Clinical trial NCT03009058
Conditions: Metastatic Cancer
Keywords: Unresectable cancer pancreatic melanoma breast lung colorectal cholangio sarcoma
Sponsor: Immodulon Therapeutics Ltd
Start date: 2017-05-31; Completion date: 2017-08-30
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
During this open label study patients will receive IMM-101 in conjunction with a recognised standard of care for metastatic or unresectable cancer for the patient's specific tumour type.

The primary objective of the study is to provide safety data for IMM-101 in combination with a number of selected standard of care regimens.

Detailed description:
The study will consist of three phases - Screening, Treatment and Maintenance. Patients who provide informed consent, will participate in a Screening period of up to 28 days to establish eligibility. Once eligibility is confirmed, patients will enter the Treatment Phase of the study.

In the Treatment Phase all patients will receive IMM-101 for 28 weeks.

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.

Arms: arm 1: IMM-101 will be given in combination with standard gemcitabine monotherapy. 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. arm 2: IMM-101 will be given in combination with standard gemcitabine + nab-paclitaxel combination therapy.

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. arm 3: IMM-101 will be given in combination with gemcitabine + capecitabine combination therapy.

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. arm 4: IMM-101 will be given in combination with standard FOLFIRINOX (FOLinic acid, Fluorouracil, IRINotecan and OXaliplatin) treatment.

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. arm 5: IMM-101 will be given in combination with standard FOLFOX (FOLinic acid, Fluorouracil and OXaliplatin) treatment.

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. arm 6: IMM-101 will be given in combination with standard FOLFIRI (FOLinic acid, Fluorouracil and IRInotecan) + cetuximab combination treatment.

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. arm 7: IMM-101 will be given in combination with standard gemcitabine monotherapy. 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. arm 8: IMM-101 will be given in combination with standard gemcitabine monotherapy. 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 arm 9: IMM-101 will be given in combination with standard gemcitabine + nab-paclitaxel combination therapy.

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. arm 10: IMM-101 will be given in combination with standard treatment with either pembrolizumab or nivolumab.

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 will receive IMM-101 at an increased dosing interval of every 4 weeks. In the absence of safety concerns for these patients after 3 doses of IMM-101, and following a robust safety review, all subsequent patients recruited to this treatment cohort will switch to the standard, more intensive (2-weekly induction dosing) IMM-101 dosing regimen. arm 11: IMM-101 will be given in combination with standard gemcitabine monotherapy. 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. arm 12: IMM-101 will be given in combination with standard treatment with either pembrolizumab or nivolumab. The first 3 patients entering the anti-PD1 (pembrolizumab or nivolumab) cohort will receive IMM-101 at an increased dosing interval of every 4 weeks. In the absence of safety concerns for these patients after 3 doses of IMM-101, and following a robust safety review, all subsequent patients recruited to this treatment cohort will switch to the standard, more intensive (2-weekly induction dosing) IMM-101 dosing regimen thereafter. arm 13: IMM-101 will be given in combination with standard treatment with ipilimumab. In order to ensure that there are no increased immune-related adverse events (AEs), the first 3 patients entering the ipilimumab cohort will receive IMM-101 at an increased dosing interval of every 4 weeks. In the absence of safety concerns for these patients after 3 doses of IMM-101, and following a robust safety review, all subsequent patients recruited to this treatment cohort will switch to the standard, more intensive (2-weekly induction dosing) IMM-101 dosing regimen thereafter. arm 14: IMM-101 will be given in combination with standard gemcitabine monotherapy. 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. arm 15: IMM-101 will be given in combination with standard gemcitabine + nab-paclitaxel combination therapy.

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. arm 16: IMM-101 will be given in combination with standard gemcitabine monotherapy. 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. arm 17: IMM-101 will be given in combination with low dose cyclophosphamide (300mg/m2 in patients with solid malignancies.

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.
Interventions: intervention 1: IMM-101 intervention 2: Gemcitabine intervention 3: Nab-paclitaxel intervention 4: Capecitabine intervention 5: Folinic Acid intervention 6: Fluorouracil intervention 7: Irinotecan intervention 8: Oxaliplatin intervention 9: cetuximab intervention 10: Anti-PD1 intervention 11: Ipilimumab intervention 12: Cyclophosphamide
Intervention descriptions: intervention 1: A suspension of heat killed whole cell Mycobacterium obuense NCTC 13365 intervention 2: Standard of Care chemotherapy intervention 3: Standard of Care chemotherapy intervention 4: Standard of Care chemotherapy intervention 5: Standard of Care chemotherapy intervention 6: Standard of Care chemotherapy intervention 7: Standard of Care chemotherapy intervention 8: Standard of Care chemotherapy intervention 9: Standard of Care immunotherapy intervention 10: Standard of Care immunotherapy intervention 11: Standard of Care immunotherapy intervention 12: Standard of Care chemotherapy

Protocol documents:
Prot_000.pdf: 
 
  
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. 
 

SAP_001.pdf: 
 
 
Final Statistical Analysis Plan for: 
 
NCT03009058 
 
Study 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: IMM-101-011 
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Statistical Analysis Plan 
 
Immodulon Therapeutics Limited 
 
 
 
Protocol: IMM-101-011 
 
Treatment: IMM-101  
 
 
A Novel Phase I/IIa Open-label Study of IMM-101 in Combination with 
Selected Standard of Care Regimens in Patients with Metastatic Cancer or 
Unresectable Cancer at Study Entry 
 
 
 
Author: 
 Statistical 
Consultant on behalf of Immodulon Therapeutics Limited 
Document Status: 
Final V1.0 
Version Date: 
26 September 2017 
  
 
 
 
STATEMENT OF CONFIDENTIALITY  
This document contains information confidential and/or of proprietary interest to Immodulon 
Therapeutics Limited. No part of this document may be copied or disclosed to a third party in 
any format (including oral, printed, written or electronic), without the written permission of 
Immodulon Therapeutics Limited, except insofar as it is necessary for assessment by 
appropriate bodies such as ethics committees or regulatory authorities under the same 
conditions of confidentiality. It must be returned to Immodulon Therapeutics Limited upon 
request.  
 
 
 


26Sep2017


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Contents 
2 Abbreviations ..................................................................................................................... 4 
3 Introduction ........................................................................................................................ 5 
3.1 Protocol Status and Termination by Immodulon.............................................................. 5 
4 Study Objectives ................................................................................................................ 6 
5 Study Design ...................................................................................................................... 6 
5.1 Study Schedule ................................................................................................................ 6 
5.1.1 Flowchart of Assessments: Screening and Treatment Phases ....................................... 7 
5.1.3 Flowchart of Assessments: Long-term Maintenance Treatment Phase ....................... 11 
5.2 Study Data Sets ............................................................................................................. 13 
5.2.1 All Enrolled Patients ................................................................................................... 13 
5.2.2 Safety Analysis Set (SAF) .......................................................................................... 13 
5.3 Withdrawn Patients ....................................................................................................... 13 
5.4 Randomisation ............................................................................................................... 13 
5.5 Blinding ......................................................................................................................... 13 
5.6 Sample Size ................................................................................................................... 13 
5.7 Changes in Conduct or Planned Analyses from the Protocol ......................................... 13 
6 Statistical Methodology .................................................................................................... 13 
6.1 Planned Presentations of Data: Listings ......................................................................... 13 
6.1.1 Standard Calculations ................................................................................................. 14 
6.2 Adjustment for Covariates ............................................................................................. 20 
6.2.1 Centre Effects ............................................................................................................. 20 
6.3 Protocol Violations ........................................................................................................ 20 
6.4 Missing Values – Missing Visits ................................................................................... 20 
6.5 Deviations from Statistical Analysis Plan ...................................................................... 20 
 
 
 


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2 Abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
eCRF 
Electronic Case Report Form 
CSR 
Clinical Study Report 
Immodulon 
Immodulon Therapeutics Limited 
irRC 
Immune-related response criteria 
011 study 
IMM-101-011 study 
MedDRA  
Medical Dictionary for Regulatory Activities  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAF 
Safety Analysis Set (All randomised patients from the Main Study 
who receive at least one dose of study drug) 
SQN 
Syne qua non Ltd 
SOC 
Standard of Care 
WHO 
World Health Organisation 


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3 Introduction 
This document presents the statistical analysis plan (SAP) for Immodulon Therapeutics 
Limited (Immodulon), Protocol No. IMM-101-011: A Novel Phase I/IIa Open-label Study of 
IMM-101 in Combination with Selected Standard of Care Regimens in Patients with 
Metastatic Cancer or Unresectable Cancer at Study Entry. 
3.1 Protocol Status and Termination by Immodulon 
 
On 31st July 2017, Immodulon took the decision to enroll no further patients into this Phase 
I/IIa open-label study and to close the study early. 
 
On 31st July 2017, 2 patients were on study and 1 patient was a screen failure.  Both enrolled 
patients were consented into Cohort 6 (IMM-101 + Anti-PDI (Pembrolizumab, Nivolumab)  
in metastatic melanoma). For these 2 treated patients the last study visit completed was Visit 5 
– Week 10. The End of Study / Withdrawal Visit was completed in place of Visit 6 – Week 
12 for both patients. 
It was planned to evaluate up to 20 patients in each SOC (standard of care)/tumour type, with 
a total of approximately 300 patients enrolled overall (across 7 tumour types), with 
assessment of both safety and efficacy by each SOC/tumour type.  Further details of the 
sample size evaluations are given in the study protocol. A minimum of 10 patients per cohort 
were required for an evaluation of futility with respect to the primary activity endpoint of 
response to treatment (based on immune-related response criteria [irRC]).  Given that only 
two patients were enrolled into the study, the objectives of the study described in the study 
protocol cannot be met.  
The planned statistical analysis described in the study Protocol will not now be performed due 
to the early closure of the study.  However all clinical study data will be presented in data 
listings, as described in this statistical analysis plan (SAP) and in the separate document 
containing detailed Planned Listings Shells.  Both documents will be approved before 
database lock.  The listings will be produced in accordance with the approved Listings Shells, 
by Syne qua non Ltd (SQN) (SQN Study No:  ICS16001). 
This analysis plan is based on the final protocol version 4 (released 25 October 2016) and the 
final 011 study electronic case report form (eCRF), version 4, dated 3 March 2017.  Given the 
early termination of the study, this SAP is therefore abbreviated.  Relevant sections of the 
study Protocol are referred to and for ease of reference, the full study activity schedule is 
reproduced from the study Protocol. 
 
 


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4 Study Objectives 
Full details of the study objectives, endpoints and evaluation methodology are given in the 
study Protocol. 
5 Study Design 
Full details of the study design are provided in the study Protocol. 
 
5.1 Study Schedule 
For the 2 patients enrolled into the study, the last study visit completed was Visit 5 – Week 
10. The End of Study / Withdrawal Visit was completed in place of Visit 6 – Week 12 for 
both patients.   
The study schedule of assessments is presented in Sections 5.1.1 and 5.1.2.  Note that a 
number of inconsistencies within the study Protocol version 4.0 were noted by Immodulon 
(file note IMM/011/FN/0008), approved 16 Mar 2017, as follows:- 
• The screening phase was between Day -28 to Day  -1 (not Day -7 as indicated in the 
Protocol version 4.0 study schedule of assessments) 
• The response to treatment was to be assessed at Weeks 6 and 10 and End of 
Study/Withdrawal Visit (this was omitted from the assessment schedule in error) 
• Footnote 42 (Screening and Treatment phases) and 21 (Long-term maintenance 
phase): Full text was amended to ‘Solicited and visible injection site reactions will be 
recorded and patients will be asked to assess any impact on their daily activities and 
whether the reactions are getting better, worse or staying the same. (The question 
asked was omitted from the assessment schedule in error).  


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5.1.1 Flowchart of Assessments: Screening and Treatment Phases 
 
Screening 
Phase 
Treatment Phase 
Week -4/-1 
Week 0 
Week 2 
Week 4 
Week 8 
Week 10 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Day 
Day -28 to -7 
Day 0 
Day 14 
Day 28 
Day 56 
Day 70 
Day 84 
Day 112 
Day 140 
Day 168 
Day 196 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit window (days) 
- 
- 
±3 days[1] 
±14 days[1] 
Informed consent[2] 
✓ 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
✓ 
✓[3] 
 
 
 
 
 
 
 
 
 
Demography & baseline data[4] 
✓ 
 
 
 
 
 
 
 
 
 
 
Complete medical history[5] 
✓ 
 
 
 
 
 
 
 
 
 
 
Physical examination[6] 
✓ 
 
 
 
 
 
 
 
 
 
✓ 
Safety blood and serum 
samples[7,8] 
✓[9,10,11] 
✓[11] 
✓[11,12] 
✓[11,12] 
✓[11,12] 
✓[11,12] 
✓[11,12] 
✓[11] 
✓[11] 
✓[11] 
✓[11,12] 
HLA serotyping[13] 
✓ 
 
 
 
 
 
 
 
 
 
 
Immunomarkers[14] 
✓[9] 
 
 
 
 
 
✓[12] 
 
 
✓[12] 
 
Serum pregnancy test[15] 
✓ 
 
 
 
 
 
 
 
 
 
 
Vital signs[16] 
✓ 
✓[17] 
 
 
 
 
 
 
 
 
✓ 
Weight 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓
12-lead ECG[18] 
✓ 
 
 
 
 
 
 
 
 
 
 
ECOG/WHO performance 
status[19] 
✓[20] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Tumour biopsy - slides[21,22] 
✓[23] 
 
 
 
 
 
 
 
 
 
✓[24,25] 
Tumour biopsy – core samples 
[22,26] 
✓[27,28] 
 
 
 
✓[25,29] 
 
 
 
 
 
✓[25,29]
Microsatellite phenotyping[30] 
✓ 
 
 
 
 
 
 
 
 
 

CT/MRI scan 
✓[31] 
 
 
 
 
 
✓[32] 
 
 
 
✓[32] 
Measure diameter of erythema and 
skin biopsy[26,27,33,34] 
 
 
✓[35,36] 
 
✓[35,36] 
 
 
 
 
 
✓[35,36] 


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Screening 
Phase 
Treatment Phase 
Week -4/-1 
Week 0 
Week 2 
Week 4 
Week 8 
Week 10 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Day 
Day -28 to -7 
Day 0 
Day 14 
Day 28 
Day 56 
Day 70 
Day 84 
Day 112 
Day 140 
Day 168 
Day 196 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit window (days) 
- 
- 
±3 days[1] 
±14 days[1] 
Prior/concomitant therapy[37] 
✓[38] 
✓[38] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Adverse event reporting[39] 
✓[40] 
✓[41] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Assess injection site reactions[12] 
 
 
✓[42] 
✓[42] 
✓[42] 
✓[42] 
✓[42] 
✓[42] 
✓[42] 
✓[42] 
✓[42] 
Record time interval since last dose 
of IMM-101[1,12] 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Check time interval since last dose 
of IMM-101 is ≥11 days (14 days 
±3 days)[1,12] 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
IMM-101 administration 
 
✓[41] 
✓[43] 
✓ 
✓ 
✓[43] 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Footnotes: 
ALP: alkaline phosphatase; ALT: alanine transaminase; AST: aspartate transaminase; β-hCG: β-human chorionic gonadotropin; BCG: Bacillus Calmette–Guérin; CA19.9: 
carbohydrate antigen 19.9; CEA: carcinoembryonic antigen; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; CRP: C-reactive protein; CT: computerised 
tomography; ECG: Electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; eGFR: estimated glomerular filtration rate; 
FACS: fluorescence-activated cell sorting; FBC: full blood count; GEM: gemcitabine; GGT: gamma-glutamyl transferase; Hb: haemoglobin; HLA: human leukocyte antigen; 
INR: international normalised ratio; LDH: lactate dehydrogenase; LFT: liver function test; MCH: mean cell haemoglobin; MCV: mean cell volume; miRNA: micro 
ribonucleic acid; MPV: Mean platelet volume; MRI: magnetic resonance imaging; Pt: prothrombin time; PTT: partial thromboplastin time; RBC: red blood cell; WBC: white 
blood cell; WHO: World Health Organisation.  
 
1. 
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, 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).  
2. 
Before beginning any study procedure, the patient will read and sign an informed consent form. The patient will be given a copy of the signed informed consent 
form. 


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3. 
Inclusion/exclusion criteria will be re-checked before commencing any study treatment including confirmation of anticipated life expectancy ≥3 months and a 
review of blood and serum samples. Final determination of patient eligibility will be made upon receipt of all clinical laboratory results and assessment of all 
inclusion and exclusion criteria.  
4. 
Gender, date of birth, ethnicity and height. 
5. 
Full medical history including disease history and treatment, any concurrent illnesses and history of previous injections (e.g. smallpox, yellow fever, BCG).  
6. 
A full physical examination will be performed, including assessment of injections received prior to Screening and pre-existing injection site reactions (i.e. BCG or 
prior cancer treatment reactions). Any additional physical examinations to those scheduled for this study will be performed as per the Investigator's routine 
procedures. 
7. 
Blood and serum samples (6 mL blood) CRP, FBC (Hb, Haematocrit, RBC count, WBC count, WBC differential count, platelet count, MPV, MCV, MCH), LFTs 
(ALT, ALP, AST, bilirubin [total, direct], albumin, total protein, GGT, Pt/PTT, INR, LDH), calcium, urea and electrolytes (kidney function: sodium, potassium, 
creatinine, urea, eGFR [using CKD-EPI creatinine calculation]), CEA, CA19.9. 
8. 
Any additional blood tests to those scheduled will be performed as per the Investigator's routine procedures. 
9. 
Screening blood tests should be taken within 7 days prior to the start of the study. 
10. Review of blood test results: Screening blood test results must be available at least 24 hours prior to IMM-101 administration. 
11. Patients in the anti-PD1 and anti-CTLA-4 cohorts only, prior to every course of checkpoint inhibitor as per the label: thyroid function test; ACTH; blood glucose 
test; lipase. 
12. Prior to administration of IMM-101. 
13. 4 mL whole blood (Only needs to be taken if the result is not already available for the patient).  
14. Immunological markers:  
6 mL whole blood: miRNA panel, circulating metabolites. 
6 mL whole blood will be collected from a subset of patients for FACS analysis: immune cell quantification. 
6 mL whole blood will be collected from a subset of patients to be analysed in the TruCulture system: cytokines, chemokines, immune mediators; functional 
immune cell assays, tumour markers. 
15. A Screening serum pregnancy test (β-hCG) will be performed on all eligible female patients of child bearing potential within 72 hours prior to the start of the study. 
A negative serum pregnancy test result must be obtained prior to a female patient of child bearing potential receiving study medication. Serum pregnancy tests 
should be repeated as warranted during the study. 
16. Resting blood pressure, pulse, and body temperature will be recorded as vital signs. Additional measures of vital signs to those scheduled for this study will be 
performed as per the Investigator's routine procedures.  
17. Patients should be followed by vital sign monitoring for at least 2 hours after administration of IMM-101, under medical supervision with resuscitation facilities 
available as a precautionary measure. 
18. 12-lead ECG measures will be recorded at Screening. Additional 12-lead ECG measures to those scheduled for this study will be performed as per the Investigator's 
routine procedures.  
19. 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  
20. To be eligible for inclusion in the study, patients must have an ECOG/WHO performance status of ≤2 at Day 0.  
21. Not for patients with metastatic pancreatic cancer who will receive GEM monotherapy, and patients with metastatic melanoma who will receive a PD1 checkpoint 
inhibitor  
22. Any trauma and clinical sequelae related to the mechanics of the tumour biopsy should be reported as related to the study procedure 
23. Document results and record the date of the last tumour biopsy on the patient's eCRF. 


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-For patients receiving first line treatment, if no biopsy has been performed in the 3 months prior to Screening, a biopsy should be performed during the Screening 
period, or at Day 0, when eligibility has been confirmed and before first dose of IMM-101 is administered and 10 anonymised, unstained slides prepared from the 
diagnostic specimen (any additional biopsies to those scheduled for this study will be performed as per the Investigator's routine procedures).  
-For patients receiving second, third and fourth line treatment, if no biopsy has been performed in the 2 years prior to Screening a biopsy should be performed during 
the Screening period, or at Day 0, when eligibility has been confirmed and before first dose of IMM-101 is administered and 10 anonymised, unstained slides 
prepared (any additional biopsies to those scheduled for this study will be performed as per the Investigator's routine procedures). 
24. This tumour biopsy is optional and undertaken only if the patient provides consent for it.  
25. The Investigator will schedule the biopsy at this visit. The biopsy will be performed within 2 weeks after this visit 
26. Only in patients with metastatic pancreatic cancer who will receive GEM monotherapy, and patients with metastatic melanoma who will receive a PD1 checkpoint 
inhibitor  
27. The Investigator will select the lesion to be biopsied, on the basis of a lesion that will be the most feasible to access and which provides the lowest risk to the patient. 
Three core biopsy samples will be taken from the target lesion and prepared as follows: 1 core snap frozen, 1 core paraffin embedded, 1 core cryoblock.  
28. These patients will undergo a tumour biopsy during the Screening period, or at Day 0, when eligibility has been confirmed and before first dose of IMM-101 is 
administered.  
29. The Investigator will biopsy the same lesion that was biopsied at Screening 
30. For patients with colorectal cancer only (if not already available for the patient) 
31. Document results and record date of last CT/MRI scan on the patient's eCRF. If no scan has been performed in the 30 days prior to Screening a scan should be 
performed. 
32. Scans performed to assess progression or response must match the baseline scan (i.e. if CT scan at baseline then CT scan for all other scans). Additional CT/MRI 
scans to those scheduled for this study will be performed as per the Investigator's routine procedures.  
33. Prior to administration of IMM-101 
34. Length and width  
35. From the arm into which the previous dose was administered 
36. Skin punch biopsy reactions assessed at the following visit. Any trauma and clinical sequelae related to the mechanics of the skin biopsy should be reported as 
related to the study procedure and not reported as an injection site reaction. 
37. All prescription and over-the-counter medications, including herbals, homeopathic remedies etc., will be recorded. 
38. Record any prior/concomitant therapy/medications taken up to 4 weeks before initiation of Screening and any prior/concomitant depot corticosteroids taken up to 6 
weeks before initiation of Screening 
39. All AEs will be followed until resolution, death, or 30 days after the Withdrawal/EOS visit (whichever comes first)  
40. Pre-existing conditions will be recorded.  
41. Patients will be observed for 2 hours post dose, prior to leaving the study site.  
42. Solicited and visible injection site reactions will be recorded. 
43. Patients receiving the reduced intensity IMM-101 dosing regimen will not receive IMM-101 at this visit. 
 
 
 


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5.1.3 Flowchart of Assessments: Long-term Maintenance Treatment Phase 
 
Long-term Maintenance Treatment Phase 
End of 
Study/ 
With-
drawal 
Visit[4] 
Nominal Time Point 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48 
Week 
52[1] 
Week 56 
Week 60 
Week 64 
Week 68 
Week 
nn[2,3] 
Visit/Dose 
Visit 11 
Visit 12 
Visit 13 
Visit 14 
Visit 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
Visit 20  
Visit nn 
Visit window (days) 
±14 days[5] 
Physical examination[6] 
 
 
 
 
 
 
 
 
 
 
 
✓ 
Safety blood and serum samples[7,8,9] 
✓[10] 
✓[10,11] 
✓[10] 
✓[10] 
✓[10,11] 
✓[10] 
✓[10] 
✓[10,11] 
✓[10] 
✓[10] 
✓[10,11] 
✓[12] 
Immunomarkers[8,13] 
 
✓[11] 
 
 
✓[11] 
 
 
✓[11] 
 
 
✓[11] 
✓ 
Vital signs[14] 
 
 
 
 
 
 
 
 
 
 
 
✓[14] 
Weight 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
12-lead ECG[15] 
 
 
 
 
 
 
 
 
 
 
 
✓ 
ECOG/WHO performance status[16] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
CT/MRI scan[17] 
 
 
 
 
 
 
 
 
 
 
 
✓[18] 
Prior/concomitant therapy[19] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Adverse event reporting[20] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Assess injection site reactions[8,21] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Record time interval since last dose of 
IMM-101[5,8] 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
IMM-101 administration 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Footnotes: 
ALP: alkaline phosphatase; ALT: alanine transaminase; AST: aspartate transaminase; CA19.9: carbohydrate antigen 19.9; CEA: carcinoembryonic antigen; CKD-EPI: 
Chronic Kidney Disease Epidemiology Collaboration; CRP: C-reactive protein; CT: computerised tomography; ECG: Electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; eGFR: estimated glomerular filtration rate; EOS: End of Study; FACS: fluorescence-activated cell sorting; FBC: full blood count; GGT: gamma-glutamyl 
transferase; Hb: haemoglobin; INR: international normalised ratio; LDH: lactate dehydrogenase; LFT: liver function test; MCH: mean cell haemoglobin; MCV: mean cell 
volume; miRNA: micro ribonucleic acid; MPV: Mean platelet volume; MRI: magnetic resonance imaging; Pt: prothrombin time; PTT: partial thromboplastin time; RBC: red 
blood cell; WBC: white blood cell; WHO: World Health Organisation. 


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1. A reduction in dose and/or an increase in the dosing interval may be required after one year 
2. Should the study extend beyond 68 weeks, the same pattern of assessments will continue for subsequent visits as described in this Schedule of Assessments. 
3. A reduction in dose and/or an increase in the dosing interval may be required after one year. 
4. Patients withdrawing from the study at any time should attend this EOS visit within 28±7 days after the final dose of IMM-101. 
5. 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.  
6. A full physical examination will be performed. Any additional physical examinations to those scheduled for this study will be performed as per the Investigator's 
routine procedures. 
7. Any additional blood tests to those scheduled will be performed as per the Investigator's routine procedures. 
8. Prior to administration of IMM-101.  
9. Blood and serum samples (6 mL blood) CRP, FBC (Hb, haematocrit, RBC count, WBC count, WBC differential count, platelet count, MPV, MCV, MCH), LFTs 
(ALT, ALP, AST, bilirubin [total, direct], albumin, total protein, GGT, Pt/PTT, INR, LDH), calcium, urea and electrolytes (kidney function: sodium, potassium, 
creatinine, urea, eGFR [using CKD-EPI creatinine calculation]), CEA and CA19.9.  
10. Patients in the anti-PD1 and anti-CTLA-4 cohorts only, prior to every course of checkpoint inhibitor as per the label: thyroid function test; ACTH; blood glucose 
test; lipase. 
11. Every 14 weeks or as close to this time frame as possible. 
12. Patients in the anti-PD1 and anti-CTLA-4 cohorts only: thyroid function test; ACTH; blood glucose test; lipase. 
13. Immunological markers:  
6 mL whole blood: miRNA panel, circulating metabolites. 
6 mL whole blood will be collected from a subset of patients for FACS analysis: immune cell quantification. 
6 mL whole blood will be collected from a subset of patients to be analysed in the TruCulture system: cytokines, chemokines, immune mediators; functional 
immune cell assays, tumour markers.  
14. Resting blood pressure, pulse, and body temperature will be recorded as vital signs at the EOS visit. Additional measures of vital signs to those scheduled for this 
study will be performed as per the Investigator's routine procedures.  
15. Additional 12-lead ECG measures to those scheduled for this study will be performed as per the Investigator's routine procedures. 
16. 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  
17. Scans performed to assess progression or response must match the baseline scan (i.e. if CT scan at baseline then CT scan for all other scans). Additional CT/MRI 
scans to those scheduled for this study will be performed as per the Investigator's routine procedures. 
18. Only required if no scan has been performed in the 6 weeks prior to the EOS visit.  
19. All prescription and over-the-counter medications, including herbals, homeopathic remedies etc. will be recorded. 
20. All AEs will be followed until resolution, death, or 30 days after the Withdrawal/EOS visit (whichever comes first) 
21. Solicited and visible injection site reactions will be recorded.  
 


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5.2 Study Data Sets 
The definitions of the data sets for the IMM-101-011 study are given below. 
5.2.1 All Enrolled Patients 
Enrolled patients are patients who enter the study at Visit 1 Day 0, following completion of 
screening assessments and confirmation of eligibility to enter the study.  All listings are based 
on this set of patients.  Hence data for the patient who failed screening will not be listed. 
5.2.2 Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all patients who took at least one administration of 
study treatment (IMM-101).   
5.3 Withdrawn Patients 
Details of withdrawal procedures are described in the study Protocol. 
On 31st July 2017, Immodulon took the decision to enroll no further patients into this Phase 
I/IIa open-label study and to close the study early.  Hence, the 2 enrolled patients who were 
on study at this date both completed their withdrawal visit in place of Visit 6 – Week 12.  
Their last study visit completed was Visit 5 – Week 10 for both patients.  
5.4 Randomisation 
Not applicable. 
5.5 Blinding 
Not applicable. 
5.6 Sample Size 
The study was terminated by the sponsor and the two enrolled patients were withdrawn. The 
last study visit completed was Visit 5 – Week 10. The End of Study / Withdrawal Visit was 
completed in place of Visit 6 – Week 12 for both patients.   
5.7 Changes in Conduct or Planned Analyses from the Protocol 
Due to the early termination of the study with only 2 enrolled patients, both of whom were 
withdrawn early, the objectives of the study could not be met.  Hence the planned analyses 
described in the study Protocol will not be carried out.  However, the data collected in the 
eCRF will be listed. 
6 Statistical Methodology 
6.1 Planned Presentations of Data: Listings 
The presentation of listings and conventions for the listings are contained in a separate 
document.  Both this SAP and the listings shells document will be approved before database 
lock. 
This section therefore provides a tabular summary of the planned listings including listing 
number, title, medical coding dictionary data (and version), additional derived data and details 
of derivation. 


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All patient data will be presented in separate data listings by data type. 
6.1.1 Standard Calculations 
Study day will be calculated as visit number date (or date of assessment/date of 
finding/AE/medication etc.) - date of Day 0 (first study drug administration dosing date) and 
will appear on all relevant dates throughout the listings.  Day numbers prior to first study drug 
administration dosing date (for example screening assessments) will therefore be represented 
by a negative number of days. 
The baseline value (for change from baseline calculations) will be defined as the last 
assessment prior to the first administration of study drug. The baseline value will be the 
Screening value if there is no Visit 1 day 0 value. 


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Listing number 
Listing title 
Medical 
dictionary coding 
items  
Derived data 
Derivation 
16.2.1.1 
Patient Completions and Withdrawals 
 
Time on study 
(months) 
(Date of study withdrawal 
– date of Day 0 +1 
day)/30.4375 
16.2.2.1 
Protocol Deviations 
 
 
 
16.2.2.2 
Eligibility 
 
 
 
16.2.2.3 
Informed Consent 
 
 
 
16.2.3.1 
Analysis Sets 
 
SAF 
All patients who took at 
least one administration of 
study 
treatment 
(IMM-
101).   
16.2.4.1 
Demography 
 
Age (years) 
Age is calculated in years 
from the date of informed 
consent, as the number of 
full months between date 
of birth and informed 
consent divided by 12 and 
rounded to the lowest 
integer. 
Body 
Mass 
Index (kg/m2) 
Weight (kg)/height (m)^2). 


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16.2.4.2 
Medical History (Other Than Cancer History) 
Medical history 
will be coded 
using the Medical 
Dictionary For 
Regulatory 
Activities 
(MedDRA) 
version 20 
 
 
16.2.4.3 
Cancer Diagnosis 
Cancer diagnoses 
will 
be 
coded 
using 
MedDRA 
version 20 
Time since 
diagnosis 
(months) 
(Day 0 (i.e. first study 
medication administration 
date) - date of diagnosis + 
1)/30.4375 
16.2.4.4 
HLA Serotyping at Screening 
 
 
 
16.2.4.5 
Serum Pregnancy Test 
 
 
 
16.2.4.6 
Microsatellite Phenotyping at Screening 
 
 
 
16.2.4.7 
Prior and Concomitant Medications (Excluding Cancer 
Medications) 
Medications will 
be coded using 
WHO Drug 
Dictionary, version 
September 2017 
 
 
16.2.4.8 
Standard of Care Therapy 
Medications will 
be coded using 
WHO Drug 
Dictionary, 
September 2017 
 
 


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16.2.4.9 
New Cancer Medications (Post-standard of Care) 
 
Medications will 
be coded using 
WHO Drug 
Dictionary, version 
September 2017 
 
 
16.2.4.10 
Radiotherapy 
 
 
 
16.2.4.11 
Cancer-related Surgery 
 
 
 
16.2.5.1 
Study Drug Administration 
 
Duration of 
exposure 
(days) 
Date 
of 
last 
study 
treatment administration – 
date 
of 
first 
study 
treatment administration + 
1 
16.2.6.1 
Tumour Biopsy - Core Samples 
 
 
 
16.2.6.2 
Target Lesions 
 
 
 
16.2.6.3 
Non-target Lesions 
 
 
 
16.2.6.4 
Target Lesion Response to Treatment 
 
 
 
16.2.6.5 
Overall Response to Treatment 
 
 
 
16.2.7.1 
Adverse Events 
Adverse events 
will be coded 
using MedDRA 
version 20 
Treatment 
emergent 
An adverse event that 
started after administration 
of study drug 
 
 
 
Time to onset Time from date of first 
administration 
of 
study 


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(d:hh:mm) 
drug to onset of adverse 
event. Note: For missing 
or partial dates and times, 
not 
calculated 
and 
is 
reported 
as 
unknown 
(UK). 
16.2.8.1.1 
All Haematology Values 
 
Change 
from 
baseline 
Value at assessment time 
point – baseline value 
H, L 
Above 
normal 
range, 
below normal range 
16.2.8.1.2 
Patients with Clinically Significant Haematology Values  
H, L 
Above 
normal 
range, 
below normal range 
16.2.8.2.1 
 
All Biochemistry Values 
 
Change 
from 
baseline 
Value at assessment time 
point – baseline value 
H, L 
Above 
normal 
range, 
below normal range 
16.2.8.2.2 
Patients with Clinically Significant Biochemistry Values  
H, L 
Above 
normal 
range, 
below normal range 
16.2.9.1 
Immunology Sampling 
 
 
 
16.2.9.2 
Injection Site Reactions 
 
 
 
16.2.9.3 
Vital Signs 
 
Change 
from 
baseline 
Value at assessment time 
point – baseline value 
16.2.9.4 
Weight 
 
Change 
from Value at assessment time 


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baseline 
point – baseline value 
16.2.9.5 
ECG Results 
 
Change 
from 
baseline 
Value at assessment time 
point – baseline value 
16.2.9.6 
Physical Examination 
 
 
 
16.2.9.7 
ECOG/WHO Performance Status 
 
Highest 
(worst) 
Maximum 
ECOG/WHO 
performance 
status 
Maximum score of the 
first and second 
evaluators’ assessments 
16.2.9.8 
Diameter of Erythema and Skin Biopsy 
 
 
 


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6.2 Adjustment for Covariates 
Not applicable. 
6.2.1 Centre Effects 
Not applicable. 
6.3 Protocol Violations 
Protocol deviations are recorded in the eCRF and presented in a data listing. 
6.4 Missing Values – Missing Visits 
There is no intention to implement any procedure for replacing missing data, other than as 
specified in this SAP. 
6.5 Deviations from Statistical Analysis Plan 
All deviations from this approved SAP will be described and justified in the final CSR.  No 
pre-database lock data review meeting will be held, however the data will be reviewed by 
Immodulon prior to database lock.