A Novel Phase I/IIa Open Label Study of IMM 101 in Combination With Selected Standard of Care (SOC) Regimens in Patients With Metastatic Cancer or Unresectable Cancer at Study Entry
Phase: PHASE1
Conditions: Metastatic Cancer
Sponsor: Immodulon Therapeutics Ltd

 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
 
 
 
 
 
NCT03009058 
 
 
 
 
PROTOCOL SYNOPSIS 
 
 
IMM-101-011 
 
A Novel Phase I/IIa Open-label Study of IMM-101 in Combination with Selected 
Standard of Care (SOC) Regimens in Patients with Metastatic Cancer or 
Unresectable Cancer at Study Entry. 
 
 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
 
 
 
 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
 
PROTOCOL TITLE: 
A Novel Phase I/IIa Open-label Study of IMM-101 in Combination 
with Selected Standard of Care (SOC) Regimens in Patients with 
Metastatic Cancer or Unresectable Cancer at Study Entry. 
SHORT TITLE: 
MODULATE 
PROTOCOL NUMBER: 
IMM-101-011 
EUDRACT NUMBER: 
2016-001459-28 
DRUG: 
IMM-101 
SPONSOR: 
Immodulon Therapeutics Limited 
 
6-9 Stockley Park 
 
Uxbridge 
 
UB11 1FW 
 
United Kingdom  
 
CHIEF 
INVESTIGATOR: 
REDACTED 
 
GI & Lymphoma Department 
 
Royal Marsden Hospital Foundation Trust 
 
Fulham Road 
 
London SW3 6JJ 
 
 
 
 
VERSION TABLE 
Version 4.00 FINAL HIGHLIGHT protocol  
25 October 2016 
Version 3.00 FINAL protocol  
09 September 2016 
Version 2.00 FINAL protocol (not submitted) 
12 August 2016 
Version 1.00 FINAL protocol (not submitted) 
01 August 2016 
 
 
 
STATEMENT OF CONFIDENTIALITY 
This protocol report may not be reproduced or communicated to a third party without the 
written permission of Immodulon Therapeutics Ltd. 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
SIGNATURE PAGE 
This study protocol was subjected to critical review. The information it contains is consistent 
with the current risk/benefit evaluation of the test preparation as well as with the moral, ethical 
and scientific principles governing clinical research as set out in the Declaration of Helsinki and 
the International Conference on Harmonisation (ICH) guidelines on Good Clinical Practice 
(GCP). 
This protocol is approved by:  
 
 
 
REDACTED 
Chief Investigator 
Royal Marsden Hospital, London 
 
Signature  
 
Date  
 
 
 
REDACTED 
Medical Monitor 
Immodulon Therapeutics Ltd 
 
 
Signature  
 
Date  
 
 
 
REDACTED 
Statistical Advisor 
Immodulon Therapeutics Ltd 
 
 
Signature  
 
Date  
 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
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 
 
 
REDACTED 
Immodulon Therapeutics Ltd. 
6-9 The Square, Stockley Park, Uxbridge,  
UB11 1FW UK 
Tel: 
  +44 (0) 208 929 9282 
Mobile:  +44 (0) 7762 783 689 
Email: el@immodulon.com 
CHIEF INVESTIGATOR: 
REDACTED 
Professor/Consultant Medical Oncologist 
GI & Lymphoma Department, Royal Marsden 
Hospital Foundation Trust, Fulham Road, London 
SW3 6JJ 
Tel.: 020 7808 2123 
Email: ProfDavid.Cunningham@rmh.nhs.uk 
SERIOUS ADVERSE EVENT CONTACT DETAILS: 
Emas Pharma 
63-65 Knowl Piece, Wilbury Way, Hitchin, 
Hertfordshire, SG4 0TY, UK. 
Tel.: +44 (0)1462 424416 
Fax: +44 (0)1462 600456 
Email: Drug.Safety@emaspharma.com  
This Protocol has been written in accordance with current ICH-GCP guidelines. 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
1. 
PROTOCOL SYNOPSIS 
Title 
 
A Novel Phase I/IIa Open-label Study of IMM-101 in Combination with 
Selected Standard of Care (SOC) Regimens in Patients with Metastatic 
Cancer or Unresectable Cancer at Study Entry. 
Short Title 
MODULATE 
Protocol Number 
IMM-101-011 
EudraCT Number 
2016-001459-28 
Investigational Product 
 
IMM-101: A suspension, in borate-buffered saline, of heat-killed whole 
cell Mycobacterium obuense (National Collection of Type Cultures 
[NCTC] 13365) for intradermal injection. 
Chief Investigator 
REDACTED  
GI & Lymphoma Department 
Royal Marsden Hospital Foundation Trust 
Fulham Road 
London, SW3 6JJ 
Number of Sites and 
Countries 
Up to 10 sites globally. 
Phase 
Phase I/IIa. 
Indication 
Patients with metastatic or unresectable cancer considered for a new line 
of recognised SOC (first, second and third line and beyond) as defined in 
this protocol. Patients must have a life expectancy of at least 3 months to 
ensure adequate time for a response to treatment to be detected.  
Study Rationale 
No safety concerns were evident in the previous Phase I and Phase II 
studies which have been performed with IMM-101, however there is 
limited safety and exposure data available. In addition, in a 110 patient 
Phase II clinical study in advanced pancreatic cancer, IMM-101, 
administered with gemcitabine, has been demonstrated to result in 
clinically relevant survival benefits and improvements in progression free 
survival (PFS). This was achieved without significant additional toxicity. 
Therefore, the Sponsor considers it appropriate to perform safety analyses 
in cancer patients in combination with a variety of selected SOC regimens. 
Activity data will also be analysed in this study. 
Selection of SOC for this protocol has been made based on scientific 
rationale and recognised  regimens for the treatment of unresectable or 
metastatic cancers.  
Study Design 
During this open-label study, patients who provide informed consent, will 
participate in a Screening period of up to a maximum of 28 days to 
establish eligibility before enrolment. Once eligibility is confirmed, 
patients will enter the Treatment Phase of the study and follow the Study 
Schedule of Assessments (Error! Reference source not found.). 
Patients will receive IMM-101 in conjunction with recognised SOC  for 
metastatic or unresectable cancer for the patient's specific tumour type. 
The recognised SOC regimens and the cancer types that will enable a 
patient to be entered into the study are as follows:  
 
Synopsis Table 1: Planned Combinations of Standard of Care and 
Type of Cancer for the IMM-101-011 Study 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
Treatment/disease 
Pancreatic 
Colorectal 
Cholangio 
Lung 
Melanoma 
Breast 
Sarcoma 
Gemcitabine 
(GEM)  
X 
 
X 
X 
X 
X 
X 
Gemcitabine + nab-
paclitaxel 
X 
 
 
X 
 
X 
 
Gemcitabine + 
capecitabine 
X 
 
 
 
 
 
 
FOLFIRINOX 
X 
 
 
 
 
 
 
FOLFOX  
 
X 
 
 
 
 
 
FOLFIRI + 
cetuximab 
 
X 
 
 
 
 
 
Anti-PD1 
(pembrolizumab, 
nivolumab)  
 
 
 
X 
X 
 
 
Anti-CTLA-4 
(ipilimumab) 
 
 
 
 
X 
 
 
Low-dose 
cyclophosphamide 
All patients with solid malignancies: Low-dose 
cyclophosphamide (300mg/m2) will be given by 
infusion approximately 4 hours prior to IMM-101 on 
days 0, 28, and 56  
anti-CTLA-4: anti-cytotoxic T-lymphocyte-associated protein-4; anti-PD1: anti-
programmed cell death-1 receptor; FOLFIRI: FOLinic acid, Fluorouracil and IRInotecan; 
FOLFIRINOX: FOLinic acid, Fluorouracil, IRINotecan and OXaliplatin; FOLFOX: 
FOLinic acid, Fluorouracil and OXaliplatin. 
Patients will only be considered for entry into the study when they are 
commencing a new line of SOC, they cannot enter the study mid-way 
through their current line of therapy. 
Following entry to the study, upon progression to immune related 
response criteria (irRC) or intolerability and toxicity to the selected SOC 
regimen, the treating physician can continue systemic treatment with an 
established line of treatment chemotherapy (in the respective disease 
group) in addition to IMM-101. An exception would be where reasons for 
discontinuation were due to IMM-101 toxicity. Changing from a selected 
SOC regimen to treatment with either an anti-PD1 or an anti-CTLA-4 
agent will not be allowed on study.. 
Standard IMM-101 Dosing Regimen: All patients (except for those 
detailed below) will receive IMM-101 every 2 weeks for the first 3 doses, 
followed by a rest period of 4 weeks, then patients will receive IMM-101 
every 2 weeks for the next 3 doses, and thereafter every 4 weeks (or as 
close to this interval as permitted due to practical or logistical 
considerations) for up to 28 weeks and will follow the Study Schedule of 
Assessments (Error! Reference source not found.).  
Reduced Intensity IMM-101 Dosing Regimen: In order to ensure that 
there are no increased immune-related adverse events (AEs), the first 3 
patients entering the anti-PD1 (pembrolizumab or nivolumab) cohort and 
the first 3 patients entering the anti-CTLA-4 (ipilimumab) cohort will 
receive IMM-101 at an increased dosing interval of every 4 weeks. In the 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
absence of safety concerns for these patients after 3 doses of IMM-101, 
and following a robust safety review, all subsequent patients recruited to 
these treatment cohorts will switch to the standard, more intensive (2-
weekly induction dosing) IMM-101 dosing regimen. 
At Week 32, if the Investigator considers it in the patients’ best interest 
patients will progress to the Maintenance Phase of the study and will 
continue to be dosed every 4 weeks (or as close to this interval as 
permitted due to practical or logistical considerations). Patients will be 
followed up for assessment of safety, response to treatment, survival, and 
immunological markers for up to 4.5 years and will follow the Study 
Schedule of Assessments (Error! Reference source not found.).  
Patients withdrawing from the study during either the Treatment or 
Maintenance Phases should attend an end of study (EOS) visit within 
28±7 days after the final dose of IMM-101. 
Prospective cohorts for safety and activity are defined in the statistical 
methodology. 
Depending on the outcome of this study, where there is evidence of 
activity of IMM-101 in any given disease, with a given SOC, a series of 
separate, randomised, follow-up, adaptive, Phase II/III studies will 
compare clinical outcomes, such as response and PFS, between 
IMM-101+SOC versus SOC alone. These Phase adaptive II/III studies 
will be statistically designed for the purposes of decision-making in terms 
of the requirement for further large-scale confirmatory randomised 
studies. 
Objectives 
The primary objective of the study is to provide safety data for IMM-101 
in combination with a number of selected SOC regimens. 
The secondary objectives of the study are to provide  
• 
Safety and tolerability data for extended admininstration (beyond 
28 weeks) of IMM-101 in combination with a number of selected 
SOC regimens ( 
• 
Synopsis Table 1). 
• 
Establish safety data for the combination of IMM 101 with anti PD1 
(pembrolizumab, nivolumab) and with anti-CTLA 4 (ipilimumab). 
• Preliminary data regarding the activity of IMM-101 (in terms of 
response to treatment) in combination with recognised SOC in a 
number of different tumour types. 
• Disease outcome data.  
• Monitoring of selected markers of tumour burden and immunological 
status in patients taking IMM-101. 
Study Duration 
The study will continue until all patients have either withdrawn from the 
study or died. It is anticipated that the study will continue for 
approximately 5 years to facilitate adequate follow up of long-term 
survivors.  
The written consent document will include permission for the Investigator 
or designee to contact the patient's general practitioner (GP) for continued 
collection of survival data in the event of withdrawal and the continued 
collection and evaluation of immune response for withdrawn patients with 
exceptional responses.  

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
Principal Selection 
Criteria 
Patients are eligible to be included in the study if they: 
1. Have metastatic or unresectable cancer and are considered by 
their physician to be indicated for a new line of SOC, as listed 
2. Are ineligible for a disease-specific clinical study with IMM-101 
3. Have an estimated life expectancy greater than 3 months (from 
Day 0) 
4. Give signed informed consent for participation in the study  
5. Have an Eastern Cooperative Oncology Group (ECOG)/World 
Health Organisation (WHO) Performance Status of ≤2 at Day 0. 
Two observers will be required to assess performance status. If 
there is any discrepancy between the two scores, the highest 
(worst) assessment will be used  
6. Have adequate bone marrow, hepatic and renal function 
including the following:  
a. Haemoglobin (Hb) ≥9.0g/dL, absolute neutrophil count 
≥1.5 x 109/L, platelets ≥75 x 109/L 
b. Total bilirubin ≤1.5 x upper limit of normal (ULN), 
excluding cases where elevated bilirubin can be 
attributed to Gilbert's Syndrome 
c. Aspartate transaminase (AST; serum glutamic 
oxaloacetic transaminase [SGOT]), alanine transaminase 
(ALT; serum glutamate pyruvate transaminase [SGPT]) 
≤5 x ULN 
d. Creatinine ≤1.5 x ULN 
e. Serum albumin >28g/L 
f. International normalised ratio (INR) <1.5 or a 
prothrombin time/partial thromboplastin time (Pt/PTT) 
within normal limits 
g. C-reactive protein (CRP) <20 mg/L for patients with 
solid tumours 
7. Are aged ≥18 years.  
Patients will be ineligible if one or more of the following statements are 
applicable: 
1. Patient has previously received treatment with IMM-101 
2. Patient is currently part way through a course of chemotherapy 
or immunotherapy 
3. Patient is receiving concomitant treatment with another 
investigational product 
4. Patient has received an investigational drug within the 4 weeks 
prior to IMM-101 administration 
5. Patient has significant cardiovascular disease as defined by: 
a. History of congestive heart failure requiring therapy 
b. History of unstable angina pectoris or myocardial 
infarction up to 6 months prior to study entry 
c. Presence of valvular heart disease 
d. Presence of a ventricular or supra-ventricular arrhythmia 
requiring ongoing treatment 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
e. Left ventricular ejection fraction (LVEF) <50% (or less 
than the institutional norm) 
6. Patient has any previous or concurrent malignancy. Patients will 
not be excluded if they have adequately treated carcinoma in situ 
of the cervix, basal cell carcinoma of the skin and/or 
non-melanoma skin cancer, or if previous malignancy was more 
than 5 years prior to Screening and there are no signs of 
recurrence 
7. Patient has co-existing active infection or medical condition 
which, in the Investigator’s judgement, will substantially 
increase the risk associated with the patient’s participation in the 
study 
8. Patient has uncontrolled hypercalcaemia (National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse 
Events [CTCAE] v4.0[1] >Grade 1) 
9. Patient has previously experienced an allergic reaction to any 
mycobacterial product. 
10. The patient has a history of non-infectious pneumonitis that 
required steroids or current pneumonitis 
11. Received live vaccine within 30 days of planned start of study 
medication 
12. Patient is pregnant or a breast-feeding woman. Female patients 
with reproductive potential must have a negative serum 
pregnancy test (β-human chorionic gonadotropin [β-hCG]) 
within 72 hours prior to start of the study. Both women and men 
must agree to use a medically acceptable, effective method of 
contraception throughout the treatment period and for at least 
6 months after discontinuation of treatment. In addition, women 
treated with low dose cyclophosphamide must be instructed to 
use adequate, effective contraception whilst taking part in the 
study and for at least 12months after discontinuation of 
treatment. Acceptable, effective methods of contraception 
include intrauterine device (IUD), intrauterine hormone 
releasing system (IUS), oral contraceptive (progestogen-only 
oral contraception that does not inhibit ovulation is not an 
acceptable method), bilateral tubal occlusion, vasectomised 
partner, and subdermal implant 
13. Patient has used depot corticosteroids in the 6 weeks before 
initiation of Screening (signing of the informed consent form 
[ICF]) 
14. Patient has had chronic use of systemic corticosteroids (>10 mg 
per day of prednisolone or equivalent for a period of 2 weeks or 
more) and/or immunosuppressant drugs (such as azathioprine, 
tacrolimus, cyclosporin) within the 2-week period before the 
first administration of IMM-101 
15. Patient has received a blood transfusion within 4 weeks prior to 
Screening 
16. In the opinion of the Investigator, the patient is unable or 
unwilling to comply with the protocol. 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
Investigational Product  
 
Formulation 
IMM-101 is a suspension of heat-killed whole cell M. obuense 
(NCTC 13365) in borate-buffered saline.  
 
Dosage 
A single 0.1 mL intradermal injection of IMM-101 (10 mg/mL). 
 
Administration 
 
Standard IMM-101 Dosing Regimen: The treatment regimen with 
IMM-101 will be one dose given every 2 weeks for the first 3 doses 
followed by a rest period of 4 weeks, then one dose every 2 weeks for the 
next 3 doses. This is followed by a dose every 4 weeks thereafter (or as 
close to this interval as permitted due to practical or logistical 
considerations).   
Reduced Intensity IMM-101 Dosing Regimen: The first 3 patients 
enrolled in the anti-PD1 cohort and the first 3 patients enrolled in the anti-
CTLA-4 cohort will be dosed at 1 mg every 4 weeks (i.e. increase in 
dosing interval) throughout. In the absence of safety signals, subsequent 
patients recruited to these treatment cohorts will be dosed with the 
standard IMM-101 dose regimen described above. 
During the Treatment Phase of the study (Doses 1 to 3 and Doses 4 to 6), 
at the discretion of the Investigator, the dose interval may be modified 
provided the minimum period between doses is at least 11 days (14±3 
days). However, in the event that this minimum dosing interval cannot be 
maintained, at the discretion of the Investigator, a half dose of IMM-101 
(0.5 mg/0.05 mL intradermal injection) should be given and at no point in 
the study should any doses of IMM-101 be administered at less than a 7-
day interval. Where this reduced dosing interval is being used the 4-week 
interval between Dose 3 and Dose 4 and between Dose 6 and Dose 7 
should still be maintained. 
In the event of an injection site reaction of ≥Grade 3 (severe) as measured 
by the NCI CTCAE v4.0[1], at the discretion of the Investigator, patients 
may be administered a half dose of IMM-101 (i.e., a single 0.05 mL 
intradermal injection of IMM-101).  
During the Maintenance Phase of the study, in the event of an injection 
site reaction ≥Grade 3 (severe) as measured by the NCI CTCAE v4.0[1], 
or at the discretion of the Investigator, patients may be administered a half 
dose of IMM-101 (0.5 mg/0.05 mL) or the dosing interval may be 
increased or both. If the dosing interval is increased, the patient should 
attend the study site for safety assessments at least every 14 weeks.   
IMM-101 is given via intradermal injection into the skin overlying the 
deltoid muscle, with the arm being alternated between each dose. 
Additional safety measures have to be considered for patients in 
thecheckpoint inhibitor (CPI) cohort due to the safety profile of the CPI. 
These safety measures are presented in Synopsis Table 2: 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
 
Synopsis Table 2: Additional Safety Measures for Patients in the 
IMM-101+CPI Cohort  
Adverse reaction 
Severity of reaction 
Action to be taken 
Any immune-
mediated adverse 
reactions 
Severe 
Permanently discontinue IMM-101 
and CPI. 
Moderate 
Withhold IMM-101 and CPI until 
condition returns to baseline, 
improves to mild severity, or there is 
complete resolution, and patient is 
receiving less than 7.5 mg prednisone 
or equivalent per day. 
 
Persistent, or 
recurring 
Withhold IMM-101+CPI until 
resolution 
Immune-mediated 
hepatitis 
All 
Evaluate liver function tests before 
each dose of ipilimumab, 
pembrolizumab or nivolumab 
Immune-mediated 
endocrinopathies 
All 
Monitor clinical chemistries, ACTH 
level, and thyroid function tests prior 
to each CPI dose. Evaluate at each 
visit for signs and symptoms of 
endocrinopathy. Initiate hormone 
replacement therapy as needed. 
Withhold IMM-101 + CPI until 
resolution 
Type 1 diabetes 
mellitus 
All 
Monitor for hyperglycemia 
Severe hyperglycemia 
Withhold IMM-101+CPI until 
resolution 
Immune-mediated 
pneumonitis 
Moderate 
Withhold IMM-101+CPI until 
resolution 
Severe, life-
threatening or 
recurrent moderate 
pneumonitis 
Permanently discontinue IMM-
101+CPI  
Immune-mediated 
colitis  
Moderate or severe 
Withhold IMM-101+CPI until 
resolution 
Life-threatening 
Permanently discontinue IMM-
101+CPI  
Immune-mediated 
nephritis 
All 
Monitor for changes in renal function 
Moderate 
Withhold IMM-101+CPI until 
resolution 
Severe or life-
threatening nephritis 
Permanently discontinue IMM-
101+CPI 
 
Prohibited Medication 
Chronically administered systemic or depot corticosteroids or 
immunosuppressant drugs (such as azathioprine, tacrolimus, cyclosporin) 
should not be administered to patients in this study. 
Visit Schedule 
The study will consist of three phases – Screening Phase, Treatment Phase 
and Maintenance Phase. Details of the Study Schedule are shown in 
Error! Reference source not found. and Error! Reference source not fo
und.. 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
Safety and Tolerability 
Endpoints: 
• 
AEs 
• 
Laboratory abnormalities 
• 
Local injection site reactions. 
Activity Endpoints: 
• 
Response to treatment, (defined as immune-related Stable Disease 
[irSD], immune-related Partial Response [irPR] and immune-related 
Complete Response [irCR]) as assessed by the Investigator 
• 
Overall survival (OS)  
• 
Immunological markers (Serum: micro ribonucleic acid [miRNA] 
panel, circulating metabolites. FACS: immune cell quantifications: 
TruCulture: cytokines, chemokines, immune mediators, functional 
immune cell assays, tumour markers)  
• 
Additional evaluations may be considered as driven by the evolving 
understanding of the mechanism of action, technical feasibility, and 
any other clinical or immunological information that may become 
available. 
Assessment of immune-related Response Criteria (irRC): 
• irCR is the disappearance of all lesions, measured or unmeasured, and 
no new lesions 
• irPR is a ≥50% drop in tumour burden from baseline as defined by the 
irRC 
• Immune-related Progressive Disease (irPD) is ≥25% increase in 
tumour burden from the lowest level recorded 
• Everything else is considered irSD.  
The justification for using this measure for this study is that even if tumour 
burden is rising, the immune system is likely to 'kick in' some months after 
first dosing and lead to an eventual decline in tumour burden for many 
patients.[2] The 25% threshold allows this apparent delay to be accounted 
for. 
In the irRC, tumour burden is measured by combining 'index' lesions with 
new lesions. Ordinarily tumour burden would be measured simply with a 
limited number of 'index' lesions (that is, the largest identifiable lesions) 
at baseline, with new lesions identified at subsequent timepoints counting 
as 'Progressive Disease'. In the irRC, by contrast, new lesions are simply a 
change in tumour burden. The irRC retains the bidirectional measurement 
of lesions that had originally been laid down in the WHO Criteria. 
Upon upon progression to irRC or intolerability and toxicity to the selected 
SOC regimen, the treating physician can continue systemic treatment with 
an established line of treatment chemotherapy (in the respective disease 
group) in addition to IMM-101. An exception would be where reasons for 
discontinuation were due to IMM-101 toxicity. Changing from a selected 
SOC regimen to treatment with either an anti-PD1 or an anti-CTLA-4 
agent will not be allowed on study. 
Statistical 
Methods/Sample Size  
The activity of IMM-101 will be assessed under each SOC by tumour type 
as follows:  
• 
For each SOC/tumour type 10 patients will be treated. After the tenth 
patient has reached the Week 28 visit, futility will be assessed in terms 
of calculating the posterior probability that response rate of SOC in 
combination with IMM-101 is at least that expected for SOC alone; if 

Protocol Synopsis 
  
CONFIDENTIAL 
Immodulon Therapeutics Ltd. 
6-9- The Square, Stockley Park, Uxbridge, UB11 1FW, UK 
this posterior probability is <33%, then IMM-101 will be considered 
as futile when administered in combination with the given SOC.  
• 
Since the first 10 patients treated for a given SOC/tumour type may 
include 3 (or possibly more) patients receiving reduced exposure to 
IMM-101, to avoid an inflation of the type II error, the assessment of 
futility may wait until 10 subjects have been treated with the standard, 
more intensive (2-weekly induction dosing) IMM-101 dosing 
regimen. The need to wait will be judged on a cohort by cohort basis 
as the trial unfolds. 
• 
If IMM-101 is found to not be futile, then a further 10 patients will be 
recruited and efficacy assessed on the total of 20 patients where 
efficacy is defined as a posterior probability of ≥80% that the response 
rate for IMM-101 administered in combination with SOC is higher 
than that expected with SOC alone. 
Safety and activity data arising from this study will be summarised and 
displayed by SOC. Safety data will be listed. Exact binomial confidence 
intervals (CIs) will be calculated for the observed response rate by tumour 
type within SOC grouping. Duration of response and survival will be 
summarised by Kaplan-Meier (KM) methods, again by tumour type and 
within each SOC grouping. 
Based on selected SOCs and tumour types, it is envisaged that 
approximately 300 patients will be recruited into this open-label study. 
CPI Cohort: An internal safety review committee will review the clinical 
safety data on a monthly basis for the anti-PD1 and the anti-CTLA-4 
cohorts. If the 3 patients for each of the 2 CPI cohorts have been enrolled 
and demonstrated no negative safety signals after 3 doses of IMM-101, all 
subsequent patients enrolled to these cohorts will receive the standard, 
more intense, IMM-101 2 weekly dosing interval for the first induction 
dosing regimen. If any of the patients in the CPI cohort receiving the 
Standard IMM-101 Dose Regimen experience any negative safety signals, 
the cohort will all be switched to the Reduced Intensity IMM-101 Dosing 
Regimen.