivo." Cancer Res. 53(23): 5791-5796. 
Boumiza R, Debard AL, Monneret G, (2005). "The basophil activation test by flow cytometry: recent 
developments in clinical studies, standardization and emerging perspectives." Clin Mol Allergy. 3: 9. 
Bracher, M., H. J. Gould, B. J. Sutton, D. Dombrowicz and S. N. Karagiannis (2007). "Three-colour flow 
cytometric method to measure antibody-dependent tumour cell killing by cytotoxicity and phagocytosis." 
J Immunol Methods. 323(2): 160-171. 
Buist, M. R., P. Kenemans, W. den Hollander, J. B. Vermorken, C. J. Molthoff, et al. (1993). "Kinetics 
and tissue distribution of the radiolabeled chimeric monoclonal antibody MOv18 IgG and F(ab')2 
fragments in ovarian carcinoma patients." Cancer Res. 53(22): 5413-5418. 
Buist, M. R., C. F. Molthoff, P. Kenemans and C. J. Meijer (1995). "Distribution of OV-TL 3 and MOv18 
in normal and malignant ovarian tissue." J Clin Pathol. 48(7): 631-636. 
Cagle, P. T., Q. J. Zhai, L. Murphy and P. S. Low (2013). "Folate receptor in adenocarcinoma and 
squamous cell carcinoma of the lung: potential target for folate-linked therapeutic agents." Arch Pathol 
Lab Med. 137(2): 241-244. 


CONFIDENTIAL 
CRUKD14001_MOv18 IgE Protocol Version 13 FINAL 29APR2021 
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EudraCT number 2014-000070-19 
 
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Canevari, S., D. Mezzanzanica, A. Mazzoni, D. R. Negri, V. Ramakrishna, et al. (1995). "Bispecific 
antibody targeted T cell therapy of ovarian cancer: clinical results and future directions." J Hematother. 
4(5): 423-427. 
Carosso A, Bugiania M, Miglioreb E, Antòc JM, DeMarcod R. Reference values of total serum IgE and 
their significance in the diagnosis of allergy in young European adults. Int Arch Allergy Immunol 
2007;142:230-238 
Casalini, P., E. Luison, S. Menard, M. I. Colnaghi, G. Paganelli, et al. (1997). "Tumor pretargeting: role 
of avidin/streptavidin on monoclonal antibody internalization." J Nucl Med. 38(9): 1378-1381. 
Cheifetz, A., M. Smedley, S. Martin, M. Reiter, G. Leone, et al. (2003). "The incidence and management 
of infusion reactions to infliximab: a large center experience." Am J Gastroenterol. 98(6): 1315-1324. 
Coney, L. R., A. Tomassetti, L. Carayannopoulos, V. Frasca, B. A. Kamen, et al. (1991). "Cloning of a 
tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein." Cancer 
Res. 51(22): 6125-6132. 
Crippa, F., G. Bolis, E. Seregni, N. Gavoni, G. Scarfone, et al. (1995). "Single-dose intraperitoneal 
radioimmunotherapy with the murine monoclonal antibody I-131 MOv18: clinical results in patients with 
minimal residual disease of ovarian cancer." Eur J Cancer. 31A(5): 686-690. 
Crippa, F., G. L. Buraggi, E. Di Re, M. Gasparini, E. Seregni, et al. (1991). "Radioimmunoscintigraphy 
of ovarian cancer with the MOv18 monoclonal antibody." Eur J Cancer. 27(6): 724-729. 
D'Angelica, M., J. Ammori, M. Gonen, D. S. Klimstra, P. S. Low, et al. (2011). "Folate receptor-alpha 
expression in resectable hepatic colorectal cancer metastases: patterns and significance." Mod Pathol. 
24(9): 1221-1228. 
De Week AL, Sanz ML, Gamboa PM, Aberer W, Bienvenu J, Blanca M, Demoly P, Ebo DG, Mayorga 
L, Monneret G, Sainte Laudy J, (2008). "Diagnostic tests based on human basophils: more potentials 
and perspectives than pitfalls. II. Technical issues." J Investig Allergol Clin Immunol;18: 143-55. 
Dreskin, S. C., P. K. Goldsmith, W. Strober, L. A. Zech and J. I. Gallin (1987). "Metabolism of 
immunoglobulin E in patients with markedly elevated serum immunoglobulin E levels." J Clin Invest. 
79(6): 1764-1772. 
Edelman, M. J., W. A. Harb, S. E. Pal, R. V. Boccia, M. J. Kraut, et al. (2012). "Multicenter trial of EC145 
in advanced, folate-receptor positive adenocarcinoma of the lung." J Thorac Oncol. 7(10): 1618-1621. 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, et al. (2009). "New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)." Eur J Cancer. 45(2): 228-
247. 
Farrell, C., C. Schweizer, J. Wustner, S. Weil, M. Namiki, et al. (2012). "Population pharmacokinetics of 
farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian 
cancer." Cancer Chemother Pharmacol. 70(5): 727-734. 
Franklin, W. A., M. Waintrub, D. Edwards, K. Christensen, P. Prendegrast, et al. (1994). "New anti-lung-
cancer antibody cluster 12 reacts with human folate receptors present on adenocarcinoma." Int J Cancer 
Suppl. 8: 89-95. 
Fu, S. L., J. Pierre, T. A. Smith-Norowitz, M. Hagler, W. Bowne, et al. (2008). "Immunoglobulin E 
antibodies from pancreatic cancer patients mediate antibody-dependent cell-mediated cytotoxicity 
against pancreatic cancer cells." Clin Exp Immunol. 153(3): 401-409. 
Garin-Chesa, P., I. Campbell, P. E. Saigo, J. L. Lewis, Jr., L. J. Old, et al. (1993). "Trophoblast and 
ovarian cancer antigen LK26. Sensitivity and specificity in immunopathology and molecular identification 
as a folate-binding protein." Am J Pathol. 142(2): 557-567. 
Global Strategy for Asthma Management and Prevention, From t. (2012). "Global Initiative for Asthma 
(GINA) 2012." Available from: http://www.ginasthma.org/ 
Gould, H. J., G. A. Mackay, S. N. Karagiannis, C. M. O'Toole, P. J. Marsh, et al. (1999). "Comparison 
of IgE and IgG antibody-dependent cytotoxicity in vitro and in a SCID mouse xenograft model of ovarian 
carcinoma." Eur J Immunol. 29(11): 3527-3537. 


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Gould, H. J., B. J. Sutton, A. J. Beavil, R. L. Beavil, N. McCloskey, et al. (2003). "The biology of IgE and 
the basis of allergic disease." Annu Rev Immunol. 21: 579-628. 
Grana, C., M. Bartolomei, D. Handkiewicz, P. Rocca, L. Bodei, et al. (2004). "Radioimmunotherapy in 
advanced ovarian cancer: is there a role for pre-targeting with (90)Y-biotin?" Gynecol Oncol. 93(3): 691-
698. 
Hanashiro, K., Y. Tokeshi, T. Nakasone, M. Sunagawa, M. Nakamura, et al. (2001). "Analysis of IgE 
turnover in non-sensitized and sensitized rats." Mediators Inflamm. 10(4): 217-221. 
Hanashiro, K., Y. Tokeshi, T. Nakasone, M. Sunagawa, M. Nakamura, et al. (2002). "Azelastine and 
suplatast shorten the distribution half-life of IgE in rats." Mediators Inflamm. 11(1): 61-64. 
Hernando, J. J., T. W. Park, H. P. Fischer, O. Zivanovic, M. Braun, et al. (2007). "Vaccination with 
dendritic cells transfected with mRNA-encoded folate-receptor-alpha for relapsed metastatic ovarian 
cancer." Lancet Oncol. 8(5): 451-454. 
Holm, J., S. I. Hansen, M. Hoier-Madsen and L. Bostad (1991). "High-affinity folate binding in human 
choroid plexus. Characterization of radioligand binding, immunoreactivity, molecular heterogeneity and 
hydrophobic domain of the binding protein." Biochem J. 280 ( Pt 1): 267-271. 
Holm, J., S. I. Hansen, M. Hoier-Madsen, P. E. Helkjaer and M. Bzorek (1995). "Folate receptor in 
malignant effusions of ovarian carcinoma." APMIS. 103(9): 663-670. 
Holm, J., S. I. Hansen, M. Hoier-Madsen, P. E. Helkjaer and C. W. Nichols (1997). "Folate receptors in 
malignant and benign tissues of human female genital tract." Biosci Rep. 17(4): 415-427. 
Holm, J., S. I. Hansen, M. Hoier-Madsen, K. Sondergaard and M. Bzorek (1994). "Folate receptor of 
human mammary adenocarcinoma." APMIS. 102(6): 413-419. 
Jensen‐Jarolim, E. and J. Singer (2011). "Why could passive Immunoglobulin E antibody therapy be 
safe in clinical oncology?" Clinical & Experimental Allergy. 41(10): 1337-1340. 
Joseph, D., Bax, H.J., Dodev, T., Georgouli, M., Nakamura, M., et al (2017) "Anti-Folate Receptor-α IgE 
but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling." Cancer Res. 2017 
Mar 1;77(5):1127-1141.  
Kalli, K. R., A. L. Oberg, G. L. Keeney, T. J. Christianson, P. S. Low, et al. (2008). "Folate receptor alpha 
as a tumor target in epithelial ovarian cancer." Gynecol Oncol. 108(3): 619-626. 
Karagiannis, S. N., M. G. Bracher, R. L. Beavil, A. J. Beavil, J. Hunt, et al. (2008). "Role of IgE receptors 
in IgE antibody-dependent cytotoxicity and phagocytosis of ovarian tumor cells by human monocytic 
cells." Cancer Immunol Immunother. 57(2): 247-263. 
Karagiannis, S. N., M. G. Bracher, J. Hunt, N. McCloskey, R. L. Beavil, et al. (2007). "IgE-antibody-
dependent immunotherapy of solid tumors: cytotoxic and phagocytic mechanisms of eradication of 
ovarian cancer cells." J Immunol. 179(5): 2832-2843. 
Karagiannis, S. N., D. H. Josephs, P. Karagiannis, A. E. Gilbert, L. Saul, et al. (2012). "Recombinant 
IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application." 
Cancer Immunol Immunother. 61(9): 1547-1564. 
Karagiannis, S. N., Q. Wang, N. East, F. Burke, S. Riffard, et al. (2003). "Activity of human monocytes 
in IgE antibody-dependent surveillance and killing of ovarian tumor cells." Eur J Immunol. 33(4): 1030-
1040. 
Kershaw, M. H., J. A. Westwood, L. L. Parker, G. Wang, Z. Eshhar, et al. (2006). "A phase I study on 
adoptive immunotherapy using gene-modified T cells for ovarian cancer." Clin Cancer Res. 12(20 Pt 1): 
6106-6115. 
Konner, J. A., K. M. Bell-McGuinn, P. Sabbatini, M. L. Hensley, W. P. Tew, et al. (2010). "Farletuzumab, 
a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I 
study." Clin Cancer Res. 16(21): 5288-5295. 
Lawson, N. and P. Scorer (2010). "Evaluation of Antibody to Folate Receptor-alpha (FR-α)." 
http://www.leicabiosystems.com/pathologyleaders/evaluation-of-antibody-to-folate-receptor-alpha-fr-
%CE%B1/ 


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Lorusso, P. M., M. J. Edelman, S. L. Bever, K. M. Forman, M. Pilat, et al. (2012). "Phase I study of folate 
conjugate EC145 (Vintafolide) in patients with refractory solid tumors." J Clin Oncol. 30(32): 4011-4016. 
Luiten, R. M., S. O. Warnaar, D. Sanborn, C. H. Lamers, R. L. Bolhuis, et al. (1997). "Chimeric bispecific 
OC/TR monoclonal antibody mediates lysis of tumor cells expressing the folate-binding protein (MOv18) 
and displays decreased immunogenicity in patients." J Immunother. 20(6): 496-504. 
Magnani, P., F. Fazio, C. Grana, C. Songini, L. Frigerio, et al. (2000). "Diagnosis of persistent ovarian 
carcinoma with three-step immunoscintigraphy." Br J Cancer. 82(3): 616-620. 
Melani, C., M. Figini, D. Nicosia, E. Luison, V. Ramakrishna, et al. (1998). "Targeting of interleukin 2 to 
human ovarian carcinoma by fusion with a single-chain Fv of antifolate receptor antibody." Cancer Res. 
58(18): 4146-4154. 
Miotti, S., S. Canevari, S. Menard, D. Mezzanzanica, G. Porro, et al. (1987). "Characterization of human 
ovarian carcinoma-associated antigens defined by novel monoclonal antibodies with tumor-restricted 
specificity." Int J Cancer. 39(3): 297-303. 
Molthoff, C. F., H. M. Prinssen, P. Kenemans, A. C. van Hof, W. den Hollander, et al. (1997). "Escalating 
protein doses of chimeric monoclonal antibody MOv18 immunoglobulin G in ovarian carcinoma patients: 
a phase I study." Cancer. 80(12 Suppl): 2712-2720. 
Morshed, K. M., D. M. Ross and K. E. McMartin (1997). "Folate transport proteins mediate the 
bidirectional transport of 5-methyltetrahydrofolate in cultured human proximal tubule cells." J Nutr. 
127(6): 1137-1147. 
Naumann, R., J. Symanowski, S. Ghamande, N. Gabrail, L. Gilbert, et al. (2010). "PRECEDENT: a 
randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, 
versus PLD alone, in subjects with platinum-resistant ovarian cancer." J Clin Oncol. 28(15 suppl): 393s. 
Neuchrist, C., J. Kornfehl, M. Grasl, H. Lassmann, D. Kraft, et al. (1994). "Distribution of 
immunoglobulins in squamous cell carcinoma of the head and neck." Int Arch Allergy Immunol. 104(1): 
97-100. 
O'Shannessy, D. J., E. B. Somers, E. Albone, X. Cheng, Y. C. Park, et al. (2011). "Characterization of 
the human folate receptor alpha via novel antibody-based probes." Oncotarget. 2(12): 1227-1243. 
Paganelli, G., C. Belloni, P. Magnani, F. Zito, A. Pasini, et al. (1992). "Two-step tumour targetting in 
ovarian cancer patients using biotinylated monoclonal antibodies and radioactive streptavidin." Eur J 
Nucl Med. 19(5): 322-329. 
Parker, N., M. J. Turk, E. Westrick, J. D. Lewis, P. S. Low, et al. (2005). "Folate receptor expression in 
carcinomas and normal tissues determined by a quantitative radioligand binding assay." Anal Biochem. 
338(2): 284-293. 
Reichert, J. M. and V. E. Valge-Archer (2007). "Development trends for monoclonal antibody cancer 
therapeutics." Nat Rev Drug Discov. 6(5): 349-356. 
Ross, J. F., P. K. Chaudhuri and M. Ratnam (1994). "Differential regulation of folate receptor isoforms 
in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical 
implications." Cancer. 73(9): 2432-2443. 
Rudman, S. M., D. H. Josephs, H. Cambrook, P. Karagiannis, A. E. Gilbert, et al. (2011). "Harnessing 
engineered antibodies of the IgE class to combat malignancy: initial assessment of FcvarepsilonRI-
mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I 
hypersensitivity." Clin Exp Allergy. 41(10): 1400-1413. 
Rustin, G. J. (2003). "Use of CA-125 to assess response to new agents in ovarian cancer trials." Journal 
of Clinical Oncology. 21(10 suppl): 187s-193s. 
Simons, F., L. R. Ardusso, M. B. Bilo, Y. M. El-Gamal, D. K. Ledford, et al. (2011a). "World Allergy 
Organization anaphylaxis guidelines: summary." J Allergy Clin Immunol. 127(3): 587-593 e581-522. 
Simons, F., L. R. Ardusso, M. B. Bilò, Y. M. El-Gamal, D. K. Ledford, et al. (2011b). "World Allergy 
Organization guidelines for the assessment and management of anaphylaxis." The World Allergy 
Organization Journal. 4(2): 13. 


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Toffoli, G., C. Cernigoi, A. Russo, A. Gallo, M. Bagnoli, et al. (1997). "Overexpression of folate binding 
protein in ovarian cancers." Int J Cancer. 74(2): 193-198. 
Toffoli, G., A. Russo, A. Gallo, C. Cernigoi, S. Miotti, et al. (1998). "Expression of folate binding protein 
as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian 
cancer." Int J Cancer. 79(2): 121-126. 
van Zanten-Przybysz, I., C. Molthoff, J. K. Gebbinck, S. von Mensdorff-Pouilly, R. Verstraeten, et al. 
(2002). "Cellular and humoral responses after multiple injections of unconjugated chimeric monoclonal 
antibody MOv18 in ovarian cancer patients: a pilot study." J Cancer Res Clin Oncol. 128(9): 484-492. 
van Zanten-Przybysz, I., C. F. Molthoff, J. C. Roos, M. A. Plaizier, G. W. Visser, et al. (2000). 
"Radioimmunotherapy with intravenously administered 131I-labeled chimeric monoclonal antibody 
MOv18 in patients with ovarian cancer." J Nucl Med. 41(7): 1168-1176. 
van Zanten-Przybysz, I., C. F. Molthoff, J. C. Roos, R. H. Verheijen, A. van Hof, et al. (2001). "Influence 
of the route of administration on targeting of ovarian cancer with the chimeric monoclonal antibody 
MOv18: i.v. vs. i.p." Int J Cancer. 92(1): 106-114. 
Wang, Y., B. B. Newell and J. Irudayaraj (2012). "Folic acid protected silver nanocarriers for targeted 
drug delivery." J Biomed Nanotechnol. 8(5): 751-759. 
Watanabe, K., M. Kaneko and Y. Maitani (2012). "Functional coating of liposomes using a folate- 
polymer conjugate to target folate receptors." Int J Nanomedicine. 7: 3679-3688. 
Weitman, S. D., R. H. Lark, L. R. Coney, D. W. Fort, V. Frasca, et al. (1992). "Distribution of the folate 
receptor GP38 in normal and malignant cell lines and tissues." Cancer Res. 52(12): 3396-3401. 
Zennaro, D., C. Capalbo, E. Scala, M. Liso, E. Spillner, et al. (2011). " IgE, IgG4 and IgG response to 
tissue-specific and environmental antigens in patients affected by cancer." Allergy. 66(Suppl. 94): 100. 
Zimmerman, J. (1990). "Folic acid transport in organ-cultured mucosa of human intestine. Evidence for 
distinct carriers." Gastroenterology. 99(4): 964-972. 




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16.2  Appendix 2: Declaration Of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on 
identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. 
Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. 
It is the duty of the physician to promote and safeguard the health of patients, including those who 
are involved in medical research. The physician's knowledge and conscience are dedicated to the 
fulfilment of this duty. 
4. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.” 
5. 
Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. 
In medical research involving human subjects, the well-being of the individual research subject 
must take precedence over all other interests. 
7. 
The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best current interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
8. 
In medical practice and in medical research, most interventions involve risks and burdens. 
9. 
Medical research is subject to ethical standards that promote respect for all human subjects and 
protect their health and rights. Some research populations are particularly vulnerable and need 
special protection. These include those who cannot give or refuse consent for themselves and 
those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
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12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14. The design and performance of each research study involving human subjects must be clearly 
described in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest, incentives for subjects and provisions for treating 
and/or compensating subjects who are harmed as a consequence of participation in the research 
study. The protocol should describe arrangements for post-study access by study subjects to 
interventions identified as beneficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws 
and regulations of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or eliminate 
any of the protections for research subjects set forth in this Declaration. The committee must have 
the right to monitor ongoing studies. The researcher must provide monitoring information to the 
committee, especially information about any serious adverse events. No change to the protocol 
may be made without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician 
17. or other health care professional. The responsibility for the protection of research subjects must 
always rest with the physician or other health care professional and never the research subjects, 
even though they have given consent. 
18. Medical research involving a disadvantaged or vulnerable population or community is only justified 
if the research is responsive to the health needs and priorities of this population or community and 
if there is a reasonable likelihood that this population or community stands to benefit from the results 
of the research. 
19. Every medical research study involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by 
the condition under investigation. 
20. Every clinical trial must be registered in a publicly accessible database before recruitment of the 
first subject. 
21. Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
22. Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
23. Participation by competent individuals as subjects in medical research must be voluntary. Although 
it may be appropriate to consult family members or community leaders, no competent individual 
may be enrolled in a research study unless he or she freely agrees. 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information and to minimize the impact of the study on their physical, mental and 
social integrity. 


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25. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, and any other relevant aspects of the study. The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
26. For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where consent 
would be impossible or impractical to obtain for such research or would pose a threat to the validity 
of the research. In such situations the research may be done only after consideration and approval 
of a research ethics committee. 
27. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a research 
study that has no likelihood of benefit for them unless it is intended to promote the health of the 
population represented by the potential subject, the research cannot instead be performed with 
competent persons, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incompetent is able to give assent to decisions 
about participation in research, the physician must seek that assent in addition to the consent of 
the legally authorized representative. The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research population. In such 
circumstances the physician should seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent 
to remain in the research should be obtained as soon as possible from the subject or a legally 
authorized representative. 
31. Authors, editors and publishers all have ethical obligations with regard to the publication of the 
results of research. Authors have a duty to make publicly available the results of their research on 
human subjects and are accountable for the completeness and accuracy of their reports. They 
should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results should be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest should be declared in the publication. Reports of 
research not in accordance with the principles of this Declaration should not be accepted for 
publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
32. The physician may combine medical research with medical care only to the extent that the research 
is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects. 


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33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best current proven intervention, except in the following circumstances: 
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
• 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of serious 
or irreversible harm. Extreme care must be taken to avoid abuse of this option. 
34. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to 
interventions identified as beneficial in the study or to other appropriate care or benefits. 
35. The physician must fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never interfere with the patient-physician relationship. 
36. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally 
authorized representative, may use an unproven intervention if in the physician's judgement it offers 
hope of saving life, re-establishing health or alleviating suffering. Where possible, this intervention 
should be made the object of research, designed to evaluate its safety and efficacy. In all cases, 
new information should be recorded and, where appropriate, made publicly available. 


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16.3 Appendix 3: Assessment of Disease Response 
Assessment of disease response in this study should be performed according to RECIST criteria, as 
summarised below.  Investigators may choose to limit the number of target lesions to only 5, or they 
may analyze more target lesions than the RECIST 1.1 formalism allows, without a specific limitation on 
the number of target lesions per organ. 
New response evaluation criteria in solid tumours (RECIST criteria): 
Revised RECIST guideline (version 1.1)  
E.A. Eisenhauer et al. (2009) European Journal of Cancer 45: 228-247 
Note that this is an abridged version of the RECIST criteria.  Please refer to the above article for detailed 
appendices and if in doubt. 
1. 
Measurability of tumour at baseline 
1.1 
Definitions 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as follows: 
1.1.1  Measurable 
Tumour lesions: Must be accurately measured in at 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 5 mm; see Appendix II on imaging 
guidance). 
• 10mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must 
be >15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. See 
also notes below on ‘Baseline documentation of target and non-target lesions’ for information on lymph 
node measurement. 
1.1.2  
Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes with ≥10 
to <15mm short axis) as well as truly non-measurable lesions.  Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques. 
1.1.3.  Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 


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Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.  
• 
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 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, 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. 
Lesions with prior local treatment: 
• 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such lesions 
would be considered measurable.  
1.2.  Specifications by methods of measurements 
1.2.1.  Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
1.2.2.  Method of assessment 
The same method of assessment and the same technique should be used to characterise each identified 
and reported lesion at baseline and during follow-up.  Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical exam. 
Clinical lesions:  
Clinical lesions will only be considered measurable when they are superficial and ≥10mm diameter as 
assessed using calipers (e.g. skin nodules).  For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is suggested.  As noted above, when 
lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
since it is more objective and may also be reviewed at the end of the study. 
Chest X-ray:  
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since 
CT is more sensitive than X-ray, particularly in identifying new lesions.  However, lesions on chest X-
ray may be considered measurable if they are clearly defined and surrounded by aerated lung.   


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CT, MRI:  
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment.  This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5mm or less.  When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans).  More details concerning the use of both CT and MRI for 
assessment of objective tumour response evaluation are provided in the publication from Eisenhauer et 
al.  
Ultrasound:  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next (described in greater detail 
in Appendix II).  If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: 
The utilisation of these techniques for objective tumour evaluation is not advised.  However, they can 
be useful to confirm complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response or surgical resection is an endpoint. 
Tumour markers:  
Tumour markers alone cannot be used to assess objective tumour response.  If markers are initially 
above the upper normal limit, however, they must normalise for a patient to be considered in complete 
response.   
Cytology, histology:  
These techniques can be used to differentiate between PR and CR in rare cases (for example, residual 
lesions in tumour types such as germ cell tumours, where known residual benign tumours can remain).   
2.  
Tumour response evaluation 
2.1  
Assessment of overall tumour burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumour 
burden at baseline and use this as a comparator for subsequent measurements.  Measurable disease 
is defined by the presence of at least one measurable lesion (as detailed above in Section 1).   
2.2.  
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline (this means in instances where patients 
have only one or two organ sites involved a maximum of two and four lesions respectively will be 
recorded).  For evidence to support the selection of only five target lesions, see analyses on a large 
prospective database in the article by Bogaerts et al.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be selected.  An example is provided 
in Fig. 3 of Appendix II of the publication by Eisenhauer et al. 


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Lymph nodes merit special mention since they are normal anatomical structures which may be visible 
by imaging even if not involved by tumour.  Pathological nodes which are defined as measurable and 
may be identified as target lesions, must meet the criterion of a short axis of ≥15 mm by CT scan.  Only 
the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumour.  Nodal size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagital or coronal).  The 
smaller of these measures is the short axis.  For example, an abdominal node which is reported as 
being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement. All other pathological nodes (those 
with short axis ≥10 mm but <15 mm) should be considered non-target lesions.  Nodes that have a short 
axis <10 mm are considered non- pathological and should not be recorded or followed. 
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. If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters will 
be used as reference to further characterise any objective tumour regression in the measurable 
dimension of the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ (more details 
to follow). In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
2.3.  
Response criteria 
2.3.1.  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 diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm.  (Note: the appearance of one or more new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
2.3.2.  Special notes on the assessment of target lesions 
Lymph nodes.  
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study.  This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal lymph 
node is defined as having a short axis of <10 mm.  Case report forms or other data collection methods 
may therefore be designed to have target nodal lesions recorded in a separate section where, in order 
to qualify for CR, each node must achieve a short axis <10 mm.  For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 


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Target lesions that become ‘too small to measure’. 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm).  However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so faint on 
CT scan that the radiologist may not feel comfortable assigning an exact measure and may report them 
as being ‘too small to measure’.  When this occurs it is important that a value be recorded on the case 
report form.  If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned.  (Note: It is less likely that this rule will be used 
for lymph nodes since they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well).  This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness).  The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error.  To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment: 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum.  Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of each individual lesion.  If 
the lesions have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3.  Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumour marker 
level.  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 (see comments below) of existing non-target 
lesions.  (Note: the appearance of one or more new lesions is also considered progression). 
2.3.4.  Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease. 
In this setting, 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 
quality for unequivocal progression status.  The designation of overall progression solely on the basis 
of change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the patient has only non-measurable disease. 
This circumstance arises in some phase III trials when it is not a criterion of study entry to have 
measurable disease.  The same general concepts apply here as noted above, however, in this instance 


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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 (by 
definition: if all lesions are truly non-measurable) a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumour burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localised to widespread, or may be described in protocols as ‘sufficient to 
require a change in therapy’.  If ‘unequivocal progression’ is seen, the patient should be considered to 
have had overall PD at that point.  While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so; therefore the increase 
must be substantial. 
2.3.5.  New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important.  There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not attributable. 
to differences in scanning technique, change in imaging modality or findings thought to represent 
something other than tumour (for example, some ‘new’ bone lesions may be simply healing or flare of 
pre-existing lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression.  An example of this is the patient who 
has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals 
metastases.  The patient’s brain metastases are considered to be evidence of PD even if he/she did not 
have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning 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: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
b. 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).  A ‘positive’ FDG-
PET scan lesion means one which is FDG avid with an uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image. 
• 
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 not PD. 


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2.4  
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until the 
end of treatment taking into account any requirement for confirmation (not required in this trial). Should 
a response not be documented until after the end of therapy in this trial, post-treatment assessment 
may be considered in determination of best overall response as long as no alternative anti-cancer 
therapy has been given.  The patient’s best overall response assignment will depend on the findings of 
both target and non-target disease and will also take into consideration the appearance of new lesions. 
2.4.1.  Time point response 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 1 on the 
next page provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline.   
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
2.4.2. 
Missing assessments and not evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) 
at that time point.  If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point response.  This 
would be most likely to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and at follow-up only two lesions were assessed, but those gave a sum of 
80 mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion. 
2.4.3.  Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Best response in these trials (in which confirmation of complete or partial response is NOT required): is 
defined as the best response across all time points (for example, a patient who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a best overall response of 
PR).  When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline.  If the minimum time is not met when SD is otherwise the best time point response, the 
patient’s best response depends on the subsequent assessments.  For example, a patient who has SD 
at first assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD.  The same patient lost to follow-up after the first SD assessment would be considered 
inevaluable.  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 


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Table 1 – Time point response: patients with target (+/–non-target) disease 
Target lesions  
Non-target lesions  
New lesions  
Overall response  
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any  
Any  
Yes  
PD  
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable.  
Table 2 – Time point response: patients with non-target disease only 
Non-target lesions  
New lesions  
Overall response  
CR  
No  
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD(a) NE 
Not all evaluated 
No 
PD 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
 
CR = complete response, PD = progressive disease, and NE = inevaluable.  
(a) ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised. 
2.4.4.  Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ size 
(<10 mm), they may still have a measurement reported on scans.  This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes.  As noted earlier, this means that patients with CR may not have a total 
sum of ‘zero’ on the case report form (CRF). 
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 objective progression even after discontinuation of treatment.  
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping study 
therapy.  The objective response status of such patients is to be determined by evaluation of target and 
non-target disease as shown in Tables 1 and 2. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response.  
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where 
a residual radiographic abnormality is thought to represent fibrosis or scarring. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at the next 


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scheduled assessment, progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. 
2.6.2.  Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on 
study). 
The duration of overall complete response is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
2.6.3.  Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest sum on study 
(if the baseline sum is the smallest, this is the reference for calculation of PD).  
 
 


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16.4 Appendix 4: Treatment of Anaphylaxis  
[Based on (Simons et al., 2011a; Simons et al., 2011b)] 
If the patient experiences symptoms suggestive of an infusion-related reaction or cytokine release, the 
infusion must be slowed or interrupted, and the patient must be treated with oxygen, paracetamol, 
antihistamines, fluid resuscitation and/or steroids, as clinically indicated.  
Anaphylaxis should be suspected if: 
• 
There is a sudden onset and rapid progression of symptoms 
• 
The reaction is > Grade 2 in severity (see Appendix 5) and fails to respond to the 
conservative measures outlined above  
or  
• 
The reaction is > Grade 2 in severity and associated with rapid onset of urticaria (within 10 
minutes of starting the infusion). 
• 
The patient experiences life-threatening airway and/or breathing and/or circulation 
problems 
If anaphylaxis is suspected based on these criteria: 
• 
Summon help (resuscitation team) 
• 
Stop the infusion 
• 
Inject epinephrine (adrenaline) intramuscularly into the mid-anterolateral aspect of the thigh 
o 
0.5-1mL 1:1000 epinephrine  
o 
Record the time of dose and repeat it in 5-15 minutes if needed (e.g. because of 
progressing hypotension and/or laryngeal oedema). 
• 
Place the patient on his/her back or in a position of comfort if there is respiratory distress 
and/or vomiting; elevate the legs 
• 
If not already started, give high-flow (6-8 L/min) supplemental oxygen by face mask  
• 
If not already started, give 1-2 litres of 0.9% isotonic saline rapidly (e.g. 5-10 mL/kg in the 
first 5-10 minutes), as clinically indicated 
• 
Give chlorphenamine 10mg IM or slow IV  
• 
Consider hydrocortisone 200mg IM or slow IV 
• 
Consider bronchodilators if clinically indicated.  
Cardiac arrest associated with anaphylaxis 
• 
If indicated, perform cardiopulmonary resuscitation as per Adult Life Support guidelines 
The possibility of early recurrence of symptoms following the initial episode should always be 
considered. In patients requiring treatment with epinephrine, chlorphenamine and corticosteroids should 
be continued for 24 hours (total) to minimise the possibility of a ‘late reaction’ (which sometimes occurs 
4-6 hours after an anaphylactic episode). In the event of recurrence or other evidence that residual 
MOv18 IgE could be contributing to an ongoing systemic reaction, the use of omalizumab should be 
considered. Omalizumab is a monoclonal antibody licensed and NICE-approved for severe persistent 
allergic asthma; it acts by binding to the Fc domain of IgE and preventing binding to both FcαRI and 
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16.7 Appendix 7: Levels of Asthma Control (GINA Guidelines 2012$) 
A. Assessment of current clinical control (preferably over 4 weeks) 
Characteristic 
Controlled (all of the 
following) 
Partly controlled (any 
measure present) 
Uncontrolled 
Daytime symptoms 
None (twice or less/week) 
More than twice/week 
Three or more 
features of 
partly controlled 
asthma*† 
Limitation of activities 
None 
Any 
Nocturnal 
symptoms/awakening 
None 
Any 
Need for reliever/rescue 
treatment 
None (twice or less/week) 
More than twice/week 
Lung function (PEF or 
FEV1) ‡ 
Normal 
<80% predicted or 
personal best (if known) 
 
B. Assessment of future Risk (risk of exacerbations, instability, rapid decline in lung function, 
side effects) 
Features that are associated with increased risk of adverse events in the future include: 
Poor clinical control, frequent exacerbations in past year*, ever admission to critical care for asthma, 
low FEV1, exposure to cigarette smoke, high dose medications 
$ (Global Strategy for Asthma Management and Prevention, 2012) 
*Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate 
† By definition, an exacerbation in any week makes that an uncontrolled asthma week 
‡ Without administration of a bronchodilator 
N.B. Patients with current uncontrolled asthma (according to Part A above) or at high future risk 
(indicated by at least one of the criteria listed in Part B above, other than exposure to cigarette smoke 
and use of high dose medications) are not eligible for the study. 


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16.8 Appendix 8: Skin Prick testing to evaluate sensitivity to MOv18 IgE 
Skin prick testing will be performed and the response assessed at 15, 30 and 60 mins post skin prick 
test initiation, before each administration of IV MOv18 IgE solution.  Testing for sensitivity to MOv18 IgE 
will include a negative saline control and a positive histamine control to verify that the patient’s skin is 
normally responsive.  
Essential safety equipment: 
Always have an emergency kit available in or close to the clinic room.  This must include: 
▪ Oxygen 
▪ Injectable Epinephrine (Adrenaline) B.P. 1:1,000 (1mg/mL) 
▪ Hydrocortisone cream  
▪ Oral Prednisolone 
▪ IV hydrocortisone 
▪ Oral antihistamines e.g. cetirizine, chlorpheniramine 
▪ IV chlorphenamine 
▪ Inhaled bronchodilator e.g. salbutamol 
▪ Nebuliser masks 
Method  
The following method is based on the standard operating procedure on how to perform adult skin prick 
testing from the BSACI Nurses in Allergy Committee (Kathryn Powrie 15.10.2015 final v7): 
http://www.bsaci.org/Guidelines/SOPs. Minor deviations from these methods are allowed if agreed in 
writing by the sponsor and they are according to local SOPs and practice”. 
Skin prick testing is a method used to determine the presence of specific IgE. Skin prick testing should 
only be interpreted in conjunction with a clinical history as a positive skin prick test alone is not diagnostic 
of clinical disease (1,2). Depending on the allergen, approximately half of positive tests occur in patients 
who are not allergic to that allergen.  Skin prick testing should be performed by an appropriately trained 
and competent healthcare worker who is also trained in recognition and treatment of anaphylaxis (3).   
Exclusions  
Skin prick test reactions are inhibited by antihistamines and may be inhibited by tricyclic 
antidepressants, topical corticosteroids and UV light treatment.  Therefore, where possible inhibitory 
medication should be stopped or alternative testing methods considered (1,2).  Anti-histamines should be 
stopped prior to testing (see Protocol Sections 4.1.2 and 5.7). 
Cautions 
Caution should be taken when considering skin prick testing in pregnancy, for patients with unstable 
asthma or those taking beta blockers and/or ACE inhibitors(1,2). 
Equipment  
• 
MOv18 IgE solution for skin prick testing, and positive and negative control solutions (stored 
at +2-+8oC).  Check expiry date and date opened (some manufacturers state that skin test 
solutions should be used within 6 months of opening.) (4) 
• 
Pen 
• 
Individual sterile skin prick testing lancets 


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• 
Sharps bin 
• 
Tissues 
• 
Skin test measure/ruler  
• 
Timer / clock / watch 
• 
Essential safety equipment (see above) including adrenaline 1:1000 (5) 
Preparation 
Verbal consent for the procedure should be obtained.  The procedure should be undertaken in 
accordance with local infection control policy using appropriate hand hygiene measures.  Select 
appropriate test site free from eczema / dermatitis, the preferred site is the forearm but the back may 
also be used. 
 
PROCEDURE (1,2,3,6) 
RATIONALE 
 
Ensure test site is free from body 
lotion and moisturisers 
Body lotion / moisturiser can 
cause allergen drops to run, 
causing cross contamination. 
 
Test site should be hygienically clean 
but does not need to be not be 
cleaned with alcohol or antiseptic 
 
Ensure patient is in a comfortable 
position sitting or, if needle phobic, 
lying down. 
Rest arm on a level surface, using 
pillow if necessary.  
To ensure patient is relaxed and 
able to remain still during the 
test. 
Mark the test sites approximately 
2.5cm apart, using first letter of 
allergen being tested.  Avoid the skin 
creases (elbow and wrist) 
To ensure any reactions do not 
overlap so that accurate 
measurements can be made. 
Begin with the negative control and 
end with the positive control 
To provide consistency, to 
prevent cross contamination 
from the histamine control and 
for patient comfort because the 
histamine control reaction time 
is the quickest. 
Place one drop of each selected 
allergen solution* next to relevant 
marked site. 
*for prick to prick testing see 
additional guidance below. 
To ensure accurate identification 
of the allergen when results are 
read 


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Using gentle pressure, push the 
lancet through allergen solution and 
into the surface layer of the skin at a 
90O angle. 
To ensure that the allergen 
penetrates the outer surface of 
the skin. 
To reduce risk of causing 
bleeding. 
To ensure a standardised test 
 
Discard lancet into sharps bin 
To ensure safe disposal of 
sharps  
 
Repeat the procedure for each 
allergen and the controls using a new 
lancet each time 
To prevent cross contamination 
of the allergens 
 
Remove surplus allergen by blotting 
test sites with tissue ensuring that 
there is no cross contamination 
between test sites. 
To remove excess allergen 
solution and prevent cross 
contamination of test sites. 
 
Advise patients not to scratch the test 
sites whilst waiting for the results to 
develop 
To allow for accurate reading of 
results. 
 
Advise patients to report promptly 
any systemic adverse reaction  
To ensure prompt treatment of 
any adverse reaction 
   
 
Results should be read at 15, 30 and 
60 minutes after the test.  Measure 
the wheal diameter in mm.  For 
asymmetric wheals measure the 
longest extent of the wheal in mm 
and the extent 90o to the first 
measurement (eg 3x3mm). 
An imprint of the result can also be 
made by drawing round the wheal in 
pen and taking a print using skin tape 
which can then be stuck onto the 
results sheet. 
The flare may also be recorded. 
To ensure accurate assessment 
of the reaction is recorded. 


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Any pseudopodia should be noted 
but not included in the measurement 
of the wheal 
 
 
A wheal diameter of more than 3mm 
larger than the negative control is a 
positive reaction 
 
 
A wheal response to the negative 
control indicates dermographism 
Document the response to the 
negative control.  Interpretation 
of other positive results must 
allow for subtraction of the 
negative control. The need for 
further, alternative testing should 
be considered by the clinician 
who has requested the test. 
 
Absence of a wheal at the positive 
control suggests that a topical or oral 
medication with antihistaminic 
properties may have been taken.  
Repeat the positive control and if still 
negative record as an invalid test. 
Document that the positive 
control has not reacted. Either 
repeat the skin tests off anti-
histamines /other medication or 
the requesting clinician can 
consider specific IgE serology. 
 
Advise the patient that the wheals will 
fade, usually within an hour. 
To inform the patient 
 
Topical 1% hydrocortisone, oral anti-
histamines or a cold compress may 
be given to relieve severe itch in line 
with a prescription. 
To enhance patient comfort and 
relieve severe itch 
 
Record the outcome of the test in the 
patient’s notes including; 
• 
date of test 
• 
patient name, date of birth 
and hospital number 
• 
skin prick test method 
• 
wheal size in mm 
• 
any recent antihistamine 
medication with date/time of 
last dose. 
• 
If a positive response is 
observed, the time point of 
the response should be 
recorded i.e. 15, 30 or 60 
min assessment point. 
• 
name, designation and 
signature of person 
performing the skin prick test 
Ensure accurate documentation. 
To note: If the skin prick test is 
positive at ANY of the three time 
points, that will constitute a 
positive result. 
References 
1 The skin prick test – European Standards Clinical and Translational Allergy 3:3 
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565910/ 
2 Bousquet et al (2012) Practical guide to skin prick tests in allergy to     
   aeroallergens Allergy 67: 18-24 


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   http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2011.02728.x/pdf     
   [accessed 16.01.2015] 
3 Fitzsimons R et al (2014) Allergy Nurse Competency Document BSACI       
   http://www.bsaci.org/professionals/nurses-specialising-in-allergies [accessed   
   16.01.2015] 
4 Summary of product characteristics Soluprick Timothy Grass ALK Abello  
   http://www.alk- abello.com   /UK/products/soluprickSQ/Lists/Soluprick%20SQ/  
Timothy%20Grass%20SmPC.pdf [accessed 15.10.2015] 
5 UK Resuscitation Council (2008) Emergency Treatment of Anaphylactic   
   Reactions https://www.resus.org.uk/search/?q=anaphylaxis  
6 King et al (2010) Paediatric Skin Prick Testing SOP BSACI  
   http://www.bsaci.org/Guidelines/Skin Prick Testing.pdf [accessed 16.01.2015]