An Open Label Long Term Follow up Study for Patients With Melanoma Who Were Previously Enrolled in the Phase I Study IMM-101-001
Phase: PHASE1
Conditions: Malignant Melanoma
Sponsor: Immodulon Therapeutics Ltd

 
 
Final Study Protocol for: 
 
 
Study IMM-101-008 
NCT01559818 
 
A Long Term Follow up Study for Patients Who Previously Took Part in the 
Phase I Study IMM-101-001 

Protocol No. IMM-101-008 
 
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Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge, UB11 1FW 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
 
PROTOCOL TITLE: 
An Open Label Long-term Follow-up Study for Patients with 
Melanoma who were Previously Enrolled in the Phase I Study IMM-
101-001 
 
PROTOCOL NUMBER: 
IMM-101-008 
EUDRACT NUMBER: 
2011-003967-31 
DRUG: 
IMM-101 
SPONSOR: 
Immodulon Therapeutics Limited 
 
6-9 Stockley Park 
                                                
Uxbridge 
                                                
UB11 1FW 
 
United Kingdom 
 
CHIEF 
INVESTIGATOR: 
Professor Angus Dalgleish 
 
St George's University of London 
 
Cranmer Terrace 
 
London 
 
SW17 0RE 
 
United Kingdom 
 
 
 
 
 
 
VERSION TABLE 
Version 1.0 
15th September2011 
Version 2.0 incorporating Amendment No. 1.0 
21st November 2011 
Version 3.0 incorporating Amendment No. 2.0 
13th February 2012 
Version 4.0 incorporating Amendment No. 3.0 
1st July 2012 
Version 5.0 incorporating Amendment No. 4.0 
1st November 2013 
Version 6.0 incorporating Amendment No 5.0 
28 July 2014 
Version 7.0 incorporating Amendment No 6.0 
7 November 2014  
Version 8.0 incorporating Amendment No 7.0 
05 June 2015 
 
STATEMENT OF CONFIDENTIALITY 

Protocol No. IMM-101-008 
 
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This protocol report may not be reproduced or communicated to a third party without the 
written permission of Immodulon Therapeutics Ltd. 

Protocol No. IMM-101-008 
 
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Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge, UB11 1FW 
CONTACT DETAILS 
SPONSOR: 
 
 
Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge, UB11 
1FW United Kingdom (UK) 
Tel: 
+44 (0) 208 929 9282 
Fax: 
+44 (0) 208 929 9283 
MEDICAL MONITOR 
 
 
Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge, UB11 
1FW United Kingdom (UK) 
Tel: 
+44 (0) 208 929 9282 
Fax: 
+44 (0) 208 9299283 
OUT OF HOURS MEDICAL COVER: 
020 3137 8172 
CHIEF INVESTIGATOR: 
Professor Angus Dalgleish 
Foundation Professor of Oncology 
St George's University of London 
Cranmer Terrace, 
London, SW17 0RE 
UK 
Tel.: +44 (0) 20 8725 0809 
Fax: +44 (0) 20 8725 0158 
Email: dalgleis@sgul.ac.uk 
SERIOUS ADVERSE EVENT CONTACT DETAILS: 
Emas Ltd. 
71 Knowl Piece, 
Wilbury Way, Hitchin 
Hertfordshire, SG4 0TY 
Tel.: +44 (0) 1462 422717 
Fax: +44 (0) 1462 600456 
Email: Drug.Safety@emas-medical.com 
  
This Protocol has been written in accordance with current ICH-GCP guidelines. 

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TABLE OF CONTENTS 
 
SIGNATURE PAGE 
2 
CONTACT NAMES 
3 
TABLE OF CONTENTS 
5 
1. 
GLOSSARY 
8 
2. 
PROTOCOL SYNOPSIS 
10 
3. 
BACKGROUND INFORMATION 
12 
3.1 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT 
12 
3.2 
NON-CLINICAL FINDINGS 
12 
3.3 
CLINICAL FINDINGS 
12 
3.4 
POTENTIAL RISKS AND BENEFITS 
14 
3.5 
TREATMENT 
14 
3.6 
CONDUCT OF STUDY 
14 
3.7 
POPULATION 
15 
4. 
STUDY OBJECTIVES AND PURPOSE 
15 
4.1 
OBJECTIVES 
15 
4.2 
RATIONALE 
15 
5. 
INVESTIGATIONAL PLAN 
15 
5.1 
ENDPOINTS 
15 
5.1.1 
Safety and Tolerability 
15 
5.1.2 
Efficacy 
15 
5.1.3 
Exploratory 
16 
5.2 
OVERALL STUDY DESIGN AND PLAN 
16 
5.2.1 
Study Procedures 
17 
5.3 
STUDY TREATMENT 
18 
5.3.1 
Identity of Investigational Product 
18 
5.3.2 
Packaging and Labelling 
18 
5.3.3 
Storage 
18 
5.3.4 
Destruction of Surplus Medication 
19 
5.4 
DURATION OF STUDY PARTICIPATION 
19 
5.5 
DISCONTINUATION CRITERIA 
19 
5.6 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
19 
5.7 
CODE BREAKS 
19 
5.8 
SOURCE DATA 
19 
5.9 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS 
20 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
20 
6.1 
PATIENT INCLUSION CRITERIA 
20 
6.2 
PATIENT EXCLUSION CRITERIA 
20 
6.3 
PATIENT WITHDRAWAL CRITERIA 
21 
6.3.1 
Removal of Patients from Therapy or Assessment 
21 
6.3.2 
Pregnancy 
21 
6.4 
TERMINATION OF STUDY 
22 
6.4.1 
Regular Termination of Study 
22 

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6.4.2 
Premature Termination of Study 
22 
6.5 
FURTHER TREATMENT AFTER THE END OF THE STUDY 
22 
7. 
TREATMENT OF PATIENTS 
22 
7.1 
TREATMENTS ADMINISTERED 
22 
7.1.1 
IMM-101 
22 
7.2 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
23 
7.3 
SELECTION OF DOSES IN THE STUDY 
23 
7.4 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT 
24 
7.5 
DOSE ADJUSTMENT CRITERIA 
24 
7.6 
CONCOMITANT MEDICATION 
24 
7.7 
ASSESSMENT OF COMPLIANCE 
25 
8. 
ASSESSMENT OF EFFICACY 
25 
8.1 
EFFICACY PARAMETERS 
25 
8.1.1 
Exploratory 
26 
8.2 
ASSESSING, RECORDING AND ANALYSING EFFICACY PARAMETERS 
26 
9. 
ASSESSMENT OF SAFETY AND TOLERABILITY 
26 
9.1 
SAFETY AND TOLERABILITY PARAMETERS 
26 
9.1.1 
Adverse Events 
26 
9.1.2 
Laboratory Evaluation 
29 
9.1.3 
Other Parameters Specific to Study Design 
29 
9.2 
ASSESSING, RECORDING AND ANALYSING SAFETY PARAMETERS 
30 
9.3 
APPROPRIATENESS OF MEASUREMENTS 
31 
9.4 
RECORDING AND REPORTING ADVERSE EVENT/INTERCURRENT ILLNESSES 
31 
9.5 
ADVERSE EVENT FOLLOW-UP PROCEDURES 
32 
10. 
STATISTICS 
33 
10.1 
STATISTICAL METHODS 
33 
10.1.2 
Interim Analysis 
34 
10.2 
SAMPLE SIZE 
34 
10.3 
LEVEL OF SIGNIFICANCE 
34 
10.4 
CRITERIA FOR THE TERMINATION OF THE STUDY 
34 
10.5 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED AND SPURIOUS DATA 
34 
10.6 
DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN 
34 
10.7 
PATIENT SELECTION FOR ANALYSES 
34 
10.7.1 
Analysis Sets 
34 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
34 
11.1 
SOURCE DATA 
35 
11.2 
SOURCE DOCUMENTS 
35 
11.3 
DIRECT ACCESS 
35 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
35 
12.1 
QUALITY CONTROL 
35 
12.2 
QUALITY ASSURANCE 
36 
12.2.1 
Inspection 
36 
12.2.2 
Audit 
36 
13. 
ETHICS 
36 

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13.1 
ETHICAL CONDUCT OF THE STUDY 
36 
13.2 
INDEPENDENT ETHICS COMMITTEE APPROVAL 
36 
13.3 
INFORMED CONSENT 
37 
13.4 
MODIFICATION OF PROTOCOL 
37 
14. 
DATA HANDLING AND RECORD KEEPING 
38 
14.1 
COMPLETION OF CASE REPORT FORMS 
38 
14.2 
ARCHIVING 
38 
15. 
FINANCING AND INSURANCE 
39 
16. 
PUBLICATION POLICY 
39 
17. 
ADMINISTRATIVE PROCEDURES 
39 
17.1 
STUDY PERSONNEL 
39 
17.2 
STUDY MONITORING 
39 
17.2.1 
Return of Case Report Forms 
40 
17.3 
PRE-STUDY DOCUMENTATION REQUIREMENTS 
40 
18. 
REFERENCES 
40 
19. 
APPENDICES 
41 
APPENDIX 1 
STUDY FLOW CHART OF ASSESSMENTS  
APPENDIX 2 
WHO PERFORMANCE STATUS 
APPENDIX 3 
STUDY ACKNOWLEDGEMENT / PROTOCOL SIGNATURE PAGE 
 
APPENDIX 4 
SUMMARY OF PROTOCOL AMENDMENTS  
 
 

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1. 
GLOSSARY  
 
ABPI 
Association of the British Pharmaceutical Industry 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BCG 
 
Bacille Calmette-Guérin vaccine; a preparation of attenuated live 
Mycobacterium bovis 
BRM 
Biological Response Modifiers 
CPMP 
Committee for Proprietary Medicinal Products 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CT 
Computerised Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DTH 
 
 
 
Delayed-Type Hypersensitivity: A cell-mediated immune response that peaks 
24 to 72 hours after stimulation with an antigen to which the body has 
previously been exposed; in an antigen skin test, a local DTH reaction 
characterized by redness and induration (hardness and swelling) indicates 
past exposure 
ECG 
Electrocardiogram 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials is the European 
Clinical Trials Database of all clinical trials commencing in the European 
Union from 1 May 2004 onwards 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN-α 
Interferon-alpha 
IMM-101 
Suspension of heat-killed whole cell Mycobacterium obuense 
IUD 
Intrauterine Device 
MCB 
Master Cell Bank 
MHRA 
Medicines and Healthcare products Regulatory Agency 
M. obuense 
Mycobacterium obuense 
MRI 
Magnetic Resonance Imaging 
M. vaccae 
Mycobacterium vaccae 

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N 
Number (of patients) 
NCI 
National Cancer Institute 
NCTC 
National Collection of Type Cultures 
NK 
Natural Killer Cells 
OS 
Overall Survival 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Th2 
T helper 2 cells 
UK 
United Kingdom 
WHO 
World Health Organisation 
WMA 
World Medical Association 

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Immodulon Therapeutics Ltd. 
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2. 
PROTOCOL SYNOPSIS 
Title 
 
An open label long term follow up study of patients with melanoma who 
were previously enrolled in the Phase I study IMM-101-001  
Protocol Number 
IMM-101-008 
EudraCT Number 
2011-003967-31 
Investigational Product 
IMM-101: A suspension, in borate-buffered saline, of heat-killed whole 
cell Mycobacterium obuense for intradermal injection. 
Chief Investigator 
Professor Angus Dalgleish 
St George's University of London 
Cranmer Terrace 
London, SW17 0RE, United Kingdom (UK) 
Number of Sites  
Two, The London Clinic, Advanced Therapies Centre, London, UK and 
St George’s Hospital, London, UK 
Phase 
Long term follow up following a Phase I study  
Indication 
Melanoma 
Study Design 
 
 
Patients who were previously enrolled in Study IMM-101-001 and who 
provide informed consent will be eligible to participate in this study. 
Once eligibility is confirmed, a full medical history covering the period 
from their completion of Study IMM-101-001 to date will be taken. 
The patient will then enter the Treatment Phase of the study and follow 
the Study Flow Chart of Assessments (Appendix 1). 
Objectives 
 
 
x To determine the long term safety profile of IMM-101 administered 
intradermally for extended use  
x To document the clinical course of the patients previously enrolled 
in Study IMM-101-001. 
x To monitor selected markers of tumour burden and immunological 
status. 
Study Duration 
Patients will continue until death or withdrawal. In the case of 
withdrawal, separate consent will be sought to allow the continued 
collection on patient status. 
  
Sample Size 
 
Surviving patients from the IMM-101-001 protocol (EudraCT number: 
2009-012447-42) will be invited to enrol in the study. 
Principal Selection 
Criteria 
 
 
 
 
 
 
Patients are eligible to be included in the study if they: 
1. Were previously enrolled in Study IMM-101-001  
2. Consent to make their disease and treatment history for the 
intervening period between their completion of Study IMM-
101-001 and enrolment in this study available to the Sponsor 
3. Give signed informed consent for participation in the study  
Patients will be ineligible if one or more of the following statements are 
applicable: 

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1. Female patient of child-bearing potential who is not, in the 
opinion of the Investigator, using an approved method of birth 
control (e.g., physical barrier [patient and partner], contraceptive 
pill or patch, spermicide and barrier, or intrauterine device 
[IUD]). Those patients that utilise hormonal contraceptives must 
have used the same method for at least three months before 
additional barrier contraception (as described above) is 
discontinued from being used concomitantly with the hormonal 
contraception. Patient of non-child-bearing potential are defined 
as having 12 month amenorrhoea or are surgically sterile. 
2. Female patient who is pregnant, breast feeding or planning a 
pregnancy during the course of the study. A pre-treatment urine 
pregnancy test measuring human chorionic gonadotrophin 
(hCG) must be negative. 
3. Patient is unable or unwilling to comply with the protocol. 
Investigational Product 
Formulation 
IMM-101, a suspension of heat-killed whole cell M. obuense in borate-
buffered saline. IMM-101 10 mg/mL will be provided either as a 0.3 mL 
volume in a 1 mL single use vial or a 2.0 mL volume in a 4 mL single 
use vial.   
 
Dosage 
A single 0.1 mL intradermal injection of IMM-101 (10 mg/mL). 
 
Administration 
The treatment regimen with IMM-101 will be one dose given every 
4 weeks or as close to this interval as permitted due to practical or 
logistic considerations.  The dose given and/or the interval may be 
modified at the discretion of the Investigator provided the minimum 
period between doses is no less than 14 days.  If the dosing interval is 
increased, the patient should still attend the study site for safety 
assessments preferably every 3 months but, if this is not possible, every 
6 months at a minimum. 
IMM-101 is given via intradermal injection into the skin overlying the 
deltoid muscle, with the arm being alternated between each dose. 
Endpoints 
Safety 
x 
Local injection site tolerability 
x 
Adverse Events. 
Efficacy 
x 
Overall survival (OS) 
x 
Reduction in metastatic disease 
Exploratory 
Blood samples will be collected and sera prepared for analysis of 
immunological markers and mediators.  
Exploratory endpoints may include a change in one or more markers of 
immune 
status 
based 
on 
cellular 
involvement, 
function 
or 
cytokine/immune mediator production such as, for example, cytokines 
and antibodies, or any other clinically or immunologically relevant 
assays that may become pertinent during the course of the long-term 
follow up.  Note: Exploratory endpoints will be specified in a separate 
laboratory manual and will be reported separately to the main safety and 
tolerability endpoints of the study. 
Statistical Methods  
Descriptive summary of the results of the study will be provided along 
with full listings. No formal analysis of the results is anticipated. 

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3. 
BACKGROUND INFORMATION 
The proposed study will explore the long term safety and tolerability of continued 
administration of IMM-101 in patients who were previously enrolled in the Phase I safety and 
tolerability study IMM-101-001.  
IMM-101-001 
was 
a 
first-in-human, 
open-label, 
dose-escalation, 
intra-patient, 
placebo-controlled study, in adult patients with confirmed diagnosis of stage III or IV 
melanoma to evaluate the safety and tolerability of three doses of IMM-101. The study also 
characterized local responses to this immunotherapeutic agent in order to delineate 
unexpected / unacceptable local reactions from those indicative of an appropriate 
immunological response in this patient group. Results are presented in Section 3.3. 
It has been shown that, following administration of various cancer vaccines, delayed-type 
hypersensitivity (DTH) is a significant and independent predictor of survival in cancer 
patients.  Although this finding has been inconsistent it may reflect mechanistic variation 
rather than a spurious correlation.  If localised inflammation is reflective of a generalised 
immune activation, this may in turn indicate an increase in anti-tumour immune responses. 
IMM-101 has effects on the immune system which are hypothesised to be beneficial to this 
patient population: 
x Induction of innate and Type I immunity with promotion of cell-mediated cytotoxicity. 
x Induction of immunoregulation which should help to control the adverse effects of 
chronic inflammation or inappropriate Teffector activity (Th2 biased) at the site of the 
tumour. 
3.1 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT 
IMM-101 is a suspension of heat-killed whole cell Mycobacterium obuense in borate-
buffered saline, produced to Good Manufacturing Practice (GMP) for intradermal 
administration to humans. 
3.2 
NON-CLINICAL FINDINGS 
Preliminary work in vitro has been carried out to investigate effects of exposure to 
M. obuense on cellular and molecular markers of immune status in human whole blood cells. 
Guinea pig sensitisation assays confirming similar local reactivity to that induced with the 
related organism M. vaccae and results from non-clinical safety studies performed in 
accordance with Good Laboratory Practice (GLP), together suggest that IMM-101 can be 
safely administered to humans by the intradermal route.  
Further details can be found in the Investigator’s Brochure (1).  
3.3 
CLINICAL FINDINGS 
Study Number IMM-101-001: This was an open-label, dose-escalation, intra-patient, 
placebo-controlled study, in adult patients with confirmed diagnosis of stage III or IV 
melanoma to evaluate the safety and tolerability of three doses of IMM-101. 
A total of 19 patients were enrolled into the study between 10 March 2010 and 27 July 2010, 
and the study was completed by 23 September 2010; six patients received placebo followed 
by 3 doses of IMM-101 0.1 mg, six patients received placebo followed by 3 doses of 

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IMM-101 0.5 mg, and six patients received placebo followed by 3 doses of IMM-101 1.0 mg, 
over a 4 week period.  One patient received placebo followed by 2 doses of IMM-101 0.5 mg 
but was withdrawn after the second dose of IMM-101 as they were found retrospectively to 
have been ineligible at study entry due to brain metastases; an additional patient was recruited 
to this dose cohort to ensure data on six patients were collected.   
The placebo injection was administered on Day -3 and the IMM-101 injections over a 4-week 
period (Day 0, 14 and 28).  All injections were administered intradermally.  At each dosing 
level, one patient was administered IMM-101 at least 24 hours in advance of the remaining 
patients in order to review safety evaluations and observe local injection site reactions.  The 
decision to dose-escalate was preceded by a comprehensive review of safety data from the 
previous dose cohort.   
There were no dose limiting toxicities observed and no evidence to suggest a clinically 
significant impact upon haematological indices, biochemical parameters or cardiac function.  
All documented changes in vital signs from screening to end of study were unremarkable. 
There were no treatment-emergent adverse events (AEs) reported in the period following the 
placebo injection and before the first dose of IMM-101 – thus allowing a clear definition of 
the tolerability of the test product.  
Eighteen patients (95%) reported at least one treatment-emergent AE after receiving 
IMM-101. Over the course of the study, a total of 119 treatment-emergent AEs were 
reported.  There were 86 reports of treatment-emergent AEs that would be accepted as typical 
of a post-vaccination state (such as injection site reactions, joint pains/aches, headaches and 
flu-like symptoms) occurring at all dose levels.  These were mainly mild in intensity, mostly 
resolved in a matter of days and responded well to simple supportive medication (e.g. 
paracetamol). They were entirely consistent with the pooled information available on 
M. vaccae, a closely related organism, and were generally less intense than symptoms 
typically observed following Bacille Calmette-Guérin (BCG) vaccination of tuberculin 
negative individuals. 
Sixteen patients (84%) reported at least one treatment-related AE.  A total of 56 treatment-
related events were reported; the most frequently reported treatment-related adverse events 
were in the ‘administration site conditions’ category.  All these injection reactions (local 
swelling, pain, erythema and occasionally mild ulceration) were considered ‘non-serious’ by 
the Investigator; no patient withdrew due to an intolerable injection site reaction. 
Only one serious adverse event (SAE) was reported; one patient in the IMM-101 0.5 mg 
group was hospitalised with progressive shortness of breath and found to have progressive 
disease (metastatic lung lesion). The SAE was reported to be unrelated to IMM-101 by the 
Investigator. 
The data collected at site to document and characterise injection site reactions indicated a 
trend for resolution over time, with the earlier and older skin reactions appearing reduced in 
size compared to the more recent ones at the end of the study.  Furthermore, it appears that 
repeated administration does not predispose the patient towards larger or more intense 
reactions after subsequent administrations.   
In summary, the study was conducted per protocol and provided considerable knowledge 
concerning the administration of IMM-101 and management of any side-effects.  The AEs 
observed so far with IMM-101 are in line with expectations, are manageable and are in 
keeping with data from non-clinical models and past experience in humans with similar 
whole cell mycobacterial preparations.  The injection site reactions are consistent for this 

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Immodulon Therapeutics Ltd. 
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class of product and are well tolerated by the patients.  Local skin reactions should be viewed 
as a normal and predicted reaction to exposure to a preparation of mycobacterial antigens.   
3.4 
POTENTIAL RISKS AND BENEFITS 
The main risk associated with the administration of IMM-101 is the development of injection 
site reactions.  The observed profile of adverse events is in line with expectations, is 
manageable and is in keeping with data from non-clinical models and past experience in 
humans treated with similar whole cell mycobacterial preparations. The injection site 
reactions are consistent for this class of product and have been well tolerated by these 
patients to date both in the context of the Phase I study and following subsequent multiple 
administrations on a named patient basis.  
No safety concerns were evident in the Phase 1 study. However, there was only relatively 
limited patient exposure to IMM-101 with each patient receiving just 3 doses on study. There 
is the potential risk that repeated administration of IMM-101 may result in an increase in the 
injection site reactions. This risk will be carefully managed through close Investigator 
supervision and the obligation to reduce the dose, delay administration or withdraw the 
patient from the study in the presence of unexpectedly severe or long-lasting site reactions. 
In light of the ”3E‘s” hypothesis of cancer (Elimination, Equilibrium and Escape) (2), 
continued treatment with IMM-101 could have the beneficial effect of, if not inducing 
“Elimination”, of prolonging or helping to restore the “Equilibrium” mode, which should be a 
clinically acceptable situation. While a potential benefit from participation in this study 
cannot be ruled out, the study is not designed to provide evidence for the potential therapeutic 
efficacy of IMM-101. 
3.5 
TREATMENT  
IMM-101 is a suspension of heat-killed whole cell M. obuense sourced from the National 
Collection of Type Cultures (NCTC) with reference NCTC 13365 and produced in 
accordance with GMP. 
The treatment regimen with IMM-101 will be one dose given every 4 weeks or as close to 
this interval as permitted due to practical or logistic considerations.  The dose interval may be 
modified at the discretion of the Investigator provided the minimum period between doses in 
no less than 14 days.  If the dosing interval is increased, the patient should still attend the 
study site for safety assessments preferably every 3 months but, if this is not possible, every 6 
months at a minimum. 
IMM-101 (10 mg/mL) will be administered as a single 0.1 mL intradermal injection into the 
skin overlying the deltoid muscle, with the arm being alternated between each dose. In the 
event of unacceptable local reaction, the dose of IMM-101 may be reduced or the dosing 
interval prolonged at the discretion of the Investigator. 
3.6 
CONDUCT OF STUDY 
This clinical study will be conducted in compliance with this Protocol, the current version of 
the guidelines of the World Medical Association Declaration of Helsinki as revised, the ICH 
Good Clinical Practice (GCP) guidelines (CPMP/ICH/135/95), designated standard operating 
procedures (SOPs), and with local laws and regulations relevant to the use of new therapeutic 
agents in the United Kingdom. 

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3.7 
POPULATION 
All surviving patients from the IMM-101-001 protocol (EudraCT number: 2009-012447-42) 
will be invited to enrol in the study by the Principal Investigator. 
4. 
STUDY OBJECTIVES AND PURPOSE 
4.1 
OBJECTIVES 
The objectives for this study are:  
a) to determine the long term safety profile of IMM-101 administered intradermally for 
extended use  
b) to document the long term clinical course of the patients previously enrolled in Study 
IMM-101-001 
c) to monitor selected markers of tumour burden and immunological status. 
4.2 
RATIONALE 
No safety concerns were evident in the previous Phase 1 study which these patients all 
participated in, however, there was only relatively limited patient exposure to IMM-101 in 
the context of the study with each patient receiving just 3 doses on study.   
All 18 eligible patients had completed the study by the end of September 2010 and the 
majority continued to receive IMM-101 on a named patient basis under the supervision of the 
Chief Investigator. As of August 2011, a number of patients have stopped treatment (3 died, 1 
stopped due to pregnancy and 2 for unknown reasons). All remaining patients have expressed 
a wish to continue to receive treatment and the Chief Investigator has confirmed that they 
consider it in these patients’ best interest to do so.  
The Sponsor considers it more appropriate to continue treatment of this cohort of patients in 
the context of a formal long term follow up safety study rather than on a named patient basis 
so that the patients can be followed for long term safety. 
5. 
INVESTIGATIONAL PLAN 
5.1 
ENDPOINTS 
5.1.1 
Safety and Tolerability 
x 
Local and systemic toxicities. 
x 
Adverse Events with documentation of number, type and degree of toxicities as 
measured by the National Cancer Institute (NCI) Common Toxicity Criteria for 
Adverse Events (CTCAE) v4.0 [5] where appropriate. 
5.1.2 
Efficacy 
x 
Overall survival (OS). 
x 
Reduction in metastatic disease. 
5.1.3 
Exploratory  
Blood samples will be collected and sera prepared for analysis of immunological markers and 
mediators.  

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Exploratory endpoints may include a change in one or more markers of immune status based 
on cellular involvement, function or cytokine/immune mediator production such as, for 
example, cytokines and antibodies, or any other clinically or immunologically relevant assays 
that may become pertinent during the course of the clinical trial. 
Note: Exploratory endpoints will be specified in a separate laboratory manual and will be 
reported separately to the main safety, tolerability and efficacy endpoints of the study. 
5.2 
OVERALL STUDY DESIGN AND PLAN 
This is an open-label long term follow up study. The study will consist of two phases: 
1. Screening and enrolment 
Patients, who provide informed consent, will participate in a screening period of up to 
28 days to establish eligibility. Once eligibility is confirmed a full disease and 
treatment history covering the period from their completion of Study IMM-101-001 to 
date will be taken. 
2. Treatment 
Patients can receive ongoing treatment every 4 weeks or as close to this interval as 
permitted due to practical or logistic considerations until death or withdrawal, unless 
such therapy is contraindicated, the patient does not wish to continue or the study is 
terminated by the Sponsor. At no point should the elapsed period between IMM-101 
doses be less than 14 days. The Study Flow Chart of Assessments is provided as 
Appendix 1. 
Patients may choose to withdraw from the study at any time and for any reason. IMM-101 
should be stopped or the dosing regimen reduced if felt to be necessary by the Investigator 
and/or patient (e.g., intolerable injection site reactions).  In the event of an injection site 
reaction of Grade 3 and above, and/or if significant ulceration, tenderness or 
lymphadenopathy is observed, at the discretion of the Investigator, patients may be 
administered a half dose of the study drug (i.e., a single 0.05 mL intradermal injection of 
IMM-101) or the timing of the injection may be delayed.  If the dosing interval is increased, 
the patient should still attend the study site for safety assessments preferably every 3 months 
but, if this is not possible, every 6 months at a minimum.  In addition, if the patient does not 
attend the clinic for a study visit within a calendar month, the clinic will telephone the patient 
to enquire about injection site reactions, adverse events, concomitant medications and any 
other concerns.  Details of the call will be recorded in the patient notes with appropriate 
information on adverse events and concomitant medications also being recorded in the CRF.  
The blood sample for exploratory analysis should continue to be taken every 6 months.  
Any change in the dose of study drug administered or the frequency of dose administration 
should be recorded in the patient's case report form (CRF). In the case of withdrawal, 
separate consent will be sought to allow the continued collection on patient status. 
5.2.1 
Study Procedures  
5.2.1.1 
Screening and Enrolment (Day -28 to Day 0) 
Patients will complete the screening assessments within 28 days of admission to the study, to 
establish their eligibility to participate. Written, dated informed consent will be obtained from 
the patient before any study specific activities are performed. 

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The patient's general practitioner (GP) will be informed in writing about the participation of 
their patient in the study. A record will be kept of patients who undergo the pre-treatment 
screening but who do not enrol into the study on a “Patient Screening Log”. 
The following procedures and assessments will be conducted during the screening phase and 
recorded in the patient's CRF: 
x Informed consent. 
x Patient eligibility (inclusion/exclusion criteria). 
x Demographics and baseline data (gender, date of birth, race, height and presence of 
pre-existing injection site reactions). 
x Best effort must be made to document disease and treatment history including during 
the period since completion of Study IMM-101-001. 
x Documentation of any concurrent illnesses. 
x Documentation of date of last dose of IMM-101. 
x Document results and record date of last computerised tomography (CT) scan. 
x Record the most recent report of disease staging. 
x Urine pregnancy test if applicable. 
x Both male and female patients should be instructed to use adequate contraception 
whilst taking part in the study. 
x WHO performance status (see Appendix 2). 
x Any prior/concomitant therapy/medications (taken up to 2 weeks before screening). 
x AE/SAE reporting (from the time of signing informed consent). 
 
5.2.1.2 
Treatment Phase 
Day 0  
This visit should take place as soon as eligibility is confirmed; the following procedures will 
be carried out before the first dose of IMM-101 on study.   
x Re-check the patient's eligibility (i.e., inclusion and exclusion criteria). 
x Re-check that at least 14-days have elapsed since the last dose of IMM-101 given as 
part of the named patient program. 
x Blood samples for exploratory endpoints. 
x Assess pre-existing injection site reactions. 
x IMM-101 administration (intradermal injection). 
x Any concomitant medications. 
x AE/SAE reporting. 
Subsequent Visits at nominal 4 week intervals 
x Check that at least 14-days have elapsed since the last dose of IMM-101. 

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x Assess injection site reactions. 
x Any concomitant medications. 
x AE/SAE reporting. 
x IMM-101 administration (intradermal injection). 
Nominally Week 24, 48, 72 and 96 (i.e., approximately every 6 months until death or 
withdrawal) 
In addition to the assessments outlined above which are to be conducted at every visit a blood 
sample will be taken for exploratory endpoints. 
5.3 
STUDY TREATMENT 
5.3.1 
Identity of Investigational Product 
The strain of M. obuense used to produce IMM-101 was sourced from the NCTC and is a 
stable 'rough variant' strain.  IMM-101 is produced by conventional culturing techniques, 
from the source culture M. obuense NCTC 13365, from which a master cell bank (MCB) has 
been created. Following growth under controlled conditions, the harvested organisms are 
heat-killed (by autoclaving) and formulated at a concentration of 50 mg (wet weight) per mL, 
as a suspension in borate-buffered saline, pH 7.7-8.3. This bulk product is then further diluted 
with borate-buffered saline to 10 mg/mL under aseptic conditions. The final product is 
presented as a fine suspension in borate-buffered saline, pH 7.7-8.3, in single use 1.0 mL 
capacity glass vials, each containing 0.3 mL or single use 4.0 mL capacity glass vials, each 
containing 2.0 mL. The suspension is turbid, containing yellow-orange particles that settle to 
the bottom of the vial on standing and are easily re-suspended with gentle shaking. 
Primary manufacture is undertaken to GMP standards at BioElpida, Dardilly, France. 
Formulation of drug product and aseptic filling is carried out by Nova Laboratories, 
Leicester, UK. Rigorous in-process control testing and final product testing against pre-
defined specifications provide assurance of the quality of IMM-101. 
Batch number(s) and expiry date(s) will be documented, including in the Sponsor File and in 
the final clinical study report. 
5.3.2 
Packaging and Labelling 
The study drug will be labelled in English.  The label will contain the information as required 
by the MHRA. 
Labelling will be performed according to Annex 13 of the GMP guidelines of the European 
Commission, ICH-GCP guidelines, and local law. 
5.3.3 
Storage 
The study drug supplied by the Sponsor is to be used exclusively in the clinical study 
according to the instructions of this protocol. 
The product must be stored in a refrigerator at 2qC to 8qC. After the product has been 
removed from the fridge it must be allowed to equilibrate for 5 to 10 minutes before being 
used.  The product must be used within 6 hours of being removed from the fridge or it should 
be discarded. 

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Study drug must be stored in securely locked areas not generally accessible until 
administered to the patients.  The key to the storage area is to be kept by the Investigator (or 
delegated person responsible for the study drug). The store will be accessible only to those 
persons authorised by the Investigator to dispense/administer the study drug. 
Further details on drug handling will be provided in a separate manual. 
5.3.4 
Destruction of Surplus Medication 
All surplus study drug will be sent for destruction following authorisation from the Sponsor. 
5.4 
DURATION OF STUDY PARTICIPATION 
Patients can receive ongoing treatment every 4 weeks or as close to this interval as permitted 
due to practical or logistic considerations until death or withdrawal, unless such therapy is 
contraindicated, the patient does not wish to continue, or the study is terminated by the 
Sponsor. 
5.5 
DISCONTINUATION CRITERIA 
 The discontinuation criteria for individual patient and/or the entire study are presented in 
Section 6.3.  
5.6 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
The Investigator, or an approved representative, should maintain records of the product’s 
delivery to the study centre, the inventory at the centre, the use by each patient, and will 
ensure that all investigational products are stored in a secure, limited access area. These 
records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), 
and the unique code numbers assigned to the investigational product(s) and study patients.  A 
temperature log should also be kept.  Investigators should maintain records that document 
adequately that the patients were provided with the doses specified by the Protocol and 
reconcile all investigational product(s) received from the Sponsor.  
To ensure adequate records, all study treatments will be accounted for on an on-going basis 
throughout the study in drug accountability forms at the study centre.  Records will be kept in 
accordance with the applicable regulatory requirements and the Investigator will ensure that 
that study drug is dispensed only by qualified site staff.  These records will be independently 
monitored by a Study monitor. 
5.7 
CODE BREAKS 
Not applicable. 
5.8 
SOURCE DATA 
Source documents (including all demographic and medical information, CRFs, and an 
original of the signed informed consent form [ICF] indicating the study number and title) for 
each patient in the study will be maintained by the Investigator or designee (generally in the 
patient’s files), and all information in the CRFs must be traceable to the source documents. 
All data should be recorded directly into the patient’s medical record as source data.  It will 
be confirmed at the Trial Initiation Monitoring Visit which documents will be considered as 

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source data for the Investigator centre. These will be documented and reviewed by the 
monitor at each monitoring visit. 
Source documents must be available to document the existence of the patient and substantiate 
the integrity of study data collected. 
5.9 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS 
Not Applicable 
 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1 
PATIENT INCLUSION CRITERIA 
Patients are eligible to be included in the study if they: 
1. Were previously enrolled in Study IMM-101-001.  
2. Give consent to make their disease and treament history for the intervening period 
between their completion of Study IMM-101-001 and enrolment in this study 
available to the Sponsor. 
3. Give signed informed consent for participation in the study.  
6.2 
PATIENT EXCLUSION CRITERIA 
Patients will be ineligible if one or more of the following statements are applicable: 
1. Female patient of child-bearing potential who is not, in the opinion of the 
Investigator, using an approved method of birth control (e.g., physical barrier [patient 
and partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device 
[IUD]). Those patients that utilise hormonal contraceptives must have used the same 
method for at least three months before additional barrier contraception (as described 
above) is discontinued from being used concomitantly with the hormonal 
contraception. . Patient of non-child-bearing potential are defined as having 12 month 
amenorrhoea or are surgically sterile. 
2. Female patient who is pregnant, breast feeding or planning a pregnancy during the 
course of the study. A pre-treatment urine pregnancy test measuring human chorionic 
gonadotrophin (HCG) must be negative. 
3. Patient is unable or unwilling to comply with the protocol. 
6.3 
PATIENT WITHDRAWAL CRITERIA 
6.3.1 
Removal of Patients from Therapy or Assessment 
The patient will be advised in the ICF that they have the right to withdraw from the study at 
any time without prejudice, and may be withdrawn at the Investigator’s or the Sponsor’s 
discretion at any time.   
In the event that the patient drops out of the study or is withdrawn from the study, the 
withdrawal page in the patient’s CRF should be completed.  On the withdrawal page the 

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Investigator (or designee) should record the date of the withdrawal, the person who initiated 
withdrawal and the reason for withdrawal. 
The following are reasons for patient dropout/withdrawal: 
Withdrawn by the Investigator due to: 
x 
Adverse event. 
x 
Protocol violation or non-compliance with the Protocol. 
x 
Intolerable injection site reaction. 
x 
Pregnancy. 
x 
Toxicity. 
x 
Other reasons. 
Withdrawal requested by the patient due to: 
x 
An AE for which the Investigator did not consider removal from the study necessary. 
x 
Withdrawal of consent. 
x 
Other. 
Other: 
x 
Lost to follow-up. 
x 
Administrative problems. 
Reasonable effort should be made to contact any patient lost to follow-up during the course 
of the study in order to complete assessments and retrieve any outstanding data. 
For patients who leave the study or when the study ends, normal standards of care, according 
to local practice, will continue as necessary. In the case of withdrawal, separate consent will 
be sought to allow the continued collection on patient status. 
 
6.3.2 
Pregnancy 
6.3.2.1 Female Patient's Pregnancy 
Patients who become pregnant during the study should be withdrawn from the study 
immediately. 
Patients should be instructed to notify the Investigator if it is determined after completion of 
(or withdrawal from) the study that they became pregnant during the study. 
Whenever possible a pregnancy should be followed to term, any premature terminations 
reported to Emas Drug Safety, and the status of the mother and child should be reported to 
the Sponsor after delivery and at important developmental milestones during the first year. 
6.3.2.2 Male Patient's Partner's Pregnancy 
Male patients should be instructed to use adequate contraception whilst taking part in the 
study.  

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Male patients should be instructed to notify the Investigator if it is determined that during the 
study or after completion of the study that their partner became pregnant during the 
Treatment Phase of the study. 
Whenever possible any pregnancy should be followed to term, any premature terminations 
reported, and the status of the mother and child should be reported to the Sponsor and/or 
Emas Drug Safety after delivery and at important developmental milestones during the first 
year. 
6.4 
TERMINATION OF STUDY 
6.4.1 
Regular Termination of Study 
The end of this study is defined as the date of the last visit of the last patient undergoing this 
study.  Within 90 days of the end of the clinical study, the Sponsor will notify the 
Independent Ethics Committee (IEC) and MHRA of the regular termination of the study as 
required according to national laws and regulations.  If the study has to be terminated early, 
this period shall be reduced to 15 days and the reasons clearly explained. 
6.4.2 
Premature Termination of Study 
The study may be terminated prematurely for any reason and at any time by the Sponsor, 
IEC, MHRA, or the Chief Investigator. A decision to prematurely terminate the study is 
binding on the Investigator. The IEC and MHRA will be informed about reason and date of 
termination according to the applicable laws and regulations.  
If the study is terminated prematurely, the Investigator must inform their patients and take 
care of appropriate follow-up and further treatment of the patients.  
6.5 
FURTHER TREATMENT AFTER THE END OF THE STUDY 
For patients who leave the study or when the study ends, normal standards of care, according 
to local practice, will continue as necessary. 
7. 
TREATMENT OF PATIENTS 
7.1 
TREATMENTS ADMINISTERED 
7.1.1 
IMM-101 
Formulation: IMM-101, a suspension of heat-killed whole cell M. obuense in borate-
buffered saline.  
IMM-101 will be provided either as a 0.3 mL volume in a 1 mL single use vial or as a 2.0 mL 
volume in a 4 mL single use vial.  The batch(es) used in this study are comparable to that 
previously tested in pre-clinical safety studies and the previous Phase 1 study. 
Note: The product is particulate and must be shaken gently before use to re-suspend the 
particulate matter. 
Dosage: A single 0.1 mL intradermal injection of IMM-101 (10 mg/mL). 

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Administration: The treatment regimen with IMM-101 will be one dose given every 
4 weeks or as close to this interval as permitted due to practical or logistic considerations.  
The dose interval may be modified at the discretion of the Investigator provided the minimum 
period between doses is no less than 14 days.  
IMM-101 (10 mg/mL) will be administered as a single 0.1 mL intradermal injection into the 
skin overlying the deltoid muscle, with the arm being alternated between each dose. 
7.2 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
Not Applicable. 
7.3 
SELECTION OF DOSES IN THE STUDY 
A dosing schedule with IMM-101 which includes a period of induction, characterised by a 
series of administrations at close intervals followed by a maintenance phase with a single 
administration on a monthly basis has been proposed. It is believed that the period of 
induction will act by priming and boosting the patient’s own immune system which, 
following a resting period during which anti-tumour immune responses can become 
established, would then require only periodic administrations or occasional boosting to 
maintain them.  
The concept of priming and boosting has been used in other immunotherapeutic approaches 
to cancer with effective results. In a series of clinical investigations, Prostvac™, a prostate 
cancer immunotherapeutic regimen consisting of viral vectors containing transgenes for 
prostate-specific antigen and T cell co-stimulatory molecules, was administered in a primer 
step followed by multiple administrations as boosters [3, 4].  
It is proposed that IMM-101 priming and boosting steps may stimulate both innate and 
adaptive immunity.  It may act by rapidly activating cells of the innate immune system, 
including natural killer (NK) cells and macrophages, and through repeated stimulation it may 
elicit adaptive immune responses aimed at boosting anti-tumour responses. Compared to the 
immediacy of innate immune responses, adaptive immunity requires time to develop and may 
benefit from repeated stimulation to boost cellular involvement thereby eliciting more 
effective immune responses.  Once fully established, adaptive immunity will only require 
regular administrations to maintain the responses.  
The Phase I safety study was an intra-patient placebo-controlled study, to evaluate the safety 
and tolerability of 3 doses namely 0.1 mg (1 mg/ml), 0.5 mg (5 mg/ml), and 1.0 mg (10 
mg/ml) of IMM-101. The dosing schedule was 3 doses of IMM-101 given at two-week 
intervals i.e. a period of induction or priming. In the intervening period between completing 
the Phase 1 study and enrolling onto this long term follow up study most patients will have 
been receiving IMM-101 at approximately four-week intervals, i.e., on a ‘maintenance’ cycle 
of one dose per month. It is proposed that this monthly maintenance cycle be continued in 
this long term study. 
The proposed dose of IMM-101 is 1 mg/dose (0.1 mL of a 10 mg/mL solution) administered 
intradermally.  Previous experience in the Phase I safety and tolerability study in patients 
with melanoma has suggested that this dose is safe and well tolerated.  The skin reaction that 
develops at the site of injection is characterized by erythema, local swelling and occasionally 
mild ulceration. All symptoms are to be expected given the known pharmacology of the 
product and previous extensive clinical experience with the closely related organism 
M. vaccae. Furthermore data from this safety and tolerability study with IMM-101 has 

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revealed that skin reactions resolve satisfactorily over time and appear not to be exacerbated 
by either prior or subsequent administration of IMM-101. 
7.4 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT 
The treatment regimen with IMM-101 will be one dose given every 4 weeks or as close to 
this interval as permitted due to practical or logistic considerations.  The dose interval may be 
modified at the discretion of the Investigator provided the minimum period between doses is 
no less than 14 days.  
IMM-101 (10 mg/mL) will be administered as a single 0.1 mL intradermal injection into the 
skin overlying the deltoid muscle, with the arm being alternated between each dose.  
7.5 
DOSE ADJUSTMENT CRITERIA 
There are no planned changes to the dose of the study drug.   
There are no formal stopping criteria for IMM-101. Injection site reactions are expected and 
therefore it is important not to withhold IMM-101 but, if at all possible, to continue even if at 
a lower dose. IMM-101 should only be stopped if felt to be necessary by the Investigator 
and/or patient (e.g., intolerable injection site reactions). In the event of an injection site 
reaction of Grade 3 and above, at the discretion of the Investigator, patients may be 
administered a half dose of the study drug (i.e., a single 0.05 mL intradermal injection of 
IMM-101) or the time interval between doses may be increased. Any change in the dose of 
study drug or the frequency at which it is administered should be recorded in the patient's 
CRF. 
If dosing is delayed, discontinued or the patient withdraws from the study as a result of an 
intolerable injection site reaction, this must be recorded in the CRF. 
7.6 
CONCOMITANT MEDICATION 
All concomitant medication taken during the study must be recorded in the CRF with 
indication, daily dose and dates of administration. 
Any other medication that is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study drug may be given at the discretion of 
the Investigator. 
There are no prohibited medications during this long term follow up study; however some 
medications should be used with caution when given concomitantly with IMM-101 as 
discussed below. 
Cytokines (e.g., IFN-α), other cytotoxics, monoclonal antibodies, anti-tumour vaccines, or 
biological response modifiers (BRM) as well as chronically administered systemic (i.e., 
administered for 1 week or more) or depot corticosteroids and other immunosuppressive 
drugs should be used with caution.  
Interactions with IMM-101 may be expected with potent steroidal or anti-inflammatory 
drugs. These drugs should be used with caution as they may attenuate the immune response. 
The use of these products should be at the discretion of the Investigator who should assess, 
on a case by case basis, if withholding treatment with these medications is in the patient’s 
best interest.   

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Herbal remedies, including traditional Chinese herbal products (e.g., mistletoe) might be 
expected to have a negative effect on the potential efficacy of IMM-101 and therefore it is 
recommended that these are not taken during treatment with IMM-101. 
Consideration should be given to not co-administering IMM-101 with prophylactic vaccines 
(e.g., Yellow Fever vaccine or any other live attenuated vaccine).  
7.7 
ASSESSMENT OF COMPLIANCE 
Intra-dermal injections will be administered by the Investigator (or designee) and therefore 
there will be no need to monitor patient compliance.   
Details of each study drug administration (including date and time of the injection, dose and 
site of administration) will be recorded in the patient's CRF. 
8. 
ASSESSMENT OF EFFICACY 
8.1 
EFFICACY PARAMETERS 
The efficacy objective is to document the long term clinical course of the patients previously enrolled 
in Study IMM-101-001 in terms of 
x 
Overall survival (OS) 
x 
Reduction in metastatic disease 
Overall Survival (OS) 
OS is defined as the time from enrolment to death due to any cause.  OS will be expressed 
from time of initial diagnosis, time of enrolment in the Phase 1 study as well as from time of 
enrolment in this long term follow up study. 
Patients without a death date will be censored at the date the patient was last known to be 
alive. 
Reduction in Metastatic Disease 
The Investigator will be asked to assess the presence of metastatic disease (if applicable) 
periodically following CT or MRI scan performed as routine stand of care and record one of 
the following relative to the previous assessment: 
x Worse. 
x No change. 
x Improved. 
x No longer detectable. 
 
8.1.1 
Exploratory  
Blood samples will be collected and sera prepared for analysis of immunological markers and 
mediators. Exploratory endpoints may include a change in one or more markers of immune 
status based on cellular involvement, function or cytokine/immune mediator production such 
as, for example, cytokines and antibodies, or any other clinically or immunologically relevant 
assays that may become pertinent during the course of the clinical trial. 

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Note: Exploratory endpoints will be specified in a separate laboratory manual and will be 
reported separately to the main safety, tolerability and efficacy endpoints of the study. 
8.2 
ASSESSING, RECORDING AND ANALYSING EFFICACY PARAMETERS 
There are no protocol specified methods to evaluate efficacy parameters and evaluation will 
be based on the results of the patient’s standard care. The methodology used to determine 
disease stage and tumour size may include chest, abdomen and pelvis CT scans, brain CT 
scan, and/or bone scans. It is understood that alternative imaging methodologies such as 
magnetic resonance imaging (MRI) or fluorodeoxyglucose positron emission tomography 
(FDG-PET) may be used in specific circumstances as part of normal patient care.  
9. 
ASSESSMENT OF SAFETY AND TOLERABILITY 
9.1 
SAFETY AND TOLERABILITY PARAMETERS 
The primary objective for this study is the evaluation of safety and tolerability based on: 
x 
Local and systemic toxicities. 
x 
Adverse Events with documentation of number, type and degree of toxicities as 
measured by the National Cancer Institute (NCI) Common Toxicity Criteria for 
Adverse Events (CTCAE) v4.0 where appropriate 
9.1.1 
Adverse Events 
9.1.1.1 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence, in a subject or clinical 
investigation patient administered with a pharmaceutical product, which does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the 
investigational product. 
9.1.1.2 
Adverse Drug Reaction  
During early development studies clinical experience with a new investigational product or 
its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and 
unintended responses to an investigational product related to any dose should be considered 
adverse drug reactions (ADRs).  The phrase "responses to an investigational product" means 
that a causal relationship between an investigational product and an AE is at least a 
reasonable possibility, i.e., the relationship cannot be ruled out. 
Regarding marketed investigational products: a response to a drug which is noxious and 
unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of diseases or for modification of physiological function. 
9.1.1.3 
Relationship of Adverse Events  
Assessment of causality of AEs to the study drug (IMM-101) 
Not related: 
An AE for which there is no reasonable temporal association 
between its onset and administration of the study drug, or that can 
reasonably be explained by other factors, including underlying 
disease, complications, concomitant drugs or concurrent treatment. 

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Note: Even if the Investigator feels there was no relationship to the 
study drug, the AE is to be reported. 
Unlikely to be related: A clinical event, including laboratory test abnormality, with a 
temporal relationship to study drug administration which makes a 
causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
Possibly related: 
An AE for which there is a reasonable temporal association 
between its onset and administration of the study drug (including 
the course of treatment after withdrawal of the study drug) for 
which other causal factors may not be excluded. 
Probably related: 
An AE for which there is a reasonable temporal association 
between its onset and administration of the study drug, including 
the course after withdrawal of the study drug, and which is more 
likely to be explained by the study drug than by any other cause 
(e.g. underlying disease, complications, concomitant drugs or 
concurrent treatment). 
Definitely related: 
An AE that is judged as undeniably related to administration of the 
study drug.  Factors taken into consideration when a definite 
relationship is assigned include whether the AE: 
- 
Followed a clear temporal sequence from administration of 
the study drug. 
- 
Could not be possibly explained by the known characteristics 
of the patient’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the patient. 
- 
Disappeared or decreased on cessation or reduction in dose 
of the study drug. 
- 
Reappeared or worsened when the study drug was 
re-administered. 
- 
Followed a response pattern known to be associated with 
administration of the study drug. 
9.1.1.4 
Intensity of Adverse Events 
All AEs (or toxicities) including local injection site reactions encountered during the study 
will be evaluated according to the NCI CTCAE v4.0 [5] grading system (0 to 5), where 
applicable. 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
 3 
Severe 
or 
medically 
significant 
but 
not 
immediately 
life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling limiting self 
care activities of daily living. 

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 4 
Life-threatening consequences; urgent intervention indicated. 
 5 
Death related to AE. 
9.1.1.5 
Treatment-Emergent Adverse Events 
All patients will have received IMM-101 in the context of both the Phase 1 study and on a 
Named Patient basis; therefore all AEs in this long term follow up study will be regarded as 
treatment-emergent. 
9.1.1.6 
Unexpected Adverse Event / Adverse Drug Reaction 
An unexpected AE/ADR is an AE/ADR for which the nature or severity is not consistent 
with the applicable product information (e.g., IB for an unapproved investigational product or 
summary of product characteristics [SmPC] for an authorised product). 
The term “expected” in pharmacovigilance is used to describe an event which might be 
anticipated from knowledge of the pharmacological properties of a substance. An event is 
also not to be described as “expected”, merely because it was foreseeable due to the health 
status (e.g., age, medical history) of the study patient. It refers strictly to the event being 
mentioned or listed in the applicable product information. 
9.1.1.7 
Serious Adverse Events 
A serious adverse event (SAE) is one that suggests a significant hazard, contraindication, 
side-effect, or precaution.  With respect to human clinical experience, this includes any event 
that:  
x 
Results in death (other than due to disease progression). 
x 
Is life-threatening.* 
x 
Requires in-patient hospitalisation or prolongation of existing hospitalisation. 
x 
Results in persistent or significant disability/incapacity. 
x 
Is a congenital anomaly/birth defect. 
x 
Other medically important condition. 
* Life-threatening in the definition of a SAE or adverse reaction refers to an event in which 
the patient was at risk of death at the time of event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
All of the above criteria apply to the case as a whole and should not be confused with the 
outcomes of individual reactions/events. More than one of the above criteria can be 
applicable to the one event. 
9.1.1.8 
Suspected Unexpected Serious Adverse Reaction 
A suspected, unexpected serious adverse reaction (SUSAR) is defined as a suspected adverse 
reaction related to the study drug which occurs during the study, and that is both unexpected 
(i.e., not previously identified in nature, severity, or degree of incidence based upon the 
current Investigator’s Brochure [1]) and serious. 
The term “expected” in pharmacovigilance is not used to describe an event which might be 
anticipated from knowledge of the pharmacological properties of a substance. An event is 
also not to be described as “expected”, merely because it was foreseeable due to the health 
status (e.g., age, medical history) of the study patient.  It refers strictly to the event being 
mentioned or listed in the Investigator’s Brochure (1). 

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All SAEs, whether or not deemed drug-related or expected, must be reported to the relevant 
pharmacovigilance contact within 24 hours of knowledge by fax in the format detailed by the 
SAE Reporting Form (see Section 0). 
Note: Hospitalisation/death due to disease progression will not be captured as an SAE if the 
disease progression/death is, in the Investigator’s opinion, expected as normal course of the 
disease.  However if the disease progression was faster than expected then a SAE will be 
reported. 
9.1.1.9 Significant Adverse Events 
Other significant AEs are defined as marked haematological and other laboratory 
abnormalities (other than those meeting the definition of serious) and any events that led to 
an intervention, including withdrawal of test drug, dose reduction or significant additional 
concomitant therapy. 
9.1.2 
Laboratory Evaluation 
No protocol specific laboratory evaluations will be required other than a urine pregnancy test 
at screening and at any time during the study if pregnancy is suspected. However, should an 
abnormal result constituting an adverse event be recorded as part of the patient’s standard 
care, the adverse event shall be recorded in the CRF.  
Cell functions, including cytokine production by specific cell population and/or immune 
activity, and other aspects of the immune response will be analysed as an exploratory 
endpoint (see Section 8.1.1).   
9.1.3 
Other Parameters Specific to Study Design 
9.1.3.1 
Injection Site Reactions 
Mild or moderate local reactions at the injection site are expected.  Patients are likely to 
experience a skin reaction and some discomfort around the injection site [1].  Each patient 
will be given general and written advice regarding the management of local injection site 
reactions and generalised systemic symptoms (e.g., pyrexia, headache and general malaise). 
Where symptoms persist or result in functional limitations, patients will be advised to attend 
the next possible research clinic or see their own GP. 
Before each administration of IMM-101, the injection site must be inspected for local 
reaction(s).  In addition, patients will be asked to assess their injection site reaction, and its 
effect on their daily activities: 
"Has the local reaction affected your daily activities?" 
x Not at all 
x Slightly 
x Moderately 
x Quite badly 
x Intolerably 
Although a formal assessment is performed before each injection, an injection site reaction 
may be recorded as an AE at any time if considered appropriate to do so by the Investigator. 

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In the event of an injection site reaction of Grade 3 (severe) as measured by the NCI 
CTCAE v4.0 and above, at the discretion of the Investigator, patients may be administered a 
half dose of the study drug (i.e., a single 0.05 mL intradermal injection of IMM-101) or the 
time interval between injections of IMM-101 may be extended. Any change in the dose of 
study drug administered should be recorded in the patient's CRF. 
If dosing is discontinued or the patient withdraws from the study as a result of an intolerable 
injection site reaction, this must be recorded in the CRF. 
9.1.3.2 
Pregnancy test 
A urine pregnancy test will be conducted for all females of child-bearing potential during 
screening and at any other time during the study if pregnancy is suspected (Study Flow Chart 
of Assessments, Appendix 1). 
The result must be negative for the patient to enter or continue in the study. 
9.1.3.3 
Prior/Concomitant Medications 
Prior and concomitant medications will be recorded at screening and before the first dose of 
IMM-101. Prior medications will include all medications taken in the 2 weeks before 
screening. Patients will be asked if they have taken any concomitant medication at each 
subsequent visit.   
Any changes in concomitant medication since the previous visit will also be recorded on the 
patient’s CRF. 
9.2 
ASSESSING, RECORDING AND ANALYSING SAFETY PARAMETERS 
Adverse events will be recorded on the patient’s CRF from the time of informed consent (i.e., 
screening).  AEs will be followed until 30 days after the end of study/withdrawal. The 
Investigator may contact the patient by telephone to obtain the information.  See Section 0 for 
further details. Related SAEs will be recorded regardless of time from last dose. 
Injection site reactions will be assessed and recorded in the patient's CRF before each 
injection of study drug.  These will only be recorded as an AE if deemed appropriate by the 
Investigator. In addition, the patient's assessment of the effect of the injection site reaction on 
their daily activities will be recorded at each visit, as described in Section9.1.3.1. 
9.3 
APPROPRIATENESS OF MEASUREMENTS 
The maximum volume of blood collected per patient at a single visit (at approximately 
six-monthly intervals) specifically for the exploratory endpoints will not exceed 6.0 mL.   
9.4 
RECORDING AND REPORTING ADVERSE EVENT/INTERCURRENT ILLNESSES 
It is the responsibility of the Investigator to document all AEs that occur during the study 
from patient entry.  An AE includes any noxious, pathological or unintended change in 
anatomical, physiological or metabolic functions as indicated by physical signs, symptoms 
and/or laboratory changes whether or not associated with the study drug and whether or not 
considered related to the study drug.  This includes an exacerbation of pre-existing conditions 
or events, intercurrent illnesses or drug interaction.  Anticipated day-to-day fluctuations of 
pre-existing conditions that do not represent a clinically significant exacerbation or 
worsening need not be considered AEs. 

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Patient entry into the study is defined as the time at which informed consent is obtained (this 
must be before any Protocol-specific diagnostic procedures or interventions).  All subsequent 
AEs must be reported regardless of whether or not they are considered drug related. 
Adverse events will be elicited by asking the patient a non-leading question, for example 
“Have you experienced or are you experiencing any new or changed symptoms since we last 
asked/since your last visit?”  Adverse events should be reported on the appropriate page of 
the CRF. 
Each AE will be assigned a CTCAE severity/intensity category as described in 
Section 9.1.1.4.  Further details can be found at the following website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Every effort should be made by the Investigator to explain each AE and assess its 
relationship, if any, to study drug treatment.  Causality should be assessed using the 
categories as described in Section 9.1.1.3. 
The Investigator must report in detail all adverse signs and symptoms which are either 
volunteered by patients or observed during or following the course of investigational product 
administration on the appropriate CRF page. 
In the event of a SAE/SUSAR, the Investigator will notify Emas within 24 hours: 
SAE CONTACT DETAILS: 
Emas Ltd. 
71 Knowl Piece, 
Wilbury Way, Hitchin 
Hertfordshire, SG4 0TY 
Tel.: +44 (0) 1462 422717 
Fax: +44 (0) 1462 600456 
Email: Drug.Safety@emas-medical.com 
 
The IEC must be informed if the serious or unexpected adverse reaction, in the opinion of the 
Sponsor or the Investigator, is likely to affect the safety of the patients or the conduct of the 
study. 
Pregnancy Reporting 
Pregnancy, by definition, is not considered an SAE.  If a female participant, or the female 
partner of a male participant, becomes pregnant after exposure to study product, the 
pregnancy must be reported to Emas Drug Safety within 24 hours of the Site Staff becoming 
aware of the Pregnancy.  A Pregnancy Reporting Form must be completed and faxed to Emas 
Drug Safety. 
In the event of a pregnancy being reported after exposure to study product, the pregnant 
woman should be followed to completion/termination of the pregnancy and the outcome of 
the mother and infant should be reported in follow-up using the Pregnancy Reporting Form. 
If a congenital anomaly or birth defect occurs, this must be reported to Emas Drug Safety by 
the submission of a completed SAE form. 

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9.5 
ADVERSE EVENT FOLLOW-UP PROCEDURES 
All SAEs will be followed to resolution.  All non-serious AEs will be followed until the event 
has resolved (disappeared) or until they have stabilised, and the relationship to the study drug 
is clarified. AEs will be followed until 30 days after the end of study/withdrawal. The 
Investigator may contact the patient by telephone to obtain the information. 

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10. 
STATISTICS 
10.1 
STATISTICAL METHODS 
A Statistical Analysis Plan (SAP) will be prepared as a separate document and will include a 
brief description (including templates for Tables, Listings, and Figures) of the planned 
presentation of the results.  
All patient data will be presented in separate data listings and summary statistics presented as 
appropriate. 
10.1.1.1 
Safety and Tolerability Endpoints 
The safety and tolerability endpoints will be summarised using the Safety population.  
Local and Systemic Toxicities 
Local and systemic toxicities will be presented over the treatment period in standard 
frequency tables overall and by number, degree and type.  
Adverse Events 
Summary statistics will be presented descriptively for the following safety endpoints: 
x 
Adverse Events - the number of AEs, the proportion of patients having at least one 
AE and AEs by coded terms will be presented. 
x 
Related Adverse Events - the number of related AEs, the proportion of patients having 
at least one related AE and related AEs by coded terms will be presented. Related 
AEs are defined as events that are definitely, probably or possibly related to study 
drug or with an unknown relationship.  
x 
Serious Adverse Events - the number of SAEs, the proportion of patients having at 
least one SAE and SAEs by coded terms will be presented. 
x 
Adverse Events leading to withdrawal or death - the number of AEs, the proportion of 
patients having at least one AE and AEs by coded terms will be presented.  
All AEs will be included in the patient listings and in the above summaries. 
10.1.1.2 Other Safety Endpoints 
Injection Site Reactions 
The frequency and severity of injection site reactions will be summarised.  
Other Safety Parameters 
All other safety parameters will be summarised using descriptive statistics. 
10.1.1.3 Efficacy endpoints 
Efficacy endpoints will be analysed using the Safety population. 
Disease Status and Progression 
Overall survival will be summarised by Kaplan-Meier curves. Median survival estimate as 
well as associated 95% CI will be reported. 

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Reduction in Metastatic Disease 
The changes in metastatic disease will be presented over the treatment period in standard data 
listings by time-point.  
10.1.1.4 Exploratory Endpoints 
Variables for the exploratory endpoints will be analysed and reported separately to the main 
efficacy and safety endpoints of the study. 
10.1.2 
Interim Analysis 
No formal interim analysis is planned for this study although data will be presented on a 
periodic basis for the annual Development Safety Update Report. Further analysis will be 
conducted as required. 
10.2 
SAMPLE SIZE 
N/A 
10.3 
LEVEL OF SIGNIFICANCE 
N/A 
10.4 
CRITERIA FOR THE TERMINATION OF THE STUDY 
No statistical stopping rules will be formulated for this study. Additional criteria for 
termination are described in Section 6.4. 
10.5 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED AND SPURIOUS DATA 
Missing, unused and spurious data will be treated as such. 
10.6 
DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN 
Any deviations from the original statistical plan as described in this Protocol will be agreed 
by the Sponsor and documented and justified in a Protocol Amendment, the final SAP or the 
clinical study report, as appropriate. 
10.7 
PATIENT SELECTION FOR ANALYSES 
10.7.1 
Analysis Sets 
The definition of the analysis set is in line with the ICH E9 guidelines. 
Just one analysis set will be defined: 
x Safety analysis set: All patients who receive at least one dose of the study drug.   
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The clinical monitor(s) should be given direct access to primary patient data (i.e., source 
data) which supports the data on the CRFs for the study, i.e., hospital notes, appointment 
books, original laboratory records, etc. Because this enters into the realm of patient 
confidentiality, this fact must be included in the ICF that the patient signs. Other authorised 
persons such as auditors may need to have direct access to this source data.  

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 Other authorised persons such as auditors may need to have direct access to this source data.  
11.1 
SOURCE DATA 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical study necessary for 
the reconstruction and evaluation of the study. Source data are contained in source documents 
(original records or certified copies). 
11.2 
SOURCE DOCUMENTS 
Source documents are defined as original documents, data and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, patient diaries and questionnaires or 
evaluation check lists, pharmacy dispensing records, recorded data from automated 
instruments, copies or manuscripts certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study).  
11.3 
DIRECT ACCESS 
Direct access is defined as the permission to examine, analyse, verify and reproduce any 
records and reports that are important to evaluation of a clinical study. Any party (e.g., 
domestic and foreign regulatory authorities, Sponsor or CRO monitors and auditors) with 
direct access should take all reasonable precautions within the constraints of the applicable 
regulatory requirements to maintain the confidentiality of patient identities and Sponsor 
proprietary information. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
An independent audit at the study site may take place at any time during or after the study. 
The independent audit may be carried out by the Quality Assurance (QA) department of a 
Contract Research Organisation (CRO), the QA department of the Sponsor, or a regulatory 
authority.  
12.1 
QUALITY CONTROL 
Quality Control is defined as the operational techniques and activities undertaken within the 
quality assurance system to verify that the requirements for quality of the study related 
activities have been fulfilled. 
Quality Control should be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 

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12.2 
QUALITY ASSURANCE 
Quality Assurance is defined as the planned and systematic actions that are established to 
ensure that the study is performed and the data are generated, documented (recorded) and 
reported in compliance with GCP and the applicable regulatory requirements. 
12.2.1 
Inspection 
An Inspection is defined as the act by a regulatory authority of conducting an official review 
of documents, facilities, records and any other resources that are deemed by the authorities to 
be related to the clinical study and that may be located at the site of the study, or at the 
Sponsor’s and/or CRO’s facilities, or at any other establishments deemed appropriate by the 
regulatory authorities. 
12.2.2 
Audit 
An Audit is a systematic and independent review of study related activities and documents to 
determine whether the validated study related activities were conducted and the data were 
recorded, analysed and accurately reported according to the Protocol, designated SOPs, GCP 
and the applicable regulatory requirements. 
13. 
ETHICS 
13.1 
ETHICAL CONDUCT OF THE STUDY 
This clinical study will be conducted in compliance to this Protocol, and in accordance with 
the provisions of the current guidelines of the World Medical Association Declaration of 
Helsinki, as amended, the guidelines of ICH-GCP (CPMP/ICH/135/95), designated SOPs, 
and with local laws and regulations relevant to the use of new therapeutic agents in the 
United Kingdom. 
In addition, this study will be undertaken in accordance with the Protocol and GCP on the 
conducting and monitoring of clinical studies. The IEC must be constituted according to the 
local laws/guidelines. 
13.2 
INDEPENDENT ETHICS COMMITTEE APPROVAL 
Before initiating a study, the Investigator should have written and dated approval/favourable 
opinion from the relevant IEC for the study Protocol (and any amendments), written ICF, 
consent form updates, patient recruitment procedures (e.g., advertisements), and any other 
written information to be provided to patients. Approval will be indicated in writing with 
reference to the final Protocol number and date. Details of the IECs constitution including 
names of its members and what function they perform on the committee (e.g., chairman, 
specialist, lay-member) should be made available to the Sponsor and/or CRO. 
During the study the Investigator should provide to the IEC all documents that are subject to 
review. 
The Sponsor will ensure an Investigator’s Brochure is available and will supply the 
Investigator with the Investigator’s Brochure and Protocol for the Investigator to submit to 
the local IEC for the Protocol’s review and approval. Verification of the IECs unconditional 
approval of the Protocol will be transmitted to the sponsor before the start of the study. This 
approval must refer to the study by exact Protocol title and number, identify the documents 
reviewed and state the date of review. 

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The IEC must be informed by the Investigator of all subsequent Protocol amendments and of 
unexpected SAEs occurring during the study, which are likely to affect the safety of the 
patients or the conduct of the study. Approval for such changes must be transmitted in writing 
to the Sponsor by the Investigator. 
The Investigator should provide the IEC with all relevant amendments or updates of the 
Protocol and Investigator’s Brochure. Also, the Investigator should provide written reports to 
the IEC annually or more frequently if requested on any change significantly affecting the 
conduct of the study and/or increasing risk to the patients. A final report of study outcome, if 
required, should also be submitted by the Investigator to the IEC. 
13.3 
INFORMED CONSENT 
The principles of informed consent in the Declaration of Helsinki should be implemented in 
this clinical study before Protocol-specified procedures are carried out. Information should be 
given in both oral and written form whenever possible and deemed appropriate by the IEC. 
Patients, their relatives, or if necessary, legal representatives must be given ample 
opportunity to inquire about details of the study. 
The Investigator will explain the nature, purpose and risks of the study and provide the 
patient with a copy of the Patient Information Sheet. The patient will be given sufficient time 
to consider the study’s implications before deciding whether or not to participate.  
Consent forms must be in a language fully comprehensible to the prospective patient. 
Informed consent will be documented by the use of a written consent form approved by the 
IEC and signed by the patient and the Investigator obtaining the consent. The informed 
consent form will also be annotated with the study patient number. 
The written consent document will embody the elements of informed consent as described in 
the Declaration of Helsinki and will also comply with local regulations. Consent must be 
documented by the patient’s dated signature. The signature confirms the consent is based on 
information that has been understood. Each patient’s signed ICF must be kept on file by the 
Investigator for possible inspection by regulatory authorities and the Sponsor. 
Should there be any amendments to the Final Protocol, such that would directly affect the 
patient’s participation in the study, e.g., a change in any procedure, the ICF must be amended 
to incorporate this modification and the patient must agree to sign this amended ICF 
indicating that they re-consent to participate in the study. 
Patients will be instructed that they are free to obtain further information from the 
Investigator at any time and that they are free to withdraw their consent and discontinue 
participation in the project at any time without prejudice. 
The prospective patient will also be advised that access to medical records would be required 
and his/her GP will be informed of the patient’s intention to participate in this study. 
In the case of withdrawal, separate consent will be sought to allow the continued collection 
on patient status. 
 
13.4 
MODIFICATION OF PROTOCOL 
The Investigator should not implement any deviation from, or changes of, the Protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 

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opinion from the IEC of an amendment. The only exceptions are where necessary to 
eliminate an immediate hazard(s) to study patients, or when the change(s) involves only 
logistic or administrative aspects of the study (e.g., change in monitor[s], change of telephone 
number[s]). 
As soon as possible, the implemented deviation or change, the reasons for it, and, if 
appropriate, the proposed Protocol amendment(s) should be submitted: 
a) 
to the IEC for review and approval/favourable opinion, 
b) 
to the MHRA. 
The party initiating an amendment must confirm it clearly in writing and it must be signed 
and dated by the Sponsor and the Chief Investigator. The Sponsor (or its designated CRO) 
will ensure that the Investigator submits necessary Protocol amendments to the appropriate 
IEC. 
All agreed Protocol amendments must be clearly documented using standard procedures as 
defined by the Sponsor, and must be signed and dated by the Sponsor and the Investigator. 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 
COMPLETION OF CASE REPORT FORMS 
All CRF entries must be made in black ink for duplication purposes. The Investigator must 
ensure the accuracy, completeness legibility and timeliness of data reported in the CRF and 
all required reports.  Any change or correction to a CRF must be dated, initialled and 
explained (if necessary) and must not obscure the original entry.  
Data reported on the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
14.2 
ARCHIVING 
According to ICH-GCP, the documents which should be archived are ‘essential documents’ 
which individually and collectively permit the evaluation of the conduct of a study and the 
quality of the data produced. 
Source documentation must also be archived. This may include observations and source data 
contained in medical records (certified copies or originals are acceptable for archiving 
purposes), data collection forms or CRFs and research related records held in support 
departments.  All hard copies of source documents must be retained. If electronic records of 
documents exist these must be backed up and retained with the hard copies. 
Essential documents should be retained until at least 2 years after the last approval of all 
outstanding marketing application(s) in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  Essential 
documents may need to be retained for a longer period than determined in ICH-GCP 
depending on local regulations. It is the responsibility of the Sponsor to inform the 
Investigator as to when these documents no longer need to be retained.  

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CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge, UB11 1FW 
15. 
FINANCING AND INSURANCE 
The costs necessary to perform the study will be agreed with the Investigator and will be 
documented in a separate financial agreement that will be signed by the Investigator and the 
Sponsor, in advance of the study commencing.  
The Sponsor has insurance coverage for study related medicine-induced injury and other 
liabilities incurred during clinical studies which will provide compensation for any study 
related injury according to local laws and regulations. 
16. 
PUBLICATION POLICY 
It is intended that the results of the study may be published as scientific literature. Results 
may also be used in submissions to regulatory authorities. The following conditions are to 
protect commercial confidential materials (patents, etc), not to restrict publication. 
All information concerning the investigational product (such as patent applications, formulae, 
manufacturing processes, basic scientific data, or formulation information supplied to the 
Investigator by the Sponsor and not previously published) is considered confidential by the 
Sponsor and shall remain the sole property of the Sponsor. The Investigator agrees not to use 
it for other purposes without the Sponsor’s written consent. 
It is understood by the Investigator that the Sponsor will use the information obtained during 
this clinical study in connection with the development of the investigational product and 
therefore it may be disclosed, as required, to other Sponsor Investigators or any appropriate 
International Regulatory Authorities. In order to allow for the use of information derived 
from this clinical study, the Investigator understands that he/she has an obligation to provide 
the Sponsor with complete test results. Before submitting the results of this study for 
publication or presentation, the Investigator will allow the Sponsor 30 days in which to 
review and comment upon the publication manuscript. The Sponsor agrees that before it 
publishes any results of this study, it shall provide the Investigators at least 30 days for full 
review of the publication manuscript. In accordance with generally recognised principles of 
scientific collaboration, co-authorship with any Sponsor personnel will be discussed and 
mutually agreed upon before submission of a manuscript to a publisher. 
17. 
ADMINISTRATIVE PROCEDURES 
17.1 
STUDY PERSONNEL 
Before the start of the study, each Investigator must supply the Sponsor or its designated 
CRO with the names and curricula vitae of the clinically responsible Co-Investigators of the 
study and the names of other possible participants and their professional backgrounds (e.g., 
medical doctor, nurse, etc). 
17.2 
STUDY MONITORING 
The Sponsor or its designated CRO are responsible for ensuring the proper conduct of the 
study with regards to Protocol adherence and validity of the data recorded on the CRF.  The 
clinical monitor’s duties are to aid the Investigator in the maintenance of complete, legible, 
organised and easily retrievable data. In addition, a clinical monitor will explain, interpret and 
ensure the Investigator’s understanding of all applicable regulations concerning the clinical 

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Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge, UB11 1FW 
evaluation of a pharmaceutical product and ensure an understanding of the Protocol, 
reporting responsibilities and the validity of the data. 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data entered on the CRFs and in all required reports. Data entered on the CRF, which are 
derived from source documents, should be consistent with the source documents (or the 
discrepancies should be explained). 
17.2.1 
Return of Case Report Forms 
Before acceptance, the clinical monitor will review the CRFs for completeness and adherence 
to the Protocol. 
17.3 
PRE-STUDY DOCUMENTATION REQUIREMENTS 
Before shipment of investigational product, the following documents must be 
submitted/returned to the Sponsor or its designated CRO by the Investigator: 
x 
Signed final version of the Protocol. 
x 
Signed, initialled and dated (within the last 12 months) curriculum vitae of the 
Investigator(s) (and other relevant staff, if required). 
x 
Copy of the letter or notice from the IEC approving the final version of this Protocol 
and Patient Information Sheet and ICF. 
x 
Signed Investigator Financial Agreement. 
The following documents must also be available: 
x 
Approved Patient Information Sheet/ICF Approval Form. 
x 
Sample Drug dispensing record. 
x 
Written national regulatory approval. 
x 
Written insurance statement (e.g., Association of the British Pharmaceutical Industry 
[ABPI] indemnity). 
18. 
REFERENCES 
1. Investigator’s Brochure, IMM-101: A Suspension of Whole Cell Heat-Killed 
Mycobacterium obuense in Borate-Buffered Saline for Intradermal Injection. 
Version 4, 10 Jan 2011. 
2. Dunn GP, Old LJ, Schreiber RD (2004b). The three Es of cancer immunoediting. 
Annu Rev Immunol 22:329-360 
3. Gulley JL, Arlen PM, Bastian A, et al. Combining a recombinant cancer vaccine with 
standard definitive radiotherapy in patients with localized prostate cancer. Clin 
Cancer Res. 2005; 11: 3353-62. 
4. Arlen PM, Gulley JL, Parker C et al. A randomized phase II study of concurrent 
docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent 
prostate cancer. Clin Res Cancer. 2006; 12: 1260-9. 
5. Cancer Therapy Evaluation Program, Common Toxicity Criteria for Adverse Events 
(CTCAE), Version 4.0, DCTD, NHI, DHHS, 28 May 2009.  
6. Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5: 649-655. 

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CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge, UB11 1FW 
19. 
APPENDICES 
 
Appendix 1 
Study Flow Chart of Assessments 
Appendix 2 
WHO Performance Status 
Appendix 3 
Study Acknowledgement / Protocol Signature Page 
Appendix 4 
Summary of Protocol Amendments  
 

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Immodulon Therapeutics Ltd. 
6-9 Stockley Park, Uxbridge, UB11 1FW, UK 
Appendix 1 
Study Flow Chart of Assessments 
 
Screening 
Phase 
Treatment Phase 
Day / Week 
Day -28 to 0 
Week[5] 
Day 0 
4, 8, 12, 
16, 20 
24 
28, 32, 36, 
40, 44  
48 
52, 56, 60, 
64, 68  
72 
76, 80, 84, 
88, 92   
96[3] 
Visit window (± days)[1] 
- 
- 
14 
14 
14 
14 
14 
14 
14 
14 
Informed Consent 
9 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
9 
9[2] 
 
 
 
 
 
 
 
 
Demography & Baseline Data 
9 
 
 
 
 
 
 
 
 
 
Complete Medical History 
9 
 
 
 
 
 
 
 
 
 
Disease Staging 
9 
 
 
 
 
 
 
 
 
 
Blood Samples for Exploratory 
Endpoints[7] 
 
9 
 
9 
 
9 
 
9 
 
9 
Urine  Pregnancy Test[4]  
9 
 
 
 
 
 
 
 
 
 
IMM-101 Administration 
 
9 
9 
9 
9 
9 
9 
9 
9 
9 
Check time interval since last 
dose of IMM-101 is ≥14 days 
 
9 
9 
9 
9 
9 
9 
9 
9 
9 
Assess Injection Site Reactions 
[7] 
9[6] 
9[6] 
9 
9 
9 
9 
9 
9 
9 
9 
Prior/Concomitant Therapy[7] 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
Adverse Event Reporting[7] 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
1. The dose given and/or the interval may be modified at the discretion of the Investigator provided the minimum period between doses is no less than 14 days. 
2. Inclusion/exclusion criteria will be re-checked before commencing any study treatment. 
3. Should the study continue beyond 96 weeks, the same pattern of assessments will continue for subsequent visits as described in this flow chart. 
4.  Urine pregnancy tests should be repeated as warranted during the study. 
5.  Nominal week numbers are stated. 
6.   Check for pre-existing injection site reactions.   
7. If the dosing interval is increased, the patient should still attend the study site for safety assessments preferably every 3 months but, if this is not possible, every 6 months at a 
minimum.  The blood sample for exploratory analysis should continue to be taken every 6 months.  In addition, if the patient does not attend the clinic for a study visit within a 
calendar month, the clinic will telephone the patient to enquire about injection site reactions, adverse events, concomitant medications and any other concerns. 

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Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
Appendix 2 
WHO PERFORMANCE STATUS 
 
WHO performance status assessment: 
Grade  
0 
Asymptomatic (Fully active, able to carry on all pre-disease activities without 
restriction) 
1 
Symptomatic but completely ambulatory (Restricted in physically strenuous 
activity but ambulatory and able to carry out work of a light or sedentary nature. 
For example, light housework, office work) 
2 
Symptomatic, <50% in bed during the day (Ambulatory and capable of all self 
care but unable to carry out any work activities. Up and about more than 50% of 
waking hours) 
3 
Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, 
confined to bed or chair 50% or more of waking hours) 
4 
Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair) 
5 
Death 
 
Oken et al (1982) [6] 
 
 

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Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
 
APPENDIX 4 
 
 
SUMMARY OF PROTOCOL AMENDMENTS  
 
PROTOCOL AMENDMENT 1.0 
This Protocol amendment, dated 21st November 2011, addressed the following change to the study 
Protocol (Final Version 1.0, dated 15th September 2011): 
1.  To reduce the volume of blood taken at six monthly intervals for the analysis of exploratory 
immunological endpoints. 
This Protocol Amendment was considered non-substantial. 
 
PROTOCOL AMENDMENT 2.0 
This Protocol amendment, dated 13 February 2012, addressed the following changes to the study 
Protocol (Final Version 2.0, dated 21st November 2011): 
1. A change in the third party contract responsible for SUSAR reporting. The responsibility for 
SUSAR reporting was transferred from Theradex (Europe) Limited to Emas Ltd., Hitchin, 
Herts., UK   
This Protocol Amendment was considered non-substantial. 
 
PROTOCOL AMENDMENT 3.0 
This Protocol amendment, dated 25th June 2012 addressed the following changes to the study 
Protocol (Final Version 3.0, dated 13th February 2012): 
x 
Change in the identity and site of the drug substance manufacturer.  
x 
Change in Vial Size 
x 
Revised Fax Number for the Pharmacovigilance Service Provider 
This Protocol Amendment was considered non-substantial. 
 
PROTOCOL AMENDMENT 4.0 
This protocol amendment, dated 1st November 2013 addressed the following changes to the study 
Protocol (Final Version 4.0, dated 1st July 2012): 
x Inclusion of collection of information on subject status following withdrawal from the 
study subject to provision of informed consent 
This Protocol Amendment was considered non-substantial. 
 
PROTOCOL AMENDMENT 5.0 
This protocol amendment, dated 28th July 2014 addressed the following changes to the study Protocol 
(Final Version 5.0, dated 1st November 2013): 

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Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
x 
Clarification of need for study safety assessments (assessment of injection site reactions, 
recording of adverse events and concomitant medications) to be taken preferably every 3 
months but, if not possible due to patient availability, every 6 months at a minimum. 
x 
Clarification of reason for decreasing dose of study medication or increasing dosing interval 
due to previous injection site reactions. 
x 
Change of Medical Director from Robert Tansley to Frances MacIntosh 
This Protocol Amendment was considered non-substantial. 
PROTOCOL AMENDMENT 6.0 
This protocol amendment, dated 7 November 2014 addressed the following changes to the study 
Protocol (Final Version 6.0, dated 28th July 2014): 
x 
Inclusion of the requirement that, if the patient does not attend the clinic for a study visit 
within a calendar month, the clinic will telephone the patient to enquire about injection site 
reactions, adverse events, concomitant medications and any other concerns the patient may 
have.  Details of the call will be recorded in the patient notes with appropriate information on 
adverse events and concomitant medications also being recorded in the CRF.  The maximum 
volume of blood collected per patient at a single visit (at approximately six-monthly intervals) 
specifically for the exploratory endpoints has been changed from ‘will not exceed 5.0 mL’ to 
‘will not exceed 6.0 mL’ as the correct vacutainer is available in a 6 mL size.  
This Protocol Amendment was considered non-substantial. 
PROTOCOL AMENDMENT 7.0 
This protocol amendment, dated 05 June  2015 addressed the following changes to the study Protocol 
(Final Version 7.0, dated 7 November 2014): 
x 
To show the inclusion of St George’s Hospital as an additional site. 
x 
To show the change of address of Immodulon Therapeutics. 
x 
Update the IMP out of fridge storage recommendation from ‘The product must be used within 
2 hours of being removed from the fridge’ to ‘The product must be used with 6 hours from 
being removed from the fridge. 
x 
Addition of the out of hours telephone number. 
x 
To remove progression-free survival from the study endpoints, due to no protocol-specified 
assessment schedule for CT scans. 
x 
To amend the presentation of the reduction in metastatic disease data to data listings only, due 
to CT scans not being a protocol-specified requirement, and change is recorded relative to 
previous assessment.