Clinical trial NCT02963831
Conditions: Colorectal Cancer Ovarian Cancer Appendiceal Cancer
Keywords: Oncos-102 Durvalumab Peritoneal Cyclophosphamide
Sponsor: Ludwig Institute for Cancer Research
Start date: 2017-09-07; Completion date: 2022-06-25
Enrollment: 67 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a two-part Phase 1/2 dose escalation and dose expansion study of an Adenovirus Vector (Ad5/3-D24-GMCSF), Expressing GM-CSF (GM-CSF-encoding adenovirus), ONCOS-102, in combination with anti-programmed death ligand-1 (PD-L1) antibody, durvalumab, in adult subjects with peritoneal disease who have failed prior standard chemotherapy and have histologically confirmed epithelial ovarian cancer or metastatic colorectal cancer.

Detailed description:
ONCOS-102 will be administered intraperitoneally (IP) at weekly intervals for 6 weeks.

A bolus dose of 300 mg cyclophosphamide (CPO) will be administered intravenously (IV) 1 to 3 days before the first infusion of ONCOS-102. Durvalumab will be administered by IV infusion once every four weeks (Q4W) for a total of 12 four-week cycles.

Phase 1 of the study is a dose escalation phase, which will use a 3+3 design to evaluate the safety of ONCOS-102 monotherapy before initiation of durvalumab and to identify the recommended combination dose (RCD) of a fixed dose of durvalumab (1500 mg) + ONCOS-102 at 2 dose levels (1 x 10\^11 viral particles (VPs) and 3 x 10\^11 VPs).

Subjects treated at the RCD of 3 x 10\^11 VPs ONCOS-102 will be included in the Phase 2 expansion cohort based on their tumor diagnosis.

Phase 2 of the study is the dose expansion phase, which will further explore the safety and anti-tumor activity for the RCD in 2 expansion cohorts with peritoneal disease:

1. Epithelial ovarian cancer
2. Metastatic colorectal cancer

Simon's 2-Stage MINIMAX Design will be used in Phase 2 for Expansion Cohorts 1 and 2. In the first stage, 18 subjects will be enrolled in Cohort 1 and 13 subjects in Cohort 2 (including the 6 subjects at the RCD from the dose escalation phase).

If 5 or more subjects in Cohort 1, or one or more subjects in Cohort 2, demonstrate clinical benefit (defined as percentage of subjects who are not in progression at end of Week 24), 15 additional subjects will be enrolled in Stage 2 of Cohort 1, and 14 additional subjects will be enrolled in Stage 2 of Cohort 2.

The primary endpoint is the percentage of subjects who are not in progression at the end of Week 24 as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

Arms: arm 1: ONCOS-102, 1 x 10\^11 viral particles (VPs) monotherapy for 6 weeks, followed by durvalumab 1500 mg starting on Day 71.

A bolus dose of 300 mg cyclophosphamide (CPO) was administered intravenously (IV) 1 to 3 days before the first infusion of ONCOS-102.

ONCOS-102 was infused intraperitoneally (IP) in a total volume of 500 mL saline (0.9 mg/mL sodium chloride \[NaCl\] in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1.

Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose every 4 weeks (Q4W) for 10 cycles, starting on Day 71.

Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better. arm 2: ONCOS-102, 1 x 10\^11 VPs + durvalumab 1500 mg starting on Day 15.

A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.

ONCOS-102 was infused IP in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1.

Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose Q4W for 12 cycles, starting on Day 15.

Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better. arm 3: ONCOS-102, 3 x 10\^11 VPs + durvalumab 1500 mg starting on Day 15.

A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.

ONCOS-102 was infused IP in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1.

Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose Q4W for 12 cycles, starting on Day 15.

Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better. arm 4: ONCOS-102, 3 x 10\^11 VPs + durvalumab 1500 mg starting on Day 15.

A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.

ONCOS-102 was infused IP in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1.

Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose Q4W for 12 cycles, starting on Day 15.

Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better.
Interventions: intervention 1: ONCOS-102 intervention 2: Durvalumab intervention 3: Cyclophosphamide
Intervention descriptions: intervention 1: ONCOS-102 was administered by intraperitoneal infusion at weekly intervals for 6 weeks. intervention 2: Durvalumab was administered by IV infusion once every four weeks for a total of 10 (Cohort A) or 12 four-week cycles. intervention 3: A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.

Protocol documents:
Prot_000.pdf: 
C O N F I D E N T I A L  
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Study Protocol 
LUD2015-008 
US-IND# 17217 
Amendment 6.1 
Final 
10-MAR-2022 
 
Protocol Title 
A Phase 1/2 dose escalation study with expansion cohorts to investigate the safety, biologic 
and anti-tumor activity of ONCOS-102 in combination with durvalumab in subjects with 
advanced peritoneal malignancies 
 
Objectives and Synopsis 
This is a two-part Phase 1/2 dose escalation and dose expansion study of the GMCSF-
encoding adenovirus, ONCOS-102, in combination with anti-programmed death ligand-1 (PD-
L1) antibody, durvalumab, in adult subjects with peritoneal disease who have histologically 
confirmed epithelial ovarian cancer or metastatic colorectal cancer (CRC) and have failed 
prior standard therapies. Note: the CRC cohort may include subjects with cancer originating 
from the appendix. 
ONCOS-102 will be administered intraperitoneally (IP) at weekly intervals for 6 weeks. A bolus 
dose of 300 mg cyclophosphamide (CPO) will be administered intravenously (IV) 1 to 3 days 
before the first infusion of ONCOS-102. Durvalumab will be administered by IV infusion once 
every four weeks (Q4W) for a total of 12 four-week cycles.  
Phase 1 of the study is a dose escalation phase, which will use a 3+3 design to evaluate the 
safety of ONCOS-102 monotherapy before initiation of durvalumab and to identify the 
recommended combination dose (RCD) of a fixed dose of durvalumab (1500 mg) + ONCOS-
102 at 2 dose levels (1 x 1011 viral particles (VPs) and 3 x 1011 VPs). 
Phase 2 of the study is the dose expansion phase, which will further explore the safety and 
anti-tumor activity for the RCD in 2 expansion cohorts with peritoneal disease: 
1) Platinum-resistant epithelial ovarian cancer  
2) Metastatic colorectal cancer 
Simon’s 2-Stage MINIMAX Design will be used in Phase 2 for Expansion Cohorts 1 and 2 (see 
Section 3.1.6 for sample size considerations). In the first stage, 18 subjects will be enrolled in 
Cohort 1 and 13 subjects in Cohort 2 (including the 6 subjects at the RCD from the dose 
escalation phase). If 5 or more subjects in Cohort 1, or one or more subjects in Cohort 2, 
demonstrate clinical benefit (defined as percentage of subjects who are not in progression at 
end of Week 24), 15 additional subjects will be enrolled in Stage 2 of Cohort 1, and 14 
additional subjects will be enrolled in Stage 2 of Cohort 2.  
Per Amendment 5, optional durvalumab treatment extension beyond the initial 12-cycle 
treatment period (Core Study) will be available for subjects who complete the Core Study 
with Stable Disease or better. The optional treatment extension will be permitted upon 
agreement with subject, Sponsor and Investigator, and it may continue until confirmed 
disease progression, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.  See Section 8.8 for details. 


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Per Amendment 6.1: 
By the date of implementation of this amendment, all subjects will have completed treatment 
and applicable On Study Follow-up, with the exception of one subject in optional treatment 
extension who will complete treatment and On Study Follow-up by 30 June 2022. This 
amendment provides that the Post Study Follow-up for the collection of survival data will be 
discontinued as of 30 June 2022, and the study will be completed. 
 
Primary 
Objectives 
[Endpoints] 
Dose Escalation Phase: 
Safety and Tolerability [DLTs, RCD according to CTCAE 4.03] 
Expansion Phase:   
Clinical efficacy by RECIST 1.1 [Clinical Benefit (CB), defined as percentage of 
subjects who are not in progression at end of Week 24]. 
Secondary 
Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Safety and Tolerability [CTCAE 4.03] 
Clinical Efficacy by RECIST 1.1/irRECIST [Durable Clinical Benefit (DCB, 
defined as the percentage of subjects meeting criteria of Stable Disease 
(SD), partial response (PR), or complete response (CR) over a period of at 
least 24 weeks); ORR after 8 and 24 weeks; PFS; and OS] 
Exploratory 
Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Biologic Activity [Effects on immune biomarkers, Immune Response, 
mechanisms of therapeutic resistance]. This will include CD8+ T cells in 
biopsies. PBMCs will be analysed for the presence of tumour and virus 
antigen specific CD8+ T cells as well as different immune cell 
subpopulations, such as T regulatory cells and effector cells.  
 
DLT=Dose-limiting Toxicity; RCD=Recommended Combination Dose; ORR=Objective Response Rate; 
DCB=Durable Clinical Benefit; PFS=Progression-free Survival; OS=Overall Survival; CTCAE=National Cancer 
Institute Common Terminology Criteria for Adverse Events; RECIST= Response Evaluation Criteria in Solid 
Tumors; irRECIST=immune-related RECIST 
 
Sponsor:  
Ludwig Institute for Cancer Research Ltd. New 
York, NY 
 
 
 
 
 
 
 
 
Sponsor Representative Signature and Date 
Study Chair: 
Dmitriy Zamarin, MD, PhD, Memorial Sloan 
Kettering Cancer Center, New York, NY 
 
 
 
 
 
 
 
 
Study Chair Signature and Date 
 
Confidentiality Statement 
The confidential and proprietary information in this document is owned by the Ludwig Institute for Cancer Research and 
provided to you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional 
review board(s). The information cannot be used, or divulged to any third party or published without the written consent of the 
Ludwig Institute for Cancer Research, except to the extent necessary to obtain informed consent from those persons to whom 
study medication may be administered. Any misappropriation of this information is prohibited by law. 
 


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Table of Contents 
1 
Background ............................................................................................................................. 7 
1.1 
Intraperitoneal Cancer ..................................................................................................... 7 
1.2 
Checkpoint Blockade in the Treatment of Gastrointestinal and Gynecologic 
Malignancies................................................................................................................................ 7 
1.3 
Study Drugs ...................................................................................................................... 8 
1.3.1 
Durvalumab (MEDI4736) ......................................................................................... 8 
1.3.2 
ONCOS-102 .............................................................................................................. 9 
2 
Study Rationale ..................................................................................................................... 12 
2.1 
Durvalumab Dose .......................................................................................................... 12 
2.1.1 
Pharmacokinetics (PK)/Pharmacodynamics (PD) Data .......................................... 13 
2.1.2 
Clinical Data ........................................................................................................... 13 
2.1.3 
Fixed Dosing for Durvalumab................................................................................. 13 
3 
Experimental Plan ................................................................................................................. 15 
3.1 
Study Design .................................................................................................................. 15 
3.1.1 
Study Phase ............................................................................................................ 15 
3.1.2 
Enrollment ............................................................................................................. 15 
3.1.3 
Blinding/Unblinding ............................................................................................... 17 
3.1.4 
Subject Population ................................................................................................. 17 
3.1.5 
Number of Sites/Subjects ...................................................................................... 17 
3.1.6 
Sample Size Considerations ................................................................................... 18 
3.1.7 
Treatment Arms and Treatment Schema .............................................................. 18 
3.1.7.1 
Dose Escalation Phase ................................................................................... 19 
3.1.7.2 
Dose Expansion Phase ................................................................................... 23 
3.1.8 
Dosing Adjustments, Delays, and Discontinuations .............................................. 23 
3.1.9 
DLT and MTD/RCD ................................................................................................. 23 
3.1.10 
Subject Withdrawal from Treatment or from Study ............................................. 25 
3.1.10.1 
Treatment beyond Progression ..................................................................... 25 
3.1.11 
Subject Evaluability and Replacements ................................................................. 26 
3.1.12 
Optional Study Treatment Extension ..................................................................... 26 
3.1.13 
Interim Analysis ..................................................................................................... 26 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 26 
3.1.15 
Duration of Study ................................................................................................... 27 
3.1.16 
On Study and Post Study Follow-up ...................................................................... 27 
3.1.16.1 
End of Study Visit ........................................................................................... 28 
3.2 
Study Flowchart ............................................................................................................. 29 
4 
Study Objectives and Endpoints ........................................................................................... 32 
4.1 
Safety and Tolerability ................................................................................................... 32 
4.1.1 
Endpoints and Assessment Methods ..................................................................... 32 
4.1.2 
Subject Evaluation and Statistics ........................................................................... 33 
4.2 
Clinical Efficacy ............................................................................................................... 33 


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4.2.1 
Endpoints and Assessment Methods ..................................................................... 33 
4.2.1.1 
Clinical Benefit (CB) ........................................................................................ 34 
4.2.1.2 
Objective Response Rate (ORR) ..................................................................... 34 
4.2.1.3 
Durable Clinical Benefit (DCB) ....................................................................... 34 
4.2.1.4 
Progression-free Survival (PFS) ...................................................................... 34 
4.2.1.5 
Overall Survival (OS) ...................................................................................... 34 
4.2.2 
Subject Evaluation and Statistics ........................................................................... 34 
4.3 
Biological Activity ........................................................................................................... 35 
4.3.1 
Endpoints and Assessment Methods ..................................................................... 35 
4.3.1.1 
Viral assessment ............................................................................................ 36 
4.3.1.2 
Assessment of dynamic changes in tumor microenvironment ..................... 36 
4.3.1.3 
Exploration of peripheral blood biomarkers.................................................. 36 
4.3.1.4 
Exploration of genetic predictors of response .............................................. 37 
4.3.1.5 
Assessment of cellular neoantigen responses ............................................... 37 
4.3.1.6 
Assessment of responses to CT antigens ....................................................... 38 
4.3.2 
Subject Evaluation and Statistics ........................................................................... 38 
5 
Subject Eligibility ................................................................................................................... 39 
5.1 
Inclusion Criteria ............................................................................................................ 39 
5.2 
Exclusion Criteria ........................................................................................................... 40 
5.3 
Restrictions on Concomitant Therapies ......................................................................... 44 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................ 44 
5.3.2 
Permitted Concomitant Therapies ........................................................................ 44 
6 
Study Drug Preparation and Administration......................................................................... 46 
6.1 
Durvalumab (MEDI4736) ............................................................................................... 46 
6.1.1 
Durvalumab Study Drug Information .................................................................... 46 
6.1.2 
Durvalumab Investigational Product Inspection ................................................... 46 
6.1.3 
Durvalumab Preparation ....................................................................................... 46 
6.1.4 
Durvalumab Administration .................................................................................. 47 
6.2 
ONCOS-102 .................................................................................................................... 48 
6.2.1 
ONCOS-102 Study Drug Information ..................................................................... 48 
6.2.2 
ONCOS-102 Preparation ........................................................................................ 48 
6.2.3 
ONCOS-102 Administration ................................................................................... 49 
6.3 
Estimated Study Requirements ..................................................................................... 50 
6.4 
Monitoring of Study Drug Administration ..................................................................... 50 
6.4.1 
Monitoring for Durvalumab Administration .......................................................... 50 
6.4.2 
Monitoring for ONCOS-102 Administration .......................................................... 50 
6.5 
Drug Overdose Management ........................................................................................ 51 
7 
Administrative, Legal and Ethical Requirements .................................................................. 52 
7.1 
Documentation and Reporting of Adverse Events ........................................................ 52 
7.1.1 
Definitions .............................................................................................................. 52 
7.1.2 
Additional Expedited Reporting Requirements for this Study............................... 53 
7.1.2.1 
Pregnancy ...................................................................................................... 53 
7.1.2.2 
Overdose ........................................................................................................ 54 
7.1.2.3 
Hepatic Function Abnormality ....................................................................... 54 


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7.1.2.4 
New Cancers .................................................................................................. 54 
7.1.2.5 
Deaths ............................................................................................................ 54 
7.1.3 
Severity of an Adverse Event ................................................................................. 55 
7.1.4 
Relationship of Adverse Events to Study Drug ...................................................... 55 
7.1.5 
General Reporting Requirements .......................................................................... 55 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ........................ 56 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 57 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................. 57 
7.1.8.1 
AESIs for Durvalumab .................................................................................... 57 
7.1.8.2 
Additional AESI for ONCOS-102 ..................................................................... 59 
7.2 
Administrative Sponsor Requirements .......................................................................... 60 
7.2.1 
Study Master Files .................................................................................................. 60 
7.2.2 
Case Report Form Data Collection ......................................................................... 60 
7.2.3 
Language ................................................................................................................ 60 
7.2.4 
Monitoring ............................................................................................................. 60 
7.2.5 
Protocol Amendments ........................................................................................... 61 
7.2.6 
Premature Subject Withdrawal from Treatment or from Study ........................... 61 
7.2.7 
Early Trial Termination ........................................................................................... 61 
7.2.8 
Study Drug Shipments and Accountability ............................................................ 61 
7.3 
Regulatory, Legal and Ethical Requirements ................................................................. 62 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ............................................. 62 
7.3.2 
Informed Consent .................................................................................................. 62 
7.3.3 
Institutional Review Board..................................................................................... 63 
7.3.4 
Subject Confidentiality ........................................................................................... 63 
8 
Appendices ............................................................................................................................ 64 
8.1 
Protocol Version History ................................................................................................ 64 
8.2 
Participating Study Sites, Investigators and Staff, Laboratories, and Sponsor Information
 
 ....................................................................................................................................... 74 
8.3 
Dose Adjustments and Delays for Durvalumab ............................................................. 75 
8.3.1 
Durvalumab (MEDI4736) Dose Modification Due to Toxicity ................................ 75 
8.3.2 
Durvalumab Dose Modification Not Due to Treatment-related Toxicities ........... 77 
8.4 
Dose Modifications and Delays for ONCOS-102 ............................................................ 79 
8.4.1 
Dose Modifications ................................................................................................ 79 
8.4.2 
Dose Delays Not Due to Toxicities ......................................................................... 79 
8.5 
Guidelines for RECIST 1.1 and irRECIST .......................................................................... 80 
8.6 
ECOG Performance Status ............................................................................................. 88 
8.7 
Exploratory Assessment of Correlative Immunologic Research .................................... 89 
8.8 
Details for Subjects who Continue Durvalumab Treatment beyond the Core Study .... 90 
8.8.1 
Study Flowchart for Subjects who Continue Durvalumab Treatment beyond the 
Core Study ............................................................................................................................. 91 
8.9 
List of Abbreviations ...................................................................................................... 92 
9 
References ............................................................................................................................ 94 
 


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Table of Figures 
Figure 1. Enrollment Schema .......................................................................................................... 17 
Figure 2. Dose Escalation and De-Escalation Schema .................................................................... 20 
Figure 3. Treatment Schema for Cohort A Only ............................................................................. 22 
Figure 4. Treatment Schema for All Subjects except Cohort A....................................................... 22 
 
 
 


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1 Background 
1.1 Intraperitoneal Cancer 
Intraperitoneal carcinomatosis is a serious complication of various cancers and is essentially 
considered incurable once established. Some cancers respond better than others to therapy 
consisting typically of surgery and chemotherapy. For ovarian carcinoma, which typically 
presents with peritoneal metastasis at an advanced stage, the administration of intraperitoneal 
chemotherapy versus systemic intravenous chemotherapy has conclusively demonstrated a 
survival benefit and has become standard of care for this disease since 2005.(1)  
The benefit of intraperitoneal chemotherapy for other malignancies with a propensity of 
originating or spreading to the peritoneal cavity has not been conclusively proven for 
mesothelioma, colorectal, or gastric cancers; nor has a survival benefit been demonstrated for 
hyperthermic perfusion of the abdominal cavity administered with or without chemotherapy in a 
randomized trial. Nevertheless, key opinion leaders believe that certain patients would benefit 
from such therapy. The problem is the heterogeneity of patients and their diseases and the 
inability of properly stratifying patients according to their disease characteristics. Clinicians and 
researchers are trying to develop tools which could better identify patients who benefit from 
hyperthermic intraperitoneal chemotherapy such as the peritoneal surface disease severity score 
(PSDSS).(2)  However, there is currently no universally accepted criteria for selecting patients for 
such treatment, and most decision making is up to the discretion of the treating physician. 
1.2 Checkpoint Blockade in the Treatment of Gastrointestinal and 
Gynecologic Malignancies 
Recent breakthroughs in tumor immunology and immunotherapy have led to development of 
novel therapeutic agents aiming to enhance activation of anti-tumor immune responses or to 
reverse immunosuppressive mechanisms governing tumor resistance to the immune system.(3)  
Exciting results have been reported in the clinical setting against multiple human cancers by the 
use of antibodies that target the inhibitory receptor PD-1 expressed on activated T-cells.(4)  
Durvalumab is a highly selective, human monoclonal IgG1–kappa isotype antibody targeting 
programmed cell death 1 ligand 1 (PD-L1; B7-H1; CD274) that is designed to block the negative 
immune regulatory signaling of the PD-1/PD-L1 pathway.  
Despite the significant promise of the immune checkpoint-targeting agents, the observed clinical 
efficacy, however, has not been universal and has been particularly poor in patients with 
gastrointestinal and gynecologic malignancies. These findings highlight the marked 
immunosuppressive nature of these tumors and call for development of appropriate predictive 
biomarkers and combinatorial strategies. This presents an opportunity for numerous 
combinatorial approaches, which most commonly involve combinations of immune checkpoint 
blocking antibodies with strategies thought to promote presentation of tumor antigens, either 
through exogenous vaccination or by induction of “in situ” vaccination through therapies thought 
to induce immunogenic cell death (ICD) and antigen release such as radiation therapy and 
chemotherapy.(5-7)  
Analysis of different tumor types consistently demonstrates that tumor infiltration with T cells is 
a good prognostic marker in a variety of tumor types, with most extensive data existing in 


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ovarian and colorectal cancers.(8-20)  Presumably, the T cell-infiltrated tumors are a marker of 
an ongoing spontaneous anti-tumor immune response, which results in better tumor control and 
leads to more favorable clinical outcomes. Interestingly, the prognostic value of this phenotype 
has been shown to be more powerful than traditional staging in colorectal cancer,(21) and 
studies are currently underway to validate this marker prospectively.(22)  Consistent with these 
findings, data from clinical trials indicate that patients with evidence of pre-existing anti-tumor 
immune response, namely, patients with increased tumor immune infiltration are more likely to 
benefit from such therapies.(12, 13, 23) These findings suggest that therapies that could 
potentially increase immune infiltration into tumors could sensitize patients to the effect of the 
immunomodulatory antibody therapy.  
Oncolytic viruses (OV) represent another class of emerging cancer therapeutics, which for the 
past 60 years have been evaluated in a variety of cancer types.(24) While promising activity of 
OVs has been demonstrated in a variety of animal models (primarily with intratumoral injection), 
the clinical results have not been as impressive. The major limitation of OVs is their poor delivery 
to metastatic cancer sites with systemic administration and the rapid development of 
neutralizing antibodies by the host, which limits the utility of further systemic administration.(25)  
However, in the few patients that did achieve response to oncolytic virotherapy, the observed 
clinical benefit was often durable even after completion of therapy, an effect reminiscent of the 
responses seen with immunotherapeutic approaches.(26-28)  Indeed, it has become increasingly 
recognized that modification of tumor cells by OVs may promote their recognition by the 
immune system, with activation of adaptive immune responses specific not only for viral, but 
also for tumor antigens.(29)  Evidence has emerged from both preclinical and clinical studies 
demonstrating the immune therapeutic potential of OVs, marking a new era in the development 
of these agents and suggesting a tantalizing possibility that the immunostimulatory properties of 
OVs can be steered to improve the efficacy of immunomodulatory agents.(30)  Recently, studies 
combining talimogene laherparepvec (T-VEC; an oncolytic virus) and pembrolizumab (31) or 
ipilimumab (32) in melanoma patients showed promising results. 
Given the preclinical rationale, as well as the evidence of superior prognosis in ovarian and 
colorectal cancer patients whose tumors exhibit immune infiltration, the current study will 
evaluate whether the immune response and tumor immune infiltration induced by OV could 
potentiate the therapeutic efficacy of PD-L1 blockade in these cancer types.  
1.3 Study Drugs 
This study will evaluate oncolytic virus (ONCOS-102) with the PD-L1 checkpoint inhibitor, 
durvalumab. 
1.3.1 Durvalumab (MEDI4736) 
Durvalumab is briefly described in this section below. Refer to the current Investigator’s 
Brochure for complete and current information. 
Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody (mAb) directed against 
human PD-L1. Durvalumab is selective for recombinant PD-L1 and blocks the binding of 
recombinant PD-L1 to the PD-1 and cluster of differentiation (CD) 80 receptors. As durvalumab is 
an engineered mAb, it does not induce antibody-dependent cellular cytotoxicity or complement-
dependent cytotoxicity. 


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As of the data cutoff dates in the IB (15Apr2015 to 18Sep2015), a total of 1,910 subjects have 
been enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 sponsored and 
10 collaborative studies. Of the 1,910 subjects, 1,279 received durvalumab monotherapy, 454 
received durvalumab in combination with tremelimumab or other anticancer agents, 14 received 
other agents (1 gefitinib, 13 MEDI6383), and 163 have been treated with blinded investigational 
product. No studies have been completed or terminated prematurely due to toxicity. 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique adverse events (AEs). 
Immune-related AEs (irAEs), which are important risks of immune checkpoint inhibitors, have 
been observed with durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, 
neuropathy / neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, 
pancreatitis is an important potential risk particularly with durvalumab and tremelimumab 
combination therapy. These events are manageable by available/established treatment 
guidelines as described in the study protocols (see Section 8.3).  
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies. 
1.3.2 ONCOS-102 
ONCOS-102 is briefly described in the section below. Refer to the current Investigator’s Brochure 
(IB) for complete and current information. 
ONCOS-102 (formerly CGTG-102; Ad5/3-D24-GMCSF) is a replication competent adenovirus that 
has been classified by the Gene Technology Board of Finland as a genetically modified micro-
organism (GMM). The virus properties are close to the wild type serotype 5 adenovirus but 
ONCOS-102 contains an adenovirus 3 serotype knob replacing the wild type serotype 5 knob. 
Other modifications include a 24 base pair (bp) deletion in the E1A region for tumor selectivity, 
and an added transgene coding for granulocyte-macrophage colony stimulating factor (GMCSF). 
GMCSF is an immunostimulatory cytokine that is targeted to prime the anti-tumor immune 
response in the tumor environment. 
Clinical data on the efficacy and safety of ONCOS C1 are provided from a completed Phase 1 
clinical trial (ONCOS C1) and an Advanced Therapy Access Program (ATAP). 
Clinical Study ONCOS C1 
ONCOS C1 was a single center, exploratory, open label study of ONCOS-102 given in combination 
with low dose cyclophosphamide (CPO) in subjects with refractory injectable solid tumors. 
Twelve subjects (5 male, 7 female; aged 38 to 68 years [median age 63 years]) were treated with 
ONCOS-102 (intratumorally): 3 subjects were treated with 3 x 1010 viral particles (VP)/injection, 3 
subjects with 1 x 1011 VP/injection, and 6 subjects with 3 x 1011 VP/injection. Dosing was 
scheduled on Days 1, 4, 8, 15, 29, 57, 85, 113, and 141. Five subjects received the maximum of 9 
doses of ONCOS-102, and 3 subjects completed the study as planned. The most common reason 
for discontinuation from the study was disease progression (6 subjects). Subjects also took oral 
cyclophosphamide 50 mg daily throughout the treatment period of the trial. The underlying 
cancer types differed widely across the study population with 9 different cancer types reported 
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Treatment with ONCOS-102 in combination with low dose CPO was well tolerated, with no dose-
limiting toxicity. Therefore, a maximum tolerated dose was not established and is believed not to 
be relevant after treatment with rapidly replicating virus. The recommended dose for further 
development of ONCOS-102 is 3 x 1011 VP/injection, although all 3 doses of ONCOS-102 
examined in this study could potentially be used.  
ONCOS-102 induced a systemic anti-tumor CD8+ T-cell response that was correlated with a 
clinical response. Computed tomography (CT)/PET imaging suggested signals of efficacy as 40.0% 
of these severely ill subjects with progressive disease had stable disease at 3 months. 
All subjects reported pyrexia, which was managed successfully with antipyretic medication. This 
was also the most common treatment-related AE. Peak body temperatures were mostly 
recorded 6 to 10 hours after injection and were managed successfully with paracetamol or 
ibuprofen. Therefore, acetaminophen (1 g) can, if needed, be given 4 to 6 hours after each 
dose of ONCOS-102 to reduce the incidence of chills or fever, which are expected after viral 
therapy. Prophylactic medication should be avoided to allow the initial induction of cytokines 
and fever. Other common AEs reported in at least 50% of subjects were fatigue, nausea, 
injection site pain, chills and decreased appetite. Most of the AEs were Grade 1 or 2. Grade 3 AEs 
were reported in 6 subjects and there were no Grade 4 AEs. Seven serious adverse events (SAEs) 
were reported by 5 subjects: 5 of these SAEs were deemed unrelated to study medication while 2 
(peripheral oedema and hypoalbuminaemia in the same subject) were deemed possibly related 
to study medication. This last subject died due to underlying malignant disease 1 month after her 
last ONCOS-102 treatment. There were no significant laboratory or haematological changes 
suggesting an association or toxic effect of the study medication. The safety profile seen in 
ONCOS C1 was similar to that seen in ATAP.  
Advanced Therapy Access Program 
An ATAP for the treatment of patients with chemo-refractory tumors with oncolytic viruses was 
operational between 2007 and 2012. The ATAP was not a trial but an individualized treatment 
program regulated by the Finnish Medicines Agency as determined by EC/1394/2007. One 
hundred and fifteen patients with chemo-refractory tumors were treated with ONCOS-102 in the 
ATAP, either alone or in combination with other ATAP viruses with excellent safety data and 
signals of clinical response in individual patients. 
Efficacy: As ATAP was not a study with a predetermined protocol, assessment of efficacy with 
certainty was not possible. However, clinical responses were seen in individual patients.(33) 
Median survival of 115 patients who received ONCOS-102 either alone or in combination with 
other ATAP viruses was 164 days or 5.5 months (95% CI: 122 to 206 days) in this heavily pre-
treated refractory population. A total of 30% of patients survived for more than 300 days and 
15% for up to 600 days. 
 
Safety: The 115 patients treated in the ATAP were evaluated for safety. Only adverse reactions 
possibly related to treatment were reported in the ATAP. All patients reported at least one 
adverse reaction, regardless of the route of administration. The most frequently reported 
adverse reactions overall were pyrexia (94 patients, 81.7%), fatigue (91 patients, 79.1%), nausea 
(63 patients, 54.8%), hemoglobin decreased (54 patients, 47.0%), and chills (53 patients, 46.1%). 
Abdominal pain and thrombocytopenia were reported more frequently after IP administration 
(abdominal pain 12 patients [44.4%]; thrombocytopenia 6 patients, [22.2%]) compared with the 
overall population (31.1% and 14.8%, respectively). After intrapleural administration, the most 


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common adverse events were pain, leukopenia, and dyspnea (8 patients, 44.4% for each event), 
and influenza-like illness and cough (5 patients, 27.8% for each event).  
A total of 60 grade 3 adverse reactions were reported in 34 patients (29.6%) overall. The most 
common grade 3 adverse reactions overall were decreased hemoglobin (7 patients, 6.1%), and 
increased AST (6 patients, 5.2%). A total of 8 grade 4 adverse reactions were reported in 6 
patients (5.2%) overall: hemoglobin decrease (2 episodes in 1 patient), pulmonary embolism, 
thrombocytopenia, dyspnea, pleural effusion, ketoacidosis, and AST increase. In addition, 1 
patient experienced pulmonary embolism with fatal outcome (grade 5) after a single 
administration of 3 x 1011 VP ONCOS- 102 by a combination of intratumoral, intravenous (IV), and 
intraperitoneal (IP) routes. This event was considered not related to ONCOS-102. Eleven patients 
(9.6%) overall experienced a total of 15 grade 3 to 5 adverse reactions that were rated as serious.  
ONCOS-102 is classified as a GMM and should be handled according to biosafety level 2 (BSL-2). 
It is selectively replicative in cancer cells, and the ability to replicate in normal cells is negligible. 
There is a theoretical risk of spread of ONCOS-102 into the environment from patients who are 
undergoing treatment. In the Phase I study, no virus was detected in urine or buccal swabs at 
discharge after dosing in any patient. Virus was detected before dosing on one occasion (Day 4): 
in the urine of 1 patient, and in the buccal swabs in 3 patients, but not on subsequent dosing 
days. ONCOS-102 is an adenovirus that is genetically modified to replicate selectively in cancer 
cells; therefore, it is attenuated, compared to the wild type adenoviruses (e.g. serotypes 5 and 3) 
that commonly infect the human population. In the unlikely event of person to person spread, it 
is unlikely that ONCOS-102 would pose any clinically significant risk to patient contacts. 
ONCOS-102 can be inactivated using a suitable adenovirus neutralizing agent such as 10% bleach 
or 1.5% Barrydin liquid (PAN Biotech, Germany). These are to be used for the inactivation of spills 
and devices used for administration. 
 
 


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2 Study Rationale 
Recent pre-clinical studies demonstrated that combination of intratumorally administered 
oncolytic virus in combination with systemic immune checkpoint blockade act in synergistic 
manner.(34, 35)  Recently, clinical validation of these findings have been presented.  
In a Phase 1 study, T-VEC was combined with ipilimumab in advanced melanoma patients where 
the combination appeared to have greater efficacy than either T-VEC or ipilimumab 
monotherapy.(32, 36)  In this study, objective response rate (ORR) was 50%; 44% of patients had 
a durable response lasting ≥ 6 months; 18-month progression-free survival was 50%; and 18-
month overall survival was 67%.  
In another Phase 1 study, T-VEC was combined with pembrolizumab in advanced melanoma 
patients, where the combination was associated with clinical benefit as assessed by ORR and 
Complete Response rate. (31)  A randomized, double-blind phase 3 trial of T-VEC and 
pembrolizumab vs T-VEC placebo and pembrolizumab is under way. 
Given the preclinical and preliminary clinical rationale, the current study will evaluate a 
combination of locoregionally-administered ONCOS-102, an oncolytic adenovirus genotype 5/3 
encoding GM-CSF transgene, with systemic PD-L1 blockade using durvalumab. The choice for 
ONCOS-102 stems from existing clinical data with the virus, demonstrating safety and evidence 
of induction of anti-tumor immune responses with the virus administered as a single agent.(37-
39)  Based on these findings, ONCOS-102 was granted an orphan drug designation in relapsed 
ovarian cancer, mesothelioma and soft tissue sarcoma by the FDA and the EMA in 2014 and 
2015. Other intraperitoneally administered oncolytic adenoviruses have been evaluated in 
several trials in subjects with advanced ovarian cancer, with evidence of safety and some 
evidence of clinical activity (40-44), supporting the use of oncolytic adenovirus in this setting.  
The current study is a two-part dose escalation/dose expansion Phase 1/2 study of 
intraperitoneally administered ONCOS-102 with systemically administered durvalumab in 
subjects with advanced gynecologic and colorectal cancers with peritoneal carcinomatosis. The 
main objectives of the study will be to test the feasibility and safety of this approach, evaluate a 
range of translational endpoints, and provide initial indicators of clinical efficacy. If successful, 
this study would provide further rationale for evaluation of other locoregionally-administered 
oncolytic viruses with antibodies targeting immune checkpoints, a strategy that could be 
extended to other malignancies.  
In the dose escalation phase, a 3+3 design will be used to evaluate the safety of ONCOS-102 
monotherapy before initiation of durvalumab (Cohort A) and to identify the recommended 
combination dose (RCD) of a fixed dose of durvalumab (1500 mg) + ONCOS-102 at 2 dose levels 
(Cohorts B and C). The data from Cohort A will be used to evaluate the safety of the ONCOS-102 
regimen in this type of administration (which has not been used before) prior to the combination 
with durvalumab. 
2.1 Durvalumab Dose 
A durvalumab dose of 20 mg/kg every 4 weeks (Q4W; equivalent to a fixed dose of 1500 mg 
Q4W, which will be used in this study) is supported by in-vitro data, non-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced 


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solid tumors and from a Phase I trial performed in Japanese patients with advanced solid tumor 
(D4190C00002). See durvalumab IB for details. 
2.1.1 Pharmacokinetics (PK)/Pharmacodynamics (PD) Data 
Based on available PK/PD data from ongoing Study 1108 with doses ranging from 0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear (dose-dependent) PK consistent with 
target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg Q2W, suggesting near 
complete target saturation (membrane-bound and sPD-L1), and further shows that the 
durvalumab dosing frequency can be adapted to a particular regimen given the linearity seen at 
doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is approximately 21 
days. A dose-dependent suppression in peripheral sPD-L1 was observed over the dose range 
studied, consistent with engagement of durvalumab with PD-L1. A low level of immunogenicity 
has been observed. No patients have experienced immune-complex disease following exposure 
to durvalumab. For further information on immunogenicity, please see the current IB.  
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W. For 
further information on PK observations in Study 006, please see the current IB.  
The observed durvalumab PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W.(45)  Multiple simulations indicate that a similar overall exposure is 
expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented by the 
area under the concentration-time curve (AUC) at 4 weeks. Median maximum concentration 
(Cmax) is expected to be higher with 20 mg/kg Q4W (~1.5 fold) and median Ctrough is expected 
to be higher with 10 mg/kg Q2W (~1.25 fold). Clinical activity with the 20 mg/kg Q4W dosing 
regimen is anticipated to be consistent with 10 mg/kg Q2W with the proposed similar dose of 
20 mg/kg Q4W expected to (a) achieve complete target saturation in majority of patients; 
(b) account for anticipated variability in PK, pharmacodynamics, and clinical activity in diverse 
cancer populations; (c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK 
exposure that yielded maximal antitumor activity in animal models. 
Given the similar AUC and modest differences in median peak and trough levels at steady state, 
the observation that both regimens maintain complete sPD-L1 suppression at trough, and the 
available clinical data, the 20 mg/kg Q4W and 10 mg/kg Q2W regimens are expected to have 
similar efficacy and safety profiles, supporting further development with a dose of 20 mg/kg 
Q4W.  
2.1.2 Clinical Data 
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy and PK for the 20mg/kg Q4W (1500 mg Q4W) regimen.  
2.1.3 Fixed Dosing for Durvalumab  
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 


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Population PK analysis indicated only minor impact of body weight on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body weight-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected 
to approximate 10 mg/kg (based on median body weight of ~75 kg). A total of 1000 patients 
were simulated using body weight distribution of 40–120 kg. Simulation results demonstrate that 
body weight-based and fixed dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-subject variability with fixed dosing regimen.  
Similar findings have been reported by others.(46-49) Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, with 
fixed dosing being better for 7 of 12 antibodies. In addition, they investigated 18 therapeutic 
proteins and peptides and showed that fixed dosing performed better for 12 of 18 in terms of 
reducing the between-subject variability in PK/PD parameters.(48)  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, it was considered 
feasible to switch to fixed dosing regimens. Based on average body weight of 75 kg, a fixed dose 
of 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W) or 1500 mg Q4W durvalumab 
(equivalent to 20 mg/kg Q4W) is recommended. 
This dosing of durvalumab is recommended only for subjects with > 30 kg body weight, due to 
endotoxin exposure. Subjects with a body weight ≤ 30 kg are not eligible for enrollment in the 
current study. If a subject’s body weight drops to ≤ 30 kg while on the study, the durvalumab 
dose will be weight based as long as the body weight remains ≤ 30 kg. See Section 6.1.3 for 
details. 
 
 


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3 Experimental Plan 
3.1 Study Design 
This is a two-part Phase 1/2 dose escalation and dose expansion study of the GMCSF-encoding 
adenovirus, ONCOS-102, in combination with anti-PD-L1 antibody, durvalumab, in adult subjects 
with peritoneal disease who have histologically confirmed epithelial ovarian cancer or metastatic 
colorectal cancer and have failed prior standard therapies.  
ONCOS-102 will be administered intraperitoneally (IP) via a peritoneal Hickmann catheter (or 
institutionally preferred alternative) at weekly intervals for 6 weeks. A bolus dose of 300 mg 
cyclophosphamide (CPO) will be administered intravenously (IV) 1 to 3 days before the first 
infusion of ONCOS-102. Durvalumab will be administered by IV infusion once every four weeks 
(Q4W) for a total of 12 four-week cycles. 
Phase 1 of the study is a dose escalation phase with 3 cohorts (see Section 3.1.4 for subject 
population), which will use a 3+3 design to evaluate the safety of ONCOS-102 monotherapy 
before initiation of durvalumab (Cohort A) and to identify the recommended combination dose 
(RCD) of a fixed dose of durvalumab (1500 mg) + ONCOS-102 at 2 dose levels (Cohorts B and C).  
The data from Cohort A will be used to evaluate the safety of the ONCOS-102 regimen in this 
type of administration prior to the combination with durvalumab.  The 3 cohorts are defined as 
follows: 
• 
Cohort A: ONCOS-102, 1 x 1011 viral particles (VPs) monotherapy for 6 weeks, followed by 
durvalumab 1500 mg starting on Day 71  
(NOTE: Upon agreement between Investigator and Sponsor, if a subject in Cohort A has 
tolerated the ONCOS treatment well but is starting to get symptomatic, the first dose of 
durvalumab may be given on Day 43 (Cycle 2/Day15); durvalumab dosing will then 
continue per flowchart in Section 3.2).  
• 
Cohort B: ONCOS-102, 1 x 1011 VPs + durvalumab 1500 mg. 
• 
Cohort C: ONCOS-102, 3 x 1011 VPs + durvalumab 1500 mg. 
NOTE: if a subject’s body weight drops to ≤ 30 kg while on the study, the durvalumab dose will be 
weight based as long as the body weight remains ≤ 30 kg. See Section 6.1.3 for details.  
Phase 2, the dose expansion phase, will have 2 cohorts and will explore the safety and anti-tumor 
activity for RCD defined in Phase 1. In Phase 2, there are 2 expansion cohorts with peritoneal 
disease: 
• 
Cohort 1: Platinum-resistant epithelial ovarian cancer  
• 
Cohort 2: Metastatic colorectal cancer 
3.1.1 Study Phase 
Phase 1/2 
3.1.2 Enrollment 
Subjects will be screened for eligibility for up to 28 days after signing the informed consent form. 
Enrollment will be under ongoing review by an internal data safety-monitoring panel (see Section 
3.1.14). Eligible subjects will be registered centrally with the Sponsor before enrollment. 


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In the dose escalation phase, subjects will be enrolled sequentially into 3 cohorts (see Figure 1). 
In Cohorts A and B of the dose escalation phase, as a safety precaution, there will be a waiting 
period between the first study drug administration for the first and second subjects of the 
cohort.   
For Cohort A, (where ONCOS-102 is administered as a monotherapy until durvalumab is started 
on Day 71), the waiting period will be 2 weeks.  After completion of the ONCOS-102 
monotherapy, there will be a safety review prior to the initiation of durvalumab. (See Cohort A 
Note in Section 3.1.) 
For Cohort B, where the combination of ONCOS-102 and durvalumab will be evaluated, the 
waiting period will be 4 weeks; i.e., the second subject will not receive the first study drug 
administration until the first subject has completed Cycle 1 (Day 29 of the study).  
Per Amendment 4, a waiting period between the first study drug administration for the first and 
second subjects in the cohort is not required for Cohort C. This was based on the completion of 
the safety reviews for Cohort B (ONCOS-102 1x1011 VP +1500 mg durvalumab) and Cohort A 
(ONCOS-102 1x1011 VP +delayed 1500 mg durvalumab, which started after completion of the 6 
weekly doses of ONCOS-102). 
In the dose expansion phase, subjects will be enrolled in parallel in a non-randomized, sequential 
manner, with competitive enrollment between study sites.  The subjects will be assigned to a 
disease-specific cohort, and Simon’s 2-Stage MINIMAX Design (50) will be used to determine 
enrollment (see Figure 1).  Enrollment of 18 and 13 subjects to Cohorts 1 and 2 (including the 6 
subjects at the RCD from the dose escalation phase), respectively, will occur in the first stage, 
followed by: 
• 
For Cohort 1: if 5 or more subjects demonstrate clinical benefit (defined as percentage of 
subjects who are not in progression at end of Week 24), an additional 15 subjects will be 
enrolled to that cohort in Stage 2 for a total of 33 subjects.  
• 
For Cohort 2: if 1 or more subjects demonstrate clinical benefit at end of Week 24, an 
additional 14 subjects will be enrolled to that cohort in Stage 2 for a total of 27 subjects. 


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Figure 1. Enrollment Schema 
3.1.3 Blinding/Unblinding 
This is an open-label study. 
3.1.4 Subject Population 
Subjects with peritoneal disease who have histologic confirmation of epithelial ovarian cancer or 
metastatic colorectal cancer (CRC) will be enrolled. Note: the CRC cohort may include subjects 
with cancer originating from the appendix. 
Subjects should have failed prior treatment for advanced cancer and deemed by the Investigator 
to no longer be eligible for or have reasonable standard of care alternatives, which are felt to 
have a clinically meaningful impact on their survival. 
Subjects with ovarian cancer must have either received one line of platinum based therapy and 
have progressed within 6 months (defined as platinum resistant) or have received 2 or more lines 
of standard therapy.  
Subjects with CRC must have at least failed two lines of therapy (e.g., fluropyrimidine based 
therapies, oxaliplatin or irinotecan based therapies with or without anti-VEGF component, or for 
RAS wild-type, with or without anti-EGFR therapy). 
Co-existing distant metastases and parenchymal organ metastases will be allowed. Subjects may 
have received prior intraperitoneal therapy.   
Details on subject eligibility are found in Section 5. 
3.1.5 Number of Sites/Subjects 
Up to 78 subjects will be enrolled in the study. The study will be conducted in 5 US sites.   


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3.1.6 Sample Size Considerations 
The dose escalation phase will utilize a standard 3 + 3 design for 3 cohorts, which will result in 
the enrollment 12 to 18 subjects. 
In the expansion phase, up to 33 subjects will be enrolled in Cohort 1, and up to 27 subjects will 
be enrolled in Cohort 2, for a total of up to 60 subjects.   
The sample size rationale for Cohorts 1 and 2 of the expansion phase is based on Simon’s 2-Stage 
MINIMAX Design with a Type I error rate of 0.05 and 80% power.  
Cohort 1 
Based on recent studies of anti-PD-1/PD-L1 therapies in ovarian cancer,(51-53) the null 
hypothesis for the clinical benefit rate (number of subjects who are not in progression) at end of 
Week 24 for the ovarian cancer cohort (Cohort 1) will be 20%, which will be tested against a one-
sided alternative of 40%. In the first stage, 18 subjects will be accrued to Cohort 1. If clinical 
benefit at end of Week 24 is seen in <5 of these subjects, the study of Cohort 1 will be stopped.  
If 5 or more subjects demonstrate clinical benefit at end of Week 24, an additional 15 subjects 
will be accrued to a total of 33.  The null hypothesis will be rejected if 11 or more subjects 
experience clinical benefit at end of Week 24. 
Cohort 2 
For the metastatic colorectal cancer cohort (Cohort 2), the null hypothesis for the clinical benefit 
rate at end of Week 24 will be 5%, which will be tested against a one-sided alternative of 20%. In 
the first stage, 13 subjects will be accrued to Cohort 2. If clinical benefit at end of Week 24 is 
seen in <1 of these subjects, the study of Cohort 2 will be stopped.  If 1 or more subjects 
demonstrate clinical benefit at end of Week 24, an additional 14 subjects will be accrued to a 
total of 27.  The null hypothesis will be rejected if 4 or more subjects experience clinical benefit 
at end of Week 24.  
3.1.7 Treatment Arms and Treatment Schema 
ONCOS-102 will be administered for a total of 6 weeks while durvalumab will be given for a total 
of 12 four-week cycles (or 10 four-week cycles for Cohort A; see Section 3.1.7.1). 
Per Amendment 5, optional durvalumab treatment extension beyond the initial 12-cycle 
treatment period (Core Study) will be available for subjects who complete the Core Study with 
Stable Disease or better. The optional treatment extension will be permitted upon agreement 
with subject, Sponsor and Investigator, and it may continue until confirmed disease progression, 
unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion 
is met.  See Section 8.8 for details. 
Treatment with ONCOS-102: 
Subjects’ ascites must be manageable, as determined by the Investigator; volume and frequency 
of necessary paracentesis should not interfere with the conduct of the study. Indwelling 
paracentesis catheters are permitted per discretion of the Investigator. 
A bolus dose of 300 mg cyclophosphamide (CPO) IV will be given 1 to 3 days before the first 
administration of ONCOS-102.  


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After accessing the IP port and aspirating any ascites, if present, the ONCOS-102 will be infused 
in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per 
institutional procedures for IP infusions. The infusion should be given as soon as possible after 
preparation of the infusion solution. It is recommended that the total infusion time not exceed 2 
hours.  To ensure uniform distribution of ONCOS-102 in the peritoneal cavity during infusion, it is 
recommended that the subjects are rotated every 30 minutes, or institutional procedures may be 
followed.  See Section 6.2.3 regarding administration of ONCOS-102. 
ONCOS-102 will be administered weekly for a total of 6 weeks, starting on Day 1. Any ascites that 
re-accumulate before the next scheduled treatment dose can be drained as clinically indicated 
for comfort. If palliative paracentesis is necessary, it is recommended that at least 72 hours have 
passed from ONCOS-102 instillation to the procedure. 
Treatment with Durvalumab: 
Durvalumab will be administered at a fixed dose of 1500 mg using a 250 mL IV bag containing 
0.9% (w/v) saline or dextrose and delivered through an IV administration set. Durvalumab will be 
administered Q4W for 12 cycles, starting on Day 15 (with the exception of dose escalation Cohort 
A; see Section 3.1.7.1). NOTE: if a subject’s body weight drops to ≤ 30 kg while on the study, the 
durvalumab dose will be weight based as long as the body weight remains ≤ 30 kg. See Section 
6.1.3 for details. 
3.1.7.1 Dose Escalation Phase 
Dose escalation studies of ONCOS-102 have previously been done with intratumorally 
administered virus and several subjects have received the virus IP in the advanced therapy access 
program.  A safe dose of 3 x 1011 VPs has been established in these studies.  
During Phase 1 of the study, subjects will be evaluated for DLTs, as defined in Section 3.1.9 
before proceeding to a subsequent cohort.  Dose escalation for the determination of RCD will be 
performed based on the available dose levels (see Table 1) and the respective rules for a 
standard 3 + 3 dose escalation study design (see Figure 2). 
Table 1. Phase 1 Dose Level Cohorts: 
Cohort  
Dose Level 
Durvalumab Q4W (IV) 
ONCOS-102 (IP) 
A 
0 (Starting Level) 
1500 mg starting on  
Day 71 (Figure 3) 
1 x 1011 VP 
B 
+1 
1500 mg (Figure 4) 
1 x 1011 VP  
C 
+2 
1500 mg (Figure 4) 
3 x 1011 VP  
NOTE: if a subject’s body weight drops to ≤ 30 kg while on the study, the durvalumab dose will be 
weight based as long as the body weight remains ≤ 30 kg. See Section 6.1.3 for details. 
See Cohort A Note in Section 3.1. 
 


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Dose Escalation and De-Escalation Schema (3 + 3 Design)
1
0
 ≤1   
>1
 >1 
Treat 3 
Subjects 
@ DL and 
assess 
DLTs
Expand 
to 6 
Subjects 
@ DL and 
assess 
DLTs
DL is unsafe
DL is safe
Is DL + 1 available
and not
previously declared unsafe?
Escalation
DL = DL + 1
Yes
No
DL = Starting 
Dose Level
Is DL + 1 available
and not
previously declared unsafe?
Yes
DL is RCD
No
Is DL - 1 
available?
No
RCD cannot be 
determined
Was DL - 1 
previously declared 
safe?
No
3 subjects already 
treated @ DL?
Yes
Yes
No
Yes
De-Escalation
DL = DL - 1
DL - 1 is RCD
DL = Dose Level (per DL Table)         DLT = (Subjects with) Dose Limiting Toxicities         RCD = Recommended Combination Dose (per DL Table)
 
Figure 2. Dose Escalation and De-Escalation Schema 
 
In this study, the dose for Cohort A is the starting dose level (DL); the dose for Cohort B is DL +1; 
and the dose for Cohort C is DL +2. The dose escalation for this study may proceed as follows: 
1. Cohort A: Three subjects will be enrolled into Cohort A and treated at the DL. 
a) If 0 of the 3 subjects in Cohort A has a DLT, Cohort B (DL+1) will open to enrollment 
(see #2, Cohort B) 
b) If 1 of the 3 subjects in Cohort A has a DLT, an additional 3 subjects will be enrolled 
at the DL: 
o If no further subjects (i.e., ≤1 of 6 subjects) have a DLT, Cohort B (DL+1) will open 
to enrollment (see #2, Cohort B). 
o If any additional subjects (i.e., >1 of 6 subjects) have a DLT, the study will be 
stopped. 
c) If >1 of the 3 subjects in Cohort A has a DLT, the study will be stopped. 
2. Cohort B: If Cohort A clears, Cohort B (DL +1) will open to enrollment; 3 subjects will be 
treated at DL +1: 
a) If 0 of 3 subjects in Cohort B has a DLT, Cohort C (DL+2) will open to enrollment (see 
#3, Cohort C). 
b) If 1 of the 3 subjects in Cohort B has a DLT, an additional 3 subjects will be enrolled at 
DL +1: 
o If no further subjects (i.e., ≤1 of 6 subjects) have a DLT, Cohort C (DL+2) will open 
to enrollment (see #3, Cohort C). 
o If any additional subjects (i.e., >1 of 6 subjects) have a DLT, the dose will be de-
escalated to DL (Cohort A): 


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 
If 6 subjects were evaluated at DL with ≤1 DLT, DL will be considered the 
RCD. 
 
If 3 subjects were evaluated at DL, the DL will be expanded to 6 subjects: 
• 
If ≤1 of the 6 subjects has a DLT, DL will be considered the RCD 
• 
If > 1 of the 6 subjects have a DLT, the study will be stopped. 
c) If >1 of the 3 subjects in Cohort B has a DLT, the dose will be de-escalated to DL 
(Cohort A) and evaluated as above. 
3. Cohort C: If Cohort B clears, Cohort C (DL +2) will open to enrollment; 3 subjects will be 
treated at DL +2: 
a) If ≤ 1 of the 3 subjects in Cohort C has a DLT, the dose will be expanded to 6 subjects: 
o If ≤1 of 6 subjects in Cohort C has a DLT, DL +2 will be considered the RCD. 
o If > 1 of 6 subjects in Cohort C have a DLT, the dose will de-escalate to DL +1 
(Cohort B): 
 
If 6 subjects were evaluated at DL +1 (Cohort B) with ≤1 DLT, DL +1 will be 
considered the RCD. 
 
If 3 subjects were evaluated at DL +1 (Cohort B), the DL will be expanded to 6 
subjects: 
• 
If ≤1 of the 6 subjects in Cohort B has a DLT, DL +1 will be considered the 
RCD 
• 
If > 1 of the 6 subjects in Cohort B have a DLT, the dose will be de-
escalated to DL (Cohort A): 
• 
If 6 subjects were evaluated at DL (Cohort A) with ≤1 DLT, DL will be 
considered the RCD> 
• 
If 3 subjects were evaluated at DL, the DL will be expanded to 6 
subjects: 
 If ≤1 of the 6 subjects has a DLT, DL will be considered the RCD 
 If > 1 of the 6 subjects have a DLT, the study will be stopped. 
b) If >1 of the 3 subjects in Cohort C has a DLT, the dose will be de-escalated to DL+1 
(Cohort B) and evaluated as above 
 
The RCD for each cohort is defined as the highest dose level at which no more than 1 of 6 
subjects (i.e., < 33%) experience DLTs. The RCD cannot be determined if none of the predefined 
dose levels fulfill that criterion.  
For Cohort A, ONCOS-102 (1 x 1011 VP) will be given as monotherapy the first six weeks, and then 
durvalumab (1500 mg) will be started on Day 71 (See Figure 3). See Cohort A Note in Section 3.1. 


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Figure 3. Treatment Schema for Cohort A Only 
 
For Cohorts B and C, ONCOS-102 will be administered for a total of 6 weeks while durvalumab 
will be given for a total of 12 four-week cycles, starting on Day 15 (See Figure 4). 
 
Figure 4. Treatment Schema for All Subjects except Cohort A 
 
See Section 3.1.2 for details regarding the waiting period between the first study drug 
administration for the first and second subjects of Cohorts A and B of the dose escalation phase.  
All subjects in the dose escalation phase will remain in the facility for observation for 8 to 12 
hours after each ONCOS-102 infusion. See Section 6.4.2 for additional details. 
Based on the safety data from the dose escalation phase, the internal data safety monitoring 
panel (as defined in Section 3.1.14) will decide if an observation period will be required for the 
expansion phase. The safety review for the dose escalation phase was conducted, and it was 


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agreed that the observation period would be shortened for the expansion phase. See note below 
for expansion phase requirements, per Amendment 5. 
Note: Per Amendment 5, all subjects in the expansion phase will remain in the facility for 
observation for a minimum of 6 hours after the first dose of ONCOS-102 infusion; for subsequent 
doses, the observation period will be a minimum of 4 hours, but it may be longer based on 
Investigator’s discretion. See Section 6.4.2 for additional details. 
3.1.7.2 Dose Expansion Phase 
The subjects will be assigned to a disease-specific cohort and will receive treatment at the RCD 
determined from the dose escalation phase. In Phase 2, there are 2 expansion cohorts with 
peritoneal disease: 
• 
Cohort 1: Platinum-resistant epithelial ovarian cancer  
• 
Cohort 2: Metastatic colorectal cancer 
See Section 3.1.2 for details of enrollment into the expansion phase according to the Simon’s 
2-Stage MINMAX Design. 
As above, ONCOS-102 will be administered for a total of 6 weeks, while durvalumab will be 
administered for a total of 12 cycles, starting on Day 15. See Section 6.4 for monitoring details 
before/during/after drug administration.   
3.1.8 Dosing Adjustments, Delays, and Discontinuations 
Dose adjustment and management guidelines for toxicity related to durvalumab and ONCOS-102 
are outlined in Section 8.3 and Section 8.4, respectively.  If a toxicity occurs that requires toxicity 
management in accordance with Sections 8.3. or 8.4, and the toxicity causing agent can be 
clearly identified, then the respective guideline should be followed. If the toxicity causing agent 
cannot be identified, then the more conservative guideline should be followed. 
3.1.9 DLT and MTD/RCD 
MTDs will not be determined.  Instead, RCDs will be determined in the context of the predefined 
dose levels used during the dose escalation phase per Section 3.1.7.1. 
For Cohort A, DLTs will be assessed for the period from Day 1 of the study up to and including the 
Week 9 (Cycle 3 Day 1) study assessments, defined as the DLT Evaluation Period.  
For Cohorts B and C, the DLT Evaluation Period will be the period from Day 1 of the study up to 
and including the Week 11, (Cycle 3, Day 15) pre-dose study assessments. The decisions for dose 
escalations, de-escalations and RCD, as described in Section 3.1.7.1 will primarily be based on the 
number of subjects with DLTs occurring during the DLT Evaluation Period.  DLTs occurring outside 
the DLT Evaluation Period will also be evaluated and may impact such decisions. 
DLTs are defined as any adverse events that are possibly, probably, or definitely related to the 
administration of durvalumab or ONCOS-102 and fulfill any of the following criteria: 
1. Any Grade ≥ 3 colitis, pneumonitis, neurological event or uveitis. 
2. Any Grade 2 pneumonitis, neurological event or uveitis, with the following exception: 


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• 
Grade 2 pneumonitis, neurological event or uveitis that downgrades to Grade ≤ 1 
within 3 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
3. Any other Grade ≥ 3 toxicity, with the following exceptions: 
• 
Grade 3 irAEs that downgrade to Grade ≤ 2 within 3 days, or to Grade ≤ 1 or baseline 
within 14 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade 3 endocrinopathy that becomes asymptomatic when managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy. 
• 
Grade 3 inflammatory reactions attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 
• 
Grade 3 fatigue for ≤ 7days. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
• 
Liver transaminase elevation ≤ 8 times ULN that downgrades to Grade ≤ 2 (≤ 5 times 
ULN) within 7 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) within 7 
days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade 3 neutropenia that (1) is not associated with fever or systemic infection, and 
(2) does not require medical intervention, and (3) improves to Grade 2 within 7 days. 
• 
Grade 3 and 4 lymphopenia. 
• 
Grade 3 thrombocytopenia that (1) is not associated with clinically significant 
bleeding, (2) does not require medical intervention, and (3) improves to Grade 2 
within 7 days. 
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention within 
3 days. 
• 
Any pre-existing laboratory abnormality that deteriorates to Grade 3/4, but where 
the increment of deterioration is considered not clinically significant by both 
investigator and sponsor. 
• 
Grade 3 or 4 asymptomatic increases in amylase or lipase levels for which 
appropriate evaluation shows no clinical evidence of pancreatitis. 
4. Any Grade 3 intra-abdominal infection  
5. Any intra-abdominal hemorrhage 
6. Any intestinal perforation or fistula formation 
Immune-related AEs (irAEs) are defined as AEs of immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology.   In the absence of clinical abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a DLT. 
While rules for adjudicating DLTs are specified above, other AEs that do not fulfill the DLT criteria 
above may nevertheless be classified as DLTs after consultation between Sponsor and 
Investigators, based on the emerging safety profiles of durvalumab and ONCOS-102, respectively 
and in combination. Likewise, subjects who become not evaluable for DLT because they 
discontinued or interrupted treatment due to toxicities other than DLTs may be counted as DLT 


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subjects, if the toxicities cannot be managed in accordance with the dosing modifications 
described in Section 3.1.8. 
Subjects who experience a DLT will be discontinued from study treatment and will enter the On 
Study Follow-up and Post Study Follow-up phases of the study (see Section 3.1.16).  However, if 
it is in the best interest of the subject, the Investigator and Sponsor may agree to continue 
treatment, possibly at a lower dose level (if applicable) or discontinue one or more of the study 
drugs. 
3.1.10 Subject Withdrawal from Treatment or from Study 
A subject will be withdrawn from study treatment for any of the following reasons: 
1. Withdrawal of consent for further treatment. 
2. Pregnancy or intent to become pregnant. 
3. Dose-limiting toxicity at any time (see Section 3.1.9). 
4. Progressive disease by RECIST 1.1 and irRECIST confirmed on subsequent imaging (see 
Treatment beyond Progression, Section 3.1.10.1). 
5. Significant protocol violation or noncompliance that, in the opinion of the Investigator or 
Sponsor, warrants withdrawal. 
6. Development of intercurrent, non-cancer related illnesses or complications that prevent 
either continuation of therapy or regular follow-up. 
7. Best medical interest of the subject (at the discretion of the Investigator) 
 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn 
from the study.  If applicable, subjects who are withdrawn from study treatment should undergo 
the planned On Study and Post Study Follow-up procedures according to Section 3.1.16 and the 
flowchart in Section 3.2. 
A subject will be withdrawn from the study for the following reasons: 
1. Best medical interest of the subject at the discretion of the Investigator 
2. Initiation of alternative anti-cancer therapy (marketed or investigational) 
3. Withdrawal of consent for all follow-up. 
4. Lost to follow-up. 
5. Death 
Subjects who begin other anti-cancer therapy should immediately be considered off study and 
proceed to the Post Study Follow-up. 
See also Sections 8.3 and 8.4 for subject withdrawal due to necessary dosing interruptions or 
discontinuations.   
Section 7.2.6 provides additional details regarding documentation for early subject withdrawal 
from study treatment and early withdrawal from study. 
3.1.10.1 Treatment beyond Progression 
Accumulating evidence suggests that some subjects treated with immunotherapeutics may 
develop apparent progression of disease (by conventional response criteria) before 
demonstrating objective responses and/or stable disease. Some subjects may experience rapid 
responses that are consistent with the classical definition of response observed after 


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chemotherapy as defined by RECIST 1.1 or WHO criteria; however, other subjects may 
experience non-classical responses. Some of these non-classical responses include the 
appearance of new lesions (or potentially growth of existing lesions), in some cases a few new 
lesions will grow while other lesions actually shrink, or prolonged stable disease.(54-56)  This 
phenomenon was observed in approximately 10% of subjects in the Phase 1 study of nivolumab, 
a humanized monoclonal antibody against PD-1, and has also been reported for ipilimumab 
monotherapy.(54)   
Subjects meeting criteria for progression by irRECIST (Section 8.5) will be allowed to continue on 
therapy until confirmation of progression by irRECIST if the subject agrees and signs an 
appropriate informed consent form regarding continuation of treatment and as long as the 
following criteria are met at the discretion of the Investigator: 
a) Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression; 
b) No significant decline in ECOG performance status; 
c) Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
See Section 8.5 for additional information regarding RECIST 1.1 and irRECIST.  
3.1.11 Subject Evaluability and Replacements 
In the dose escalation phase, subjects are fully evaluable for DLT if they fulfill the criteria for the 
Per-Protocol Population for DLT Assessment (as defined in Section 4.1.2). 
Subjects who are not fully evaluable for DLT per Section 4.1.2 will be replaced. 
In the expansion phase, subjects are fully evaluable for the primary endpoint of Clinical Benefit 
(percentage of subjects who are not in progression at end of Week 24) if they fulfill the criteria 
for the Per-Protocol Population for Clinical Efficacy (as defined in Section 4.2.2). 
Subjects who are not fully evaluable for Clinical Benefit at end of Week 24 may be replaced. 
3.1.12 Optional Study Treatment Extension 
Per Amendment 5, optional durvalumab treatment extension beyond the initial 12-cycle 
treatment period (Core Study) will be available for subjects who complete the Core Study with 
Stable Disease or better. The optional treatment extension will be permitted upon agreement 
with subject, Sponsor and Investigator, and it may continue until confirmed disease progression, 
unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion 
is met.  See Section 8.8 for details. 
3.1.13 Interim Analysis 
Interim analyses will be performed at the at the end of Simon Stage 1 for Cohorts 1 and 2 as 
described in Section 3.1.2. Safety analyses will be performed to assess DLTs in the dose escalation 
cohorts (see Section 3.1.7.1).  
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal, and Ethical Requirements section of the protocol 
(see Section 7), Safety Monitoring will be performed by an internal data safety monitoring panel, 


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consisting of the Principal Investigators (and co-investigators as needed), the Sponsor’s Medical 
Monitor/Clinical Advisor, and drug safety personnel from Medimmune (AstraZeneca)/ 
TARGOVAX, providers of the study drugs.  Additional investigators and staff, or additional 
Sponsor personnel and consultants, shall participate in reviews, if indicated.  The internal data 
safety-monitoring panel will communicate by phone and/or email on a regular basis, and in 
particular, to review the safety of individual cohorts for the purpose of dose escalation per 
Section 3.1.7.1. 
An Independent Data Monitoring Board will not be utilized for this open-label study. 
The study will be suspended or possibly stopped prematurely for any of the following reasons: 
1. A death that is unexpected and at least probably related to study drug. 
2. Severe anaphylactic reaction (i.e., with respiratory and cardiovascular failure) to any of 
the study drugs. 
3. Any events that, in the judgment of the Medical Monitor, are deemed serious enough to 
warrant immediate review by the internal data safety monitoring panel.  This may 
include any symptomatic and/or irreversible treatment-related Grade 4 pneumonitis, 
colitis, dermatitis, or hepatitis or any symptomatic treatment-related Grade ≥ 3 
neurological toxicity or uveitis.  
4. Any other safety finding assessed as related to 1 or more study drugs that, in the opinion 
of the internal data safety monitoring panel, contraindicates further dosing of study 
subjects. 
5. Any interim findings that, in the opinion of the Investigators and the Sponsor, suggest 
that the study treatment has no clinical benefit for the subjects. 
Study stopping rules may be applied to individual study cohorts, if the internal data safety 
monitoring panel concludes that the identified risk to one study cohort does not carry over to 
another.  
3.1.15 Duration of Study 
Duration of Treatment and  
On Study Follow-up: 
Up to 15 months 
See Section 3.1.12 for optional durvalumab treatment 
extension 
Enrollment Period: 
27 months 
Length of Study: 
42 months 
Post Study Follow-up 
3 years from initiation of treatment 
NOTE: Per Amendment 6.1, all post study follow-up for the 
collection of survival data will be discontinued as of 30 June 
2022 (see rationale in Section 8.1, Amendment 6.1). 
3.1.16 On Study and Post Study Follow-up 
All subjects, whether they complete the study as planned, discontinue study treatment 
prematurely, or prematurely withdraw from the study as per Section 3.1.10, will be followed as 
per institutional guidelines in accordance with the usual standard of care principles.   
Subjects who complete study treatment or discontinue treatment prematurely will enter an On 
Study Follow up period for 90 days after the last study drug administration (see Section 3.2). 
Refer to Section 7.1.5 for details on recording of AEs during the On Study Follow-up.   


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If the determination is made to remove a subject from treatment at a visit that coincides with 
the first visit of the On Study Follow-up (which is 28 days after the last dose of study treatment), 
any assessments required in the first On Study Follow-up visit that are not covered as part of the 
on-treatment visit (usually correlative labs) should be done as soon as possible.  If these 
assessments cannot be done on the same day, the subject should be brought back in at the 
earliest opportunity.  Any assessments or correlative samples required by both the last on-
treatment visit and the first On Study Follow-up visit should not be repeated. 
Following the On Study Follow-up, there will be a Post Study Follow-up, where clinical outcomes 
data (dates of progression/relapse and survival) will be collected at least every 6 months 
(± 1 month) for 3 years from initiation of treatment.   
The Post Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) during the 90 days since the last administration of study drug. 
For subjects who do not continue Post Study Follow-up at one of the study sites after the end of 
study, the Principal Investigators or the clinical team, under the supervision of the Principal 
Investigator, will obtain this data through review of outside records or communication with the 
subject or his/her physician. 
See Section 3.1.12 for optional durvalumab treatment extension. 
NOTE: Per Amendment 6.1, all post study follow-up for the collection of survival data will be 
discontinued as of 30 June 2022 (see rationale in Section 8.1, Amendment 6.1). 
3.1.16.1 End of Study Visit 
If a subject is withdrawn from study according to the criteria defined in Section 3.1.10, an End of 
Study visit must be conducted at the time of withdrawal. For subjects not yet in On Study Follow-
up, this End of Study visit will be the first planned visit of the On Study Follow-up. For subjects 
already in On Study Follow-up, this End of Study visit will be the next planned visit of the On 
Study Follow-up. However, any procedures/assessments that were done within 7 days of the End 
of Study visit need not be repeated. All subjects of childbearing potential who withdraw from 
study must have a serum pregnancy test done at the End of Study visit, unless it was done within 
7 days prior to the End of Study Visit. 
After the End of Study Visit, the subject will proceed into Post Study Follow-up as described 
above, unless otherwise unable to do so (e.g., subject withdraws consent for all follow-up). 
 
 


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3.2 Study Flowchart 
 
LUD2015-008 - Study Flowchart (part 1 of 2)
Screening / 
Baseline
Cycle 4
Cycle 6
Cycle week (4-week cycles)
1
2
3
4
1
2
3
1
3
3
1
3
3
Study Week 
1
2
3
4
5
6
7
9
11
15
17
19
23
Visit Day per Cycle
-28 to -1
-3 to -1
1
8±2 15±2 22±2
1±2
8±2 15±3
1±4 15±3
15±7
1±4 15±7
15±7
Target Cumulative Visit Day
1
8
15
22
29
36
43
57
71
99
113
127
155
Cyclophosphamide 300 mg IV
x
ONCOS-102 intraperitoneally
x
x
x
x
x
x
Durvalumab 1500 mg IV (Dose Escalation Cohort A 
only)
x
x
x
x
Durvalumab 1500 mg IV (Dose Escalation Cohorts 
B and C; and Expansion Cohorts)
x
x
x
x
x
x
Disease Assessment by RECIST 1.1/irRECIST (see 
Sections 4.2 and 8.5 for details on scans and 
confirmation)
x
x
x
Blood for CA-125 for ovarian or CEA for CRC (must 
be at same time points as disease assessments; 
test will be performed by local lab)h
x
x
x
Eligibility Assessment and Informed Consent (IC)d,K
x
Demographics (incl. DoB; sex; height; race; 
ethnicity)
x
Medical history
x
x
Physical Exam (incl. weight and ECOG Perf Status)
x
x
xi
x
x
x
x
x
x
x
x
x
x
x
x
12-Lead ECGa
x
x
x
Vital Signs (T, HR, BP, RR) - See Section 6.4 for 
monitoring before/during/after drug admin
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant Medication / Procedure  (name, 
indication, dose, route, start & end dates)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after IC)e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Hematology (CBC, differential, platelets)a
Day -7 to -1
xJ
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca, 
Mg, protein, alb, TBili, AST, ALT,  ALP, LDH)a
Day -7 to -1
xJ
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry Cont. (Free  T3, Free T4, TSH)a
X
xJ
x
x
x
x
x
x
Chemistry Cont. (amylase, lipase)a
Day -7 to -1
xJ
x
x
x
x
x
x
Urinalysisa
Day -7 to -1
xJ
x
x
x
x
x
x
x
x
x
x
x
x
Coagulation parameters (PT, aPTT, INR)a
Day -7 to -1
xJ
x
x
x
x
x
x
Serum pregnancy test  (urine only on Day 1)a
Day -7 to -1
xJ
x
x
Blood for PBMC Collection and Bankingf
x
x (*f)
x
x
x
x
Blood for viral particles (Collected only during 
dose escalation phase)
xb
xb
xb
xb
xb
xb
Blood for Th1/Th2/Th17 cytokines in serum
xb
xb
xb
xb
xb
xb
xa
xa
Archival tumorK
x
Tumor Biopsy  (FFPE and frozen) for tumor 
microenvironmentc,K
x
xa
Overall Survival
Progression Free Survivalg
Treatment
Study Drug Administration 
Tumor and Disease Assessments
Study Procedures and Examinations
Cycle 1
Cycle 2
Cycle 3
Cycle 5
Other Procedures
Post Study Follow-upL
Specimens for Routine Laboratory Procedures
Specimens for Biological Markers and Correlative Studies


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LUD2015-008 - Study Flowchart (part 2 of 2)
Cycle 8
Cycle 9
Cycle 10
Cycle 11
Cycle 12
Cycle week (4-week cycles)
1
3
3
3
3
3
3
Study Week 
25
27
31
35
39
43
47
Visit Day per Cycle
1±4 15±7
15±7
15±7
15±7
15±7
15±7
Target Cumulative Visit Day
169
183
211
239
267
295
323
Cyclophosphamide 300 mg IV
ONCOS-102 intraperitoneally
Durvalumab 1500 mg IV (Dose Escalation Cohort A 
only)
x
x
x
x
x
x
Durvalumab 1500 mg IV (Dose Escalation Cohorts 
B and C; and Expansion Cohorts)
x
x
x
x
x
x
Disease Assessment by RECIST 1.1/irRECIST (see 
Sections 4.2 and 8.5 for details on scans and 
confirmation)
x
x
x
Blood for CA-125 for ovarian or CEA for CRC (must 
be at same time points as disease assessments; 
test will be performed by local lab)h
x
x
x
Eligibility Assessment and Informed Consent (IC)d,K
Demographics (incl. DoB; sex; height; race; 
ethnicity)
Medical history
Physical Exam (incl. weight and ECOG Perf Status)
x
x
x
x
x
x
x
x
x
x
12-Lead ECGa
x
Vital Signs (T, HR, BP, RR) - See Section 6.4 for 
monitoring before/during/after drug admin
x
x
x
x
x
x
x
x
x
x
Concomitant Medication / Procedure  (name, 
indication, dose, route, start & end dates)
x
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after IC)e
x
x
x
x
x
x
x
x
x
x
Blood Hematology (CBC, differential, platelets)a
x
x
x
x
x
x
x
x
x
x
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca, 
Mg, protein, alb, TBili, AST, ALT,  ALP, LDH)a
x
x
x
x
x
x
x
x
x
x
Chemistry Cont. (Free  T3, Free T4, TSH)a
x
x
x
x
x
x
x
x
x
Chemistry Cont. (amylase, lipase)a
x
x
x
x
x
x
x
x
x
Urinalysisa
x
x
x
x
x
x
x
x
x
Coagulation parameters (PT, aPTT, INR)a
x
Serum pregnancy test  (urine only on Day 1)a
x
x
x
x
x
Blood for PBMC Collection and Bankingf
x
x
Blood for viral particles (Collected only during 
dose escalation phase)
Blood for Th1/Th2/Th17 cytokines in serum
xa
x
Archival tumorK
Tumor Biopsy  (FFPE and frozen) for tumor 
microenvironmentc,K
Overall Survival
xL
Progression Free Survivalg
xL
Treatment
Study Drug Administration 
Tumor and Disease Assessments
Study Procedures and Examinations
On Study Follow-up
Post Study 
Follow-upL
Every 6 months (± 
1 month)  for 3 
years from 
initiation of 
Last Study 
Drug Dose 
+28 (+3) days
Last Study 
Drug Dose 
+56 (+7) days
 Last Study 
Drug Dose 
+91 (+7) days  
End of  Study
Every 8 weeks (± 1 week) starting 8 
weeks (± 1 week) after last 
disease assessment
Cycle 7
Every 8 weeks (± 1 week) starting 8 
weeks (± 1 week) after last 
disease assessment
Other Procedures
Post Study Follow-upL
Specimens for Routine Laboratory Procedures
Specimens for Biological Markers and Correlative Studies


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Flowchart Footnotes 
c - core needle biopsy (one 14G core divided in 3 pieces or three 18G cores); 1 for FFPE, 2 snap-frozen and stored at -70 ±10°C. Biopsies will be taken from the 
       same lesion pre- and on-treatment.   Optional: FFPE pre- and on-treatment biopsy of extraperitoneal site
d - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
f - Six CPT tubes per time point (pre-dose)  -> PBMC isolation; used for banking PBMCs and plasma ( * Only one CPT tube is required on Day 1 -> PBMC 
     isolation for assessment of T regs)
i - The physical exam on Cycle1/Day1 does not need to be repeated if it was performed on Day -1, prior to the cyclophosphamide injection. 
J - The Cycle1/Day 1 lab assessments may be done on Day -1
K- Microsatellite instability (MSI)/MMR status should be available at baseline for all subjects (ovarian cancer and colorectal cancer(CRC)); KRAS and NRAS status should 
      be available for subjects with CRC. If these results are not available, the testing may be done on archival tissue or on tissue that is obtained pre-treatment.
L - Per Amendment 6.1, all post study follow-up for the collection of survival data will be discontinued as of 30 June 2022 (see Section 8.1, Amendment 6.1)
e - See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration
      chemistry (including amylase, lipase, and thyroid pre durvalumab) and pregnancy (when applicable). 
b - pre-ONCOS-102 dose, 4-6 hours after ONCOS-102 dose, and prior to discharge (Note: the cytokine collection prior to discharge is for dose escalation phase only).
g - For subjects who did not experience progression while on study
h - Collected together with routine lab assessment blood draw (pre-dose, if applicable)
a - pre-dose (if applicable). Note: It is strongly recommended that test results are reviewed before dosing for hematology, 


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4 Study Objectives and Endpoints 
Primary 
Objective 
[Endpoints] 
Dose Escalation Phase: 
Safety and Tolerability [DLTs, RCD according to CTCAE 4.03] 
Expansion Phase:   
Clinical Efficacy by RECIST 1.1 [Clinical Benefit (CB), defined as percentage of 
subjects who are not in progression at end of Week 24]. 
Secondary 
Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Safety and Tolerability [CTCAE 4.03] 
Clinical Efficacy by RECIST 1.1/irRECIST [Durable Clinical Benefit (DCB, defined as 
the percentage of subjects meeting criteria of SD, PR, or CR over a period of at 
least 24 weeks); ORR after 8 and 24 weeks; PFS; and OS] 
Exploratory 
Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Biologic Activity [Effects on immune biomarkers, Immune Response, 
mechanisms of therapeutic resistance]. This will include CD8+ T cells in biopsies. 
PBMCs will be analysed for the presence of tumour and virus antigen specific 
CD8+ T cells as well as different immune cell subpopulations, such as T 
regulatory cells and effector cells.   
DLT=Dose-limiting Toxicity; RCD=Recommended Combination Dose; ORR=Objective Response Rate; DCB=Durable 
Clinical Benefit; PFS=Progression-free Survival; OS=Overall Survival; CTCAE=National Cancer Institute Common 
Terminology Criteria for Adverse Events; RECIST= Response Evaluation Criteria in Solid Tumors; irRECIST=immune-
related RECIST 
4.1 Safety and Tolerability 
Assessment of safety and tolerability will be performed by the internal data safety monitoring 
panel on an ongoing basis, based on data review and regular conference calls with the 
Investigators.  The safety and tolerability of each regimen will be evaluated using DLT criteria 
(Section 3.1.9).  
4.1.1 Endpoints and Assessment Methods 
Clinical laboratory tests, vital sign and weight measurements, physical exams, performance 
status evaluation, imaging scans and any other medically indicated assessments, including 
subject interviews, will be performed to detect new abnormalities and deteriorations of any pre-
existing conditions.  The investigator will evaluate any laboratory abnormalities for clinical 
significance, and clinically significant abnormalities will be recorded as adverse events.  All 
clinically significant abnormalities and deteriorations from time of signing the informed consent 
to the end of study visit will be recorded in the Case Report Forms as adverse events and graded 
according to the CTCAE Version 4.03.  See further adverse event documentation and reporting 
requirements in Section 7.1. 
For the dose escalation phase, DLTs and RCDs will be assessed as per Sections 3.1.9 and 3.1.7.1, 
respectively.  


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4.1.2 Subject Evaluation and Statistics 
The Per-Protocol (PP) Population for DLT Assessment includes: 
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9) 
• 
All subjects with no DLT who receive at least 60% of the scheduled doses of ONCOS-102 
and at least 1 dose of durvalumab (Cohorts B and C only) as well as respective safety 
assessments without major protocol violations during the DLT Evaluation Period (as 
defined in Section 3.1.9)  
 
Refer to Section 3.1.11 for subject replacement. 
The Safety Population is defined as all subjects who receive at least one dose of durvalumab or 
ONCOS-102. 
In the dose escalation phase, for the primary endpoint of determining DLTs and the RCD, the 
analysis of safety and tolerability will be based on the PP Population for DLT Assessment. 
In both phases (dose escalation and expansion), the overall analysis of safety and tolerability will 
be based on the Safety Population. 
Appropriate summaries of AEs, SAEs, laboratory data and vital sign data will be presented for 
the Safety Population overall and by cohort.  Adverse events will be coded using the MedDRA 
dictionary.  Incidences of treatment-emergent adverse events (TEAE, those events that started 
after dosing or worsened in severity after dosing) will be presented overall and by maximum 
severity and relationship to study medication. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Frequencies and percentages will be presented for the 
shifts in these categories (i.e., low to normal, low to high, high to low, etc.) from baseline to 
each post-treatment assessment time point. Additionally, for each continuous hematology and 
chemistry parameter, descriptive statistics will be presented for the changes from baseline to 
each post-treatment assessment time point.   Descriptive statistics will be presented for the 
changes in vital signs from baseline to each post-treatment assessment time point. 
4.2 Clinical Efficacy 
4.2.1 Endpoints and Assessment Methods 
Clinical efficacy will be assessed by RESIST 1.1 and irRECIST (see Section 8.5), measuring CB at 
end of Week 24, DCB over a period of at least 24 weeks, ORR after 8 and 24 weeks (based on 
disease assessments at the scheduled Weeks 9 and 25 visits), PFS, and OS. Tumor response will 
be assessed by measurement of tumor markers as applicable to each tumor type and by CT/MRI 
using RECIST 1.1 and irRECIST criteria approximately every 8 weeks (see flowchart in Section 
3.2). Every attempt should be made to use whichever imaging technique(s) and test(s) are used 
initially for repeat evaluations throughout the study, whereby the first post treatment tumor 
assessments (during On Study Follow-up) will be at least 4 weeks from the prior assessment. 


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4.2.1.1 Clinical Benefit (CB) 
Clinical Benefit is defined as percentage of subjects who are in the study and not in progression 
at end of Week 24. 
4.2.1.2 Objective Response Rate (ORR) 
ORR is defined as the percentage of subjects meeting criteria of Complete Response (CR) or 
Partial Response (PR) over a period of at least 4 weeks. 
4.2.1.3 Durable Clinical Benefit (DCB) 
DCB is defined as the percentage of subjects meeting criteria of Stable Disease (SD), partial 
response (PR), or complete response (CR) over a period of at least 24 weeks. 
4.2.1.4 Progression-free Survival (PFS) 
PFS is defined as the interval between the date of first dose to the date of earliest determination 
of Progressive Disease (PD), or to the date of death, if PD does not occur.  Subjects without 
documentation of progression at the time of the analysis will be censored at the date of last 
response assessment. Subjects with no tumor response assessment will be censored at the start 
date of the treatment. 
4.2.1.5 Overall Survival (OS) 
OS is defined as the interval between the date of first dose until the date of death or the date of 
last follow-up.  Subjects who are still alive will be censored on the date of last follow-up.  Every 
effort will be made to follow subjects for OS after they discontinue study treatment or complete 
the On Study Follow-up according to Section 3.1.16. 
NOTE: Per Amendment 6.1, all post study follow-up for the collection of survival data will be 
discontinued as of 30 June 2022 (see rationale in Section 8.1, Amendment 6.1). 
4.2.2 Subject Evaluation and Statistics 
The Intent-To-Treat (ITT) Population for Clinical Efficacy is defined as all subjects who receive at 
least one dose of durvalumab or ONCOS-102.  
The Per-Protocol (PP) Population for Clinical Efficacy of the combination therapy is defined as 
all subjects who receive at least 60% of the scheduled doses of ONCOS-102 and at least 1 dose 
of durvalumab (Cohorts B and C only) over the first 2 cycles, as well as respective disease 
assessments, without major protocol violations.   
The analysis will be based on both ITT and PP populations. Each of the 2 cohorts in the 
expansion phase will be analyzed separately. 
Tumor Response will be summarized and analyzed descriptively for each cohort and analysis 
population.   
A 95% CI based on binomial distribution will be constructed for the estimated CB, ORR, and DCB.  
The primary endpoint analyses of CB will be conducted as follows (please refer to Section 3.1.6 
for sample size rationale): 


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Cohort 1:  The null hypothesis of CB = 20% will be tested against a one-sided alternative of CB = 
40% at 0.05 level of significance based on Simon 2-stage Minimax criterion. The null hypothesis 
will be rejected if 11 or more subjects experience clinical benefit at end of Week 24. 
Cohort 2:  The null hypothesis of CB = 5% will be tested against a one-sided alternative of CB = 
20% at 0.05 level of significance based on Simon 2-stage Minimax criterion. The null hypothesis 
will be rejected if 4 or more subjects experience clinical benefit at end of Week 24.   
The number and percentage of subjects who died or had a confirmed progression, who survived 
without a confirmed progression, and who were lost to follow up (unknown survival and/or 
progression status) will be summarized.   
PFS and OS will be summarized using the 25th percentile, Median, and 75th percentile as well as 
the minimum and maximum survival time, calculated by Kaplan-Meier method, and will be 
displayed graphically. 
4.3 Biological Activity 
4.3.1 Endpoints and Assessment Methods 
Specimens for immune monitoring assays will be collected according to the flowchart in Section 
3.2. The Specimen requirements are summarized in Table 2, and full details are provided in the 
Laboratory Manual. 
Table 2. Biomarker specimen requirements 
Specimen 
FFPE Archival primary or metastatic tumor 
1st Choice: block 
2nd Choice: 35 unstained slides  
FFPE and frozen Pre-treatment biopsy  
Optional: FFPE Pre-treatment biopsy of extraperitoneal site  
FFPE and frozen On-treatment biopsy  
Optional: FFPE on-treatment biopsy of extraperitoneal site 
Pre-treatment and on treatment PBMC 
six CPT tubes per time point (pre-dose)   
Note: only one CPT tube is required on Day 1 -> PBMC isolation for assessment of T regs) 
Pre-treatment and on treatment plasma (from PBMC collection tubes) 
Blood for cytokines in serum 
Whole blood for viral particles 
Blood for CA-125 for ovarian or CEA for CRC (must be collected at same time points as disease 
assessments; test will be performed by local lab) 
 


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4.3.1.1 Viral assessment  
Viral assessments in whole blood will be done during the dose escalation phase of the study.  
Whole blood for viral particles will be collected according to the flowchart in Section 3.2. The 
samples will be tested for the presence of viral particles by quantitative PCR. 
4.3.1.2 Assessment of dynamic changes in tumor microenvironment 
Pre-treatment and on-treatment tumor biopsy tissue will be processed for RNA isolation and 
evaluated for gene expression using Nanostring nCounter PanCancer Immune Profiling Panel, 
which consists of 770 genes related to angiogenesis, inflammation, and innate and adaptive 
immune response.  Among these, the expression of the known activating co-stimulatory 
receptors such as 4-1BB (CD137), OX40, GITR, CD40, and ICOS, as well as known immune 
inhibitory proteins such as PD-L1, indoleamine dioxygenase (IDO), B7-H3, B7-H4, LAG3, TIM-3, 
PD-1, CTLA-4, VISTA, and BTLA will be assessed. The platform will in addition assess for the 
expression of around 30 know cancer-testis antigens, which will provide a potential marker for 
monitoring of peripheral serologic and cellular immune responses.  Transcriptional findings will 
be validated by immunohistochemistry/ immunofluorescence for expression of PD-L1 as a 
predictive biomarker and presence of various infiltrating immune cell subsets, including CD8 
cells, CD4+ effector cells (FoxP3-), CD4+ regulatory T cells (FoxP3+), and myeloid cells. Depending 
on tissue availability, tumors will be assessed for expression of immune inhibitory receptors and 
proteins (such as indoleamine dioxygenase (IDO), B7-H3, B7-H4, LAG3, TIM3, PD-1, CTLA-4, 
VISTA, and BTLA), and immune-activating receptors (such as 4-1BB (CD137), OX40, GITR, CD40, 
and ICOS). DNA extracted from tumors will be sent for deep sequencing of T cell receptor V beta 
chain to determine repertoire composition.  
Biomarker 
Approach 
Parameters* 
Immune cell subsets 
Nanostring +/- IHC** 
CD3, CD4, CD8, CD56, CD68, 
CD14, CD33, CD19, CD11c, 
CD103, CD163 
Targetable immune 
activating genes 
Nanostring +/- IHC** 
4-1BB, OX40, GITR, CD40, and 
ICOS 
Targetable immune 
inhibitory genes 
Nanostring +/- IHC** 
PD-L1, IDO, B7-H3, B7-H4, LAG3, 
TIM-3, PD-1, CTLA-4, VISTA, and 
BTLA 
Cancer-testis antigens 
Nanostring +/- IHC** 
e.g. NY-ESO-1, MAGE A4, etc.  
T cell receptor 
repertoire 
DNA deep sequencing 
T cell density, TCR clonality, 
clonal overlap. 
*Additional parameters will be added from the panel, depending on the results from the initial 
subjects 
**Validation by IHC will depend on tissue availability 
4.3.1.3 Exploration of peripheral blood biomarkers  
Pre-treatment and on-treatment samples will be analyzed by Nanostring platform and by flow 
cytometry to study the effects of treatment on various peripheral blood immune cell subsets. 
PBMC isolated from whole blood will be processed for multicolor flow cytometry analyses 
looking at different cell subsets such as CD4+, CD8+, NK, NKT, and regulatory T cells 
(CD25+FoxP3+), markers of T cell activation (CD25, CD62L, HLA-DR, CD150, ki67, granzyme B, 


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ICOS, CD137, OX40, GITR), inhibition/exhaustion (PD-1, LAG3, TIM3, CD160), and percentages of 
myeloid-derived suppressor cells (MDSCs) (HLA-DR, CD33, CD14, CD15, CD3, CD19, CD56, CD16). 
DNA extracted from PBMC would be sent for deep sequencing of T cell receptor V beta chain to 
determine repertoire composition. Serum cytokines and chemokines will be measured to 
evaluate for evidence of Th1/Th2/Th17 or other type of immune response.  
Biomarker 
Approach 
Parameters 
Transcriptional profile 
Nanostring 
Markers related to immune 
activation and inhibition, as 
discussed in text 
T cell activation 
Flow cytometry 
CD25, CD62L, HLA-DR, CD150, 
ki67, granzyme B, ICOS, CD137, 
OX40, GITR 
T cell exhaustion 
Flow cytometry 
PD-1, LAG3, TIM3, CD160 
MDSC 
Flow cytometry 
HLA-DR, CD33, CD14, CD15, CD3, 
CD19, CD56, CD16 
T cell receptor 
repertoire 
DNA deep sequencing 
T cell density, TCR clonality, 
clonal overlap. 
Cytokines/chemokines Serum multiplex ELISA 
Inflammatory 
cytokine/chemokine panel 
Adenovirus-specific 
immune responses 
Intracellular cytokine 
staining 
Production of IFNg and TNFa by 
antigen-stimulated PBMCs 
Adenovirus-
neutralizing 
antibodies 
Serum multiplex ELISA 
Neutralizing antibodies to 
ONCOS-102 
 
4.3.1.4 Exploration of genetic predictors of response 
To determine whether specific tumor genetic determinants influence the response to 
treatment, DNA isolated from pre-treatment or archived tumor samples will be processed for 
whole exome analysis to assess for specific driver mutations and for potential neoantigens using 
appropriate bioinformatics algorithms developed at Memorial Sloan-Kettering Cancer Center.  
Biomarker 
Approach 
Parameters 
Genetic drivers 
Whole exome sequencing 
Presence of 
mutations/alterations in a panel 
of known oncogenes/tumor 
suppressors 
Neoantigen signature 
Whole exome sequencing 
Presence of immunogenic 
epitopes based on prediction 
algorithms 
 
4.3.1.5 Assessment of cellular neoantigen responses 
Pre-treatment and on-treatment PBMCs will be collected according to the time points in Section 
3.2. Overlapping pools of peptides synthesized based on the predicted neoepitopes will be used 


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to stimulate the PBMCs and antigen-specific responses will be assessed by intracellular cytokine 
staining. 
4.3.1.6 Assessment of responses to CT antigens 
Expression of CT antigens will be evaluated by the Nanostring nCounter PanCancer Immune 
Profiling Panel and validated by IHC for the specific proteins. Serologic responses to the 
particular CT antigens will be assessed by ELISA before and after therapy. CD4 and CD8 antigen-
specific responses will be assessed by intracellular cytokine staining.  
 
Biomarker 
Approach 
Parameters 
Serology 
ELISA 
Reactivity to known cancer-testis 
antigens 
T cell responses 
Intracellular cytokine 
staining 
Production of IFNg and TNFa by 
antigen-stimulated PBMCs 
 
4.3.2 Subject Evaluation and Statistics 
Only subjects who receive at least 1 dose of durvalumab and ONCOS-102 and provide the 
baseline and at least 1 post-treatment sample (if applicable) will be evaluated.  As these 
analyses represent exploratory evaluations of potential biomarkers of response or resistance to 
therapy, descriptive statistics will be used to describe findings and potential relationships to 
outcomes to therapy. 


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5 Subject Eligibility 
5.1 Inclusion Criteria 
Note: Standard of Care procedures may be used for eligibility assessments provided they meet 
the criteria specified in either the inclusion criteria or flowchart. 
Eligible subjects must fulfill all of the following criteria: 
1. 
Subjects with peritoneal disease who have histologic confirmation of epithelial ovarian 
cancer or metastatic colorectal cancer (CRC) willill be enrolled. Note: the CRC cohort may 
include subjects with cancer originating from the appendix.  
Subjects should have failed prior treatment for advanced cancer and deemed by the 
Investigator to no longer be eligible for or have reasonable standard of care 
alternatives, which are felt to have a clinically meaningful impact on their survival. 
Subjects with ovarian cancer must have either received one line of platinum based 
therapy and have progressed within 6 months (defined as platinum resistant) or have 
received 2 or more lines of standard therapy. 
Subjects with CRC must have failed prior therapy containing fluropyrimidine, 
oxaliplatin and irinotecan, with or without anti-VEGF component, or for RAS wild-
type, with or without anti-EGFR therapy. 
Co-existing distant metastases and parenchymal organ metastases will be allowed. 
Subjects may have received prior intraperitoneal therapy. 
2. 
Measurable disease according to RECIST 1.1, defined as ≥ 1 lesion that can be 
accurately measured in at least 1 dimension (longest diameter to be recorded for non-
lymph node lesions, shortest diameter to be recorded for lymph node lesions).  Each 
lesion must be ≥ 10 mm when measured by CT or MRI. See Section 8.5. 
3. 
Availability of microsatellite instability (MSI)/MMR status for all subjects (OC and CRC) 
Availability of KRAS and NRAS status for subjects with CRC. NOTE: if these results are 
not available, the testing may be done on archival tissue or on tissue that is obtained 
pre-treatment. 
4. 
The subject is willing to undergo a core needle biopsy during screening and during Cycle 
2, Study Week 5.  
Archival tumor samples are requested but are not required for eligibility.  
5. 
Laboratory parameters for vital functions should be in the normal range, unless not 
clinically significant.  Laboratory abnormalities that are not clinically significant are 
generally permitted, except for the following laboratory parameters, which must be 
within the ranges specified, regardless of clinical significance: 
Hemoglobin 
≥ 9 g/dL  
Neutrophil count 
> 1500/mm3  
Platelet count 
≥ 100 x 109 /L (100,000/mm3) 
Serum creatinine or 
Creatinine Clearance 
≤ 1.5 x Institutional Upper Limit of Normal (ULN), or 
>40 mL/min (by Cockcroft-Gault formula) or by 24-
hour urine collection for determination of creatinine 
clearance 


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Serum bilirubin 
≤ 1.5 x ULN (except for subjects with Gilbert’s 
syndrome who will be allowed after consultation 
with their physician) 
AST/ALT 
≤ 2.5 x ULN  
Alkaline phosphatase 
≤ 2.5 x ULN 
6. 
ECOG PS ≤ 1. 
7. 
Age ≥ 18 years. 
8. 
Able and willing to provide valid written informed consent and to comply with the 
protocol. Agrees to return to the study site for study visits and examinations. 
9. 
Body weight > 30 kg 
5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Treatment with an investigational agent within 4 weeks of starting study treatment, and 
any prior drug-related toxicity (except alopecia) should have recovered to Grade 1 or 
less. 
2. 
Prior treatment with checkpoint inhibitor, including durvalumab. 
3. 
The subject has known active central nervous system metastasis, glioma and nervous 
system malignancies including carcinomatous meningitis.  Subjects with asymptomatic 
brain metastases or spinal cord compression who have been treated, are considered 
stable, and who have not received corticosteroids or anticonvulsants for at least 28 
days prior to screening may be included. 
4. 
Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local 
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, 
or human immunodeficiency virus (positive HIV 1/2 antibodies).  Subjects with a past or 
resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] 
and absence of HBsAg) are eligible.  Subjects positive for hepatitis C (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA. 
Subjects with treated hepatitis virus infections (Hepatitis B or Hepatitis C) are eligible if 
they have been definitively treated for 6 months, have no detectable viral load on 
quantitative PCR, and LFTs meet eligibility requirements. 
5. 
Subjects who are immunosuppressed, including those with known immunodeficiency.  
6. 
Uncontrolled inter-current illness including, but not limited to, ongoing or active 
infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial or other current 
severe lung disease, or psychiatric illness/social situations that would limit compliance 
with study requirement or compromise the ability of the subject to give written 
informed consent. 
7. 
History of small or large bowel obstruction within 3 months of registration, including 
subjects with palliative gastric drainage catheters. Subjects with palliative diverting 
ileostomy or colostomy are allowed if they have been symptom-free for more than 3 
months. 


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8. 
Ongoing bowel perforation or presence of bowel fistula or abscess within 3 months of 
registration. 
9. 
Subjects with rapidly progressing or advanced disease with life expectancy <3 months. 
10. 
Subjects with clinically significant cardiovascular disease, including: 
a. New York Heart Association (NYHA) Class II or higher congestive heart failure. 
b. Myocardial infarction, unstable angina, cerebrovascular accident or transient 
ischemic attack within 6 months of Day 1. 
c. Clinically significant supraventricular or ventricular arrhythmia. 
d. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fredericia’s Correction. 
e. Clinically uncontrolled hypertension. 
11. 
Any prior Grade ≥ 3 immune-related adverse event (irAE) or hypersensitivity reaction to 
monoclonal antibodies, other therapeutic proteins, or immunotherapy and the reaction 
could not be controlled or prevented on subsequent infusion with standard therapies 
such as antihistamines, 5-HT3 antagonists, or corticosteroids. 
12. 
Any unresolved irAE > Grade 1 at the time of screening. 
13. 
The subject has a history of organ transplant or allogeneic bone marrow transplant. 
14. 
Active known autoimmune disease or history of autoimmune disease that might recur.  
These include but are not limited to subjects with a history of immune related 
pneumonitis, neurologic disease, multiple sclerosis, autoimmune (demyelinating) 
neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease 
such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease, 
Crohn’s, ulcerative colitis, hepatitis; and subjects with a history of toxic epidermal 
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome. Subjects with 
vitiligo, alopecia (caused by autoimmune disease), Graves disease, or psoriasis not 
requiring systemic treatment (within the past 3 years) are allowed. 
15. 
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of investigational products or still recovering from prior surgery. 
16. 
Concurrent enrollment in another investigational study, with the exception of follow-up 
period. 
17. 
History of severe allergic reactions to any unknown allergens or components of the 
study drugs (see specific exclusions for ONCOS-102 below). 
18. 
Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders). 
19. 
Active or prior malignancy except for history of other prior malignancy treated with 
curative intent which, in the opinion of the treating investigator and the 
Sponsor, has minimal risk of interfering with safety or efficacy endpoints of the 
study.  
20. 
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of investigational product with the exceptions of topical or systemic 
corticosteroids at physiological doses that are not to exceed 10 mg/day of prednisone 
or equivalent.  See Section 5.3.2 for permitted steroids. 
21. 
Any condition that, in the clinical judgment of the treating physician, is likely to 
interfere with the interpretability of the data or prevent the subject from complying 
with any aspect of the protocol or that may put the subject at unacceptable risk. 


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22. 
Subjects with refractory ascites, for example, ascites needing drainage catheter or 
therapeutic paracentesis more often than every 4 weeks.  
23. 
Subjects must not donate blood while on study and for at least 90 days following the 
last durvalumab treatment. 
24. 
Women of childbearing potential who are found to be pregnant as evidenced by 
positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
or nursing. 
25. 
For ONCOS-102, there is a requirement for the use of barrier contraception (condom) 
for each treated subject (and/or partner), regardless of their sex or fertility, during 
treatment and for 2 months after the last dose of ONCOS-102. This can be combined 
with other contraceptive methods.  
Requirements for durvalumab to prevent pregnancy are as follows; however, during 
ONCOS-102 treatment and for 2 months after the last dose of ONCOS-102, the 
ONCOS-102 requirement stated above would also apply: 
 
Female subjects of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least one highly effective method of contraception (see table 
below) from the time of screening and must agree to continue using such precautions 
for 90 days after the final dose of investigational products. Non-sterilized male partners 
of a female subject must use male condoms plus spermicide throughout this period. 
Cessation of birth control after this point should be discussed with a responsible 
physician. Not engaging in sexual activity for the total duration of the trial and the drug 
washout period is an acceptable practice; however, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 
Female subjects should also refrain from breastfeeding throughout the period 
described above. 
Females of childbearing potential are defined as those who are not surgically sterile 
(i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal. 
Females will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause.  The following age-specific requirements 
apply:  
• 
Females <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• 
Females ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy.  
 
Non-sterilized male subjects who are sexually active with a female partner of 
childbearing potential must use male condoms plus spermicide from screening through 


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90 days after receipt of the final dose of investigational products.  Female partners (of 
childbearing potential) of a male subject must use a highly effective method of 
contraception (see table below) throughout this period. Cessation of birth control after 
this point should be discussed with a responsible physician. Not engaging in sexual 
activity for the total duration of the trial and the drug washout period is an acceptable 
practice; however, periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception. 
Male subjects should refrain from sperm donation throughout the period described 
above. 
Highly effective methods of contraception are described in the table below. A highly 
effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Note that some 
contraception methods are not considered highly effective (e.g. male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action 
[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). 
Acceptable highly effective methods of contraception are described in the following 
table: 
Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)b 
• 
Implants”: Etonogestrel-releasing 
implants: e.g., Implanon® or Norplan®  
• 
“Intravaginal Devices”: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g., NuvaRing®   
• 
“Injection”: Medroxyprogesterone 
injection: e.g., Depo-Provera® 
• 
“Combined Pill”: Normal and low dose 
combined oral contraceptive pill 
• 
“Patch”: Norelgestromin / 
ethinylestradiol-releasing transdermal 
system: e.g., Ortho Evra®    
• 
“Minipillc”: Progesterone based oral 
contraceptive pill using desogestrel: 
e.g., Cerazette® 
a - Highly effective (i.e. failure rate of <1% per year)  
b - This is also considered a hormonal method 
c - Cerazette® is currently the only highly effective progesterone based pill 
 
 


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5.3 Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study: 
1. 
Systemic treatment with high-dose glucocorticosteroids or other immunosuppressive 
treatments (e.g., methotrexate, chloroquine, azathioprine).  See Section 5.3.2 for 
exceptions.  Wash-out period: 2 weeks prior to Day 1. 
2. 
Other cancer therapy (e.g., drug, non-palliative radiation, or immunotherapy). 
Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day 1 (6 weeks 
for nitrosoureas, 7 days for crizotinib).  
3. 
Live/attenuated vaccines 1 month prior to Day 1 and for at least 6 months after the last 
dose of treatment.  
The wash-out period prior to Day 1 of the study for all non-permitted drugs should be at least 
1 week, unless stated otherwise above. 
5.3.2 Permitted Concomitant Therapies 
Subject may receive the following concomitant therapies during the study: 
1. 
Inhaled or oral steroids for treating mild to moderate asthma or allergies, or topical 
steroids for localized (< 5% of body surface area) dermatitis, not to exceed 10 mg/day 
prednisone or bioequivalent corticosteroid. 
2. 
Physiologic replacement of glucocorticoids as maintenance therapy for adrenal 
insufficiency.  Standard doses of hydrocortisone for maintenance therapy are up to 10–
20 mg/m2/day divided 2–4 times per day.  For a subject with a body surface area (BSA) 
of 1.73 m2, this translates to a total dose of up to 34.6 mg of hydrocortisone per day. 
The equivalent dose of dexamethasone is up to 1.2 mg per day.  Some subjects may 
additionally receive mineralocorticoid-replacement maintenance therapy with 
fludrocortisone.  The maintenance dose of fludrocortisone for this indication is 0.05–0.1 
mg/day. 
3. 
Paracetamol, NSAIDs, acetylsalicylic acid, and specific COX-2 inhibitors. Subjects are 
likely to develop fever. This is normal and part of the desired innate immunological 
reaction after viral therapy and can be treated with paracetamol or ibuprofen. Subjects 
should however not be premedicated with antipyretics before treatment as this may 
impact immune activation. 
4. 
Antihistamines and other non-steroidal anti-allergy medication. 
5. 
At the discretion of the investigator, any drug or non-drug therapy necessary to treat 
any condition arising during the study, including high-dose corticosteroids to treat 
immune-mediated adverse reactions.  Subjects should receive full supportive care, 
including transfusions of blood and blood products, and treatment with antibiotics, 
anti-emetics, anti-diarrheal, and analgesics, and other care as deemed appropriate, and 
in accordance with their institutional guidelines.  Use of anticoagulants such as warfarin 
is permitted; however, caution should be exercised and additional international 
normalized ratio (INR) monitoring is recommended. 


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6. 
Palliative locoregional therapy (e.g. radiation, ablation, resection) to the isolated sites 
of progressive disease, if the subject continues to derive benefit from the therapy at 
other sites.   
All prescription and nonprescription drugs must be recorded in the concomitant medications 
section of the case report form, listing generic (preferably) or brand name, indication, dose, 
route, and dates of administration.  All non-drug therapies must be recorded in the respective 
sections of the case report form. 


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6 Study Drug Preparation and Administration 
TARGOVAX will provide ONCOS-102 directly to the sites. MedImmune will supply the 
durvalumab, which will be provided to the site by the Sponsor.  Commercially available water 
for injection (WFI) and 0.9% (w/v) saline or dextrose will be supplied by each site.  
When durvalumab and ONCOS-102 are administered on the same day, durvalumab is 
administered first, and there should be at least 1 hour between the end of infusion of the 
durvalumab and the start of the infusion of ONCOS-102. See Section6.4.1 for observation period 
following administration of durvalumab. See Section 6.4.2 for observation period following 
administration of ONCOS-102. 
6.1 Durvalumab (MEDI4736) 
6.1.1 Durvalumab Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented in the QA Disposition 
of Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: 
Single use vial  
Material: 
glass 
Size: 
10 mL 
Formulation 
Liquid Solution containing 500 mg per vial of durvalumab. This 
solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% 
(weight/volume [w/v]) polysorbate 80, at pH 6.0. 
Active Ingredient Content 
Mass/Weight: 
500 mg 
Volume: 
10 mL 
Concentration: 
50 mg/mL 
Storage Conditions 
+2°C to +8°C (36°F to 46°F) Do not freeze 
Labeling 
Product name, lot number, route of administration, and 
storage conditions 
6.1.2 Durvalumab Investigational Product Inspection 
Each vial of durvalumab selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.1.3 Durvalumab Preparation  
Preparation of durvalumab and preparation of the intravenous bag are to be performed 
aseptically by the IP manager or designated personnel. No incompatibilities between 
durvalumab and polyvinylchloride or polyolefin copolymers have been observed. 
Dose Calculation: 
Subjects will receive a fixed dose of durvalumab: 1500 mg Q4W for subjects > 30 kg.   
NOTE: if a subject’s body weight drops to ≤ 30 kg while on the study, the subject will receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab as long as the body weight remains 
≤ 30 kg (e.g., a 30 kg subject would receive a 600 mg dose; a 25 kg subject would receive a 500 


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mg dose; etc.).  When the weight improves to >30 kg, the subject may return to fixed dosing of 
durvalumab 1500 mg. 
The volume of durvalumab (in mL) to add to the IV bag is calculated as follows: 
Volume of 
Durvalumab 
(mL) 
= 
Dose level (mg) 
 
÷ 
Durvalumab 
Concentration 
(nominal 50 mg/mL) 
 
Dose Preparation: 
Durvalumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, and delivered through an IV administration set with a 0.2 or 0.22 µm in-line filter. A 
volume of diluent equal to the calculated volume of durvalumab to be added to the IV bag must 
be removed from the bag prior to addition of durvalumab. The calculated volume of durvalumab 
is then added to the IV bag, and the bag is mixed by gentle inversion to ensure homogeneity of 
the dose in the bag. 
Example: For a 1500 mg dose (for subjects > 30 kg in weight), 30.0 mL of durvalumab is to be 
diluted in a 250 mL IV bag. First, 30.0 mL of diluent is removed from the IV bag, and then  30.0 
mL  of durvalumab is added to the bag. The bag is mixed by gentle inversion to ensure 
homogeneity of the dose in the bag.  
Durvalumab does not contain preservatives; any unused portion must be discarded 
6.1.4 Durvalumab Administration 
Following preparation of the dose, durvalumab will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product(s). Fully functional 
resuscitation facilities should be available. 
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
• 
Durvalumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line. 
• 
Durvalumab must not be administered via IV push or bolus, but as an IV infusion. 
• 
Durvalumab solution should not be infused with other solutions or medications. 
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 (± 5) minutes using a 0.2- or 0.22-um in-line-filter. An infusion of less 
than 55 minutes is considered a deviation.   
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed.  
• 
The total time between needle puncture of the durvalumab vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 


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8°C (36°F to 46°F). Standard infusion time is 60 ± 5 minutes.  However, if there are 
interruptions during infusion, the total allowed infusion time should not exceed 8 
hours.  In the event that either preparation time or infusion time exceeds the time 
limits, a new dose must be prepared from new vials. 
• 
See Section 8.3.1 for guidelines for infusion-related reactions. 
• 
The date, start time, interruption, and completion time of durvalumab administration 
must be recorded in the source documents.  
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.4.1.  
• 
Durvalumab does not contain preservatives, and any unused portion must be discarded.  
6.2 ONCOS-102 
6.2.1 ONCOS-102 Study Drug Information 
Manufacturer 
Targovax Oy, Finland 
Expiration/Retest Date 
Expiration/retest dates are documented on the Certificate of 
Analysis and/or stability certification. 
Container Description 
Type: 
Single use vial  
Material: 
Injection vial, Clear 
Neutral Glass, Type I 
Size: 
 
Formulation 
Clear or opalescent liquid  
Active Ingredient Content 
Mass/Weight: 
4 x 1011 VP/vial 
Volume: 
0.8 mL per vial 
Concentration: 
5 x 1011 VP/mL 
Storage Conditions 
-20 ± 5°C 
Stability after addition to 
the infusion bag 
8 hours at +15 to +25 °C  
Note: this is from the time the ONCOS-102 is added to the 
infusion bag to the end of infusion. 
Labeling 
Product name, lot number, route of administration, and 
storage conditions 
 
ONCOS-102 is formulated as a clear or opalescent liquid that is presented in glass vials sealed 
with a rubber stopper and an aluminum cap for single use. The final filling volume is 0.8 mL, and 
the VP-titer of each vial is 4 x 1011. Vials of ONCOS-102 must be stored at -20 ± 5°C and marked 
with a biohazard symbol. 
6.2.2 ONCOS-102 Preparation  
ONCOS-102 like other adenoviruses belong to Risk Group 2 (moderate individual risk, low 
community risk). Biosafety level 2 (BSL-2) containment is required for work with ONCOS-102, 
including BSL-2 facilities, equipment, practices and procedures. The room or area used for 
ONCOS-102 preparation must be approved for handling BSL-2 organisms. 
ONCOS-102 is an adenovirus that is genetically modified to replicate selectively in cancer cells. 
The ability to replicate in normal non-dividing cells is attenuated. Therefore, it is unlikely that 
ONCOS-102 would pose any clinically significant health issues to non-tumor-bearing individuals 
as it is less harmful for the healthy people than wild type adenoviruses (e.g. serotypes 5 and 3) 


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that commonly infect the human population. Moreover, GMCSF production makes viruses more 
immunogenic, enhancing clearance from normal tissues, further increasing their safety.  
Therefore, there is little potential harm to the environment. 
There is a theoretical risk of spread of ONCOS-102 into the environment from subjects who are 
undergoing treatment. However, in the Phase I study, no virus was detected in urine or buccal 
swabs at discharge after dosing in any subject. Virus was detected before dosing on one 
occasion (Day 4): in the urine of 1 subject, and in the buccal swabs in 3 subjects, but not on 
subsequent dosing days.  
ONCOS-102 can be inactivated using a suitable adenovirus neutralising agent or virucidal 
disinfectant, or similar. These are to be used for the inactivation of spills and devices used for 
administration. When preparing the infusion solution, only the required number of vials should 
be thawed; re-freezing is not allowed. 
The dose of ONCOS-102 will be diluted with saline in a 500-mL infusion bag prior to 
administration. The diluted product is stable for treatment at a temperature of +15 to +25°C for 
a maximum of 8 hours (from the time the ONCOS-102 is added to the infusion bag to the end of 
infusion). The dilution must be performed within a biosafety cabinet with a Closed System 
Transfer Device to reduce the risks posed by the possibility of generation and inhalation of 
aerosols. 
Full details of virus handling instructions and preparation will be provided in a separate ONCOS-
102 Handling Guideline.  
Waste should be handled according to local guidance and procedures. Typically, standard 
operating procedures for disposal within medical facilities will be consistent with the guidance 
given in the WHO Laboratory Biosafety Manual, 3rd Ed (2004).  
Biohazard waste containers are required both in the pharmacy/laboratory and in the treatment 
room. A separate biohazard waste bag for disposable waste, including single-use lab coats, 
sleeve covers, gloves, packaging materials and used paper wipes or textile cloths, should be 
available.  
A puncture-proof sharp item waste container is also required. Needles are not recapped or 
removed: the complete administration assembly is placed in sharps container and later disposed 
in a manner consistent with the standard practice of the institution for potentially biohazardous 
sharps waste. Full details of virus handling instructions will be provided in a separate ONCOS-
102 Handling Guideline. 
6.2.3 ONCOS-102 Administration 
ONCOS-102 will be delivered by intraperitoneal (IP) infusion via a peritoneal Hickmann catheter 
(or institutionally preferred alternative).  The ONCOS-102 will be infused in a total volume of 500 
mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per institutional procedures 
for IP infusions. The infusion should be given as soon as possible after preparation of the 
infusion solution. It is recommended that the total infusion time not exceed 2 hours. 
To ensure uniform distribution of ONCOS-102 in the peritoneal cavity during the infusion, it is 
recommended that the subjects are rotated every 30 minutes, or institutional procedures may 


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be followed. ONCOS-102 will be administered weekly for a total of 6 weeks (see separate 
ONCOS-102 Handling Guideline for additional details). 
See Section 6.4.2 for monitoring period after administration of ONCOS-102. 
6.3 Estimated Study Requirements 
Drug 
Required Quantity 
of Vials* 
Durvalumab 
3326 
ONCOS-102 
562 
Cyclophosphamide 
94 
(*includes 20% overage for 78 subjects) 
6.4 Monitoring of Study Drug Administration 
6.4.1 Monitoring for Durvalumab Administration 
Subjects will be monitored before, during and after infusion of durvalumab with assessment of 
vital signs according to the table below: 
Vital Signs Assessment on Study Drug Administration Days 
Drug 
Pre 
Dose 
During  
Infusion 
End of Infusion 
(± 5 minutes) 
30 (± 5) Minutes 
Post Infusion  
60 (± 5) Minutes 
Post Infusion  
Durvalumab  
X 
Every 15 (± 5) 
minutes 
X 
X 
X 
 
If a subject tolerates treatment well for the first 4 doses of durvalumab (i.e., no infusion 
reactions), subsequent infusions for that subject can be monitored according to the table below.  
A longer duration of observation after the end of infusion can be used if the Investigator deems 
it clinically necessary. 
Drug 
Pre 
Dose 
During  
Infusion 
End of Infusion 
(± 5 minutes) 
15 (± 5) minutes  
Post infusion  
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
 
6.4.2 Monitoring for ONCOS-102 Administration 
All subjects in the dose escalation phase will remain in the facility for observation for 8 to 12 
hours after each ONCOS-102 infusion.   
NOTE: Per Amendment 5, all subjects in the expansion phase will remain in the facility for 
observation for a minimum of 6 hours after the first dose of ONCOS-102 infusion; for 
subsequent doses, the observation period will be a minimum of 4 hours, but it may be longer, 
based on Investigator’s discretion. 


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During this period, subjects should be monitored according to institutional policy. Further 
guidance is provided below. 
It is suggested that vital signs and temperature are taken every 4 hours. Discharge or admission 
for further observation are at the discretion of the Investigator. Subjects are expected to 
develop fever. Fever without associated other symptoms, such as hemodynamic instability, is 
generally not a reason for admission. 
The following suggested guidelines may be used for the management of ONCOS-102-related 
toxicities:  
1. Isolated fever or pain may be treated with acetaminophen, NSAIDS, opioids, or as 
determined by the Investigator.  
2. For more severe reactions, aggressive symptomatic treatment may be administered, 
which may include fluids, oral or IV antihistamine, anti-pyretics, bronchodilators, pressors, 
and oxygen as indicated. Glucocorticoids may be administered for refractory symptoms 
according to the judgment of the Investigator.  
All adverse events (AEs), including clinically significant changes in vital signs and temperature, 
that occur during this observation period should be documented in the source and eCRF. Refer 
to Section 7.1.5 for details on reporting AEs and Section 7.1.6 for details on reporting serious 
AEs. 
Based on the safety data from the dose escalation phase, the internal data safety monitoring 
panel (as defined in Section 3.1.14) will decide if an observation period will be required for the 
expansion phase. The safety review for the dose escalation phase was conducted, and it was 
agreed that the observation period would be shortened for the expansion phase.  See note 
above for expansion phase requirements, per Amendment 5. 
6.5 Drug Overdose Management 
There are no known antidotes available for durvalumab or ONCOS-102.  Any overdoses with 
these drugs should be managed symptomatically.  An overdose is defined as a subject receiving 
any dose in excess of that specified in this protocol by > 10%.  All such overdoses must be 
reported, with or without associated AEs/SAEs, according to Section 7.1.2.2 . 
 


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7 
Administrative, Legal and Ethical Requirements 
7.1 Documentation and Reporting of Adverse Events 
7.1.1 Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient/subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with the treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
N.B.: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of Ludwig Institute for Cancer research (LICR) studies to include any events, 
intercurrent diseases and accidents observed while the subject is on study, i.e., during the actual 
treatment period, as well as during drug-free, pre- and post-treatment periods, under placebo 
or in a reference group receiving drug or non-drug therapy or no treatment.   
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
1. 
Results in death, 
2. 
Is life-threateningA, 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. 
Results in persistent or significant disability or incapacity, 
5. 
Is a congenital anomaly / birth defect or 
6. 
Is another medically important conditionB. 
A 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject is at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
B 
Medically important conditions that may not result in death, be immediately life-
threatening or require hospitalization may be considered as SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject or may require intervention to prevent one 
of the outcomes listed in the definition above.  Examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse. 
N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: 
mild, moderate, or severe, e.g., pain).  The event itself may be of relatively minor medical 
significance (such as severe headache).  This is not the same as “serious”, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to 
subject’s life or vital functions.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
 


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7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (See Section 7.1.6 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
1. Pregnancy 
2. Overdose (as defined in Section 6.5). 
3. Hepatic function abnormality (as defined in Section 7.1.8) 
4. New cancers 
5. Deaths 
7.1.2.1 Pregnancy 
7.1.2.1.1 Maternal Exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of durvalumab. 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs (see section 7.1.6).  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when 
he or she becomes aware of it.   
The Sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available. 
7.1.2.1.2 Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the final dose of investigational product.   
Pregnancy of the subject’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the subject’s partner.  Therefore, the local study 


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team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use. 
7.1.2.2 Overdose 
Any overdose (as defined in Section 6.5) of a study subject, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Sponsor (see 
Section 7.1.6 for Sponsor contact information). If the overdose results in an AE, the AE must also 
be recorded as an AE according to Section 7.1.5. Overdose does not automatically make an AE 
serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE according to 
Section 7.1.6. There is currently no specific treatment in the event of an overdose of 
durvalumab or ONCOS-102. The Investigator will use clinical judgment to treat any overdose. 
See Section 6.5 for additional details. 
7.1.2.3 Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed (see Section 7.1.6 for Sponsor contact information). 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study 
subject will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and MedImmune/AstraZeneca. 
7.1.2.4 New Cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after 
the subject’s inclusion in this study. 
7.1.2.5 Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined follow-
up period (On Study Follow-up) after the administration of the last dose of study drug, must be 
reported as follows: 
• 
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF. 
It should be reported as an SAE if it meets SAE reporting criteria per Section 7.1.6. 
• 
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Monitor/Physician as an SAE 
within 24 hours. It should also be documented in the eCRF. 


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• 
The report should contain a comment regarding the co involvement of PD, if 
appropriate, and should assign main and contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the eCRF. 
• 
A post mortem may be helpful in the assessment of the cause of death, and if 
performed, a copy of the post-mortem results should be forwarded to LICR within the 
usual timeframes. 
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug should be documented only in the Post Study Follow-up eCRF form. If 
the death occurred as a result of an event that started after the defined safety follow-up period 
and the event is considered to be due to a late onset toxicity to study drug, then it should also 
be reported as an SAE. 
LICR and AstraZeneca retain the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious AEs to the investigational agent(s) will be 
determined by the Investigator on the basis of his/her clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 
the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship.  Information provided in the IB and/or in Section 1 of this protocol may support 
these evaluations. 
7.1.5 General Reporting Requirements 
All serious and non-serious adverse events must be documented in the source records and on 
the respective section of the CRF, regardless of severity or the assumption of a causal 
relationship.  The documentation includes: dates of onset and resolution, severity, seriousness, 
study drug intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4. This documentation is required for 
all AEs that occur: 


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a. from the date of signing the informed consent, and 
b. until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment). 
Immune Related Adverse Events (irAEs) will be collected from the time of informed consent 
through 90 days after the last dose of the last study treatment (regardless of initiation of 
another therapy). 
7.1.6 Expedited Serious Adverse Event (SAE) Reporting Requirements 
In addition to the General Reporting Requirements specified in Section 7.1.5, all events 
meeting the criteria for an SAE per Section 7.1.1, irrespective of suspected causation, must be 
reported by the Investigator to the Sponsor’s Drug Safety Contact (primarily) or, alternatively, 
to the Primary Sponsor Contact, within 24 hours of becoming aware of the event (see contact 
information below). SAEs should be reported via the Medidata RAVE data capture system 
(which utilizes “Safety Gateway”), using the respective Adverse Event and Safety Case 
Summary eCRFs.  This includes any deaths that occur after the off-study date, but within 30 
days of last study drug administration. In the event that the SAE cannot be reported via 
Medidata RAVE, the SAE should be reported using the “Initial Serious Adverse Event Report 
Form,” provided by the Sponsor. 
Note: If an SAE cannot be reported via Medidata RAVE or the “Initial Serious Adverse Event 
Report Form” within 24 hours of becoming aware of the event, the Sponsor’s Drug Safety 
Contact (primarily) or, alternatively, the Primary Sponsor Contact, must be contacted by 
phone or email within 24 hours of becoming aware of the event. In this case, the phone or 
email notification can then be followed up through Medidata RAVE or an “Initial Serious 
Adverse Event Report Form” within one working day of the event. 
If the “Initial Serious Adverse Event Report Form” is being used, the expedited reports should be 
directed by fax or e-mail to the Drug Safety Contact (primarily) or, alternatively, the Primary 
Sponsor Contact.  Studies utilizing Medidata RAVE (and the “Safety Gateway”), built into the 
eCRF, and respective SAE reporting procedures, do not require reporting by fax or email.  
Questions related to Medidata RAVE and “Safety Gateway” procedures should be directed to 
the Drug Safety Contact or Primary Sponsor Contact (see table below for contact information). 
In urgent cases, pre-notification via phone or informal e-mail should be considered. 
Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
600 3rd Ave, 32nd Floor 
New York, New York 10016 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@lcr.org 
Primary Sponsor Contact: 
Mary Macri 
Senior Director 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
600 3rd Ave, 32nd Floor 
New York, New York 110016 
Tel: 
+1 212 450 1546 
Fax: 
+1 212 450 1535 
mmacri@lcr.org  
 


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Serious adverse events must also be reported by the Principal Investigator to the respective 
Institutional Review Board after being assigned an SAE tracking number by the Sponsor.  
Institutional Review Boards may have specific rules on which AEs need to be reported 
expeditiously, as well as, the time frames for such reporting. 
Serious Adverse Event Reports will be evaluated by the Sponsor’s Medical Monitor.  Regulatory 
authorities and other Investigators, as well as institutional and corporate partners, will be 
informed by the Sponsor as required by ICH guidelines, laws and regulations in the countries 
where the investigational agent is being administered.  In particular, SAEs that are unexpected 
and for which a causal relationship with the study drug cannot be ruled out, will be reported by 
the Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported 
within 7 Calendar days. 
Serious adverse event reporting to AstraZeneca/Medimmune is described in a separate 
agreement. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause.  Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available. 
7.1.8 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is an event of scientific and medical interest specific 
to understanding of the investigational products and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The 
rapid recording of all AEs, including AESIs, allows ongoing surveillance of these events in order 
to characterize and understand them in association with the use of the investigational products. 
7.1.8.1 AESIs for Durvalumab 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate aetiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
the irAE.  
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Medical Monitor. 
If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
AESIs observed with durvalumab and those considered AESIs for the purpose of this study are 
listed below. Further information on these AESIs (e.g. presenting symptoms) can be found in the 


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current version of the durvalumab (MEDI4736) Investigator’s Brochure (IB). Guidelines for the 
management of subjects experiencing toxicities for durvalumab can be found in Section 8.3 and 
in the following Medimmune guideline: “Medimmune’s Dosing Modification and Toxicity 
Management Guidelines for Immune- mediated, Infusion Related, and Non Immune-mediated 
Reactions (MEDI4736 (durvalumab) Monotherapy or Combination therapy with 
Tremelimumab or Tremelimumab monotherapy).” 
Diarrhea/Colitis and intestinal perforation  
Diarrhea and colitis are the most commonly observed treatment emergent AEs following dosing 
with study medications.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.   
Pneumonitis/Interstitial lung disease (ILD) 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis has 
been reported with anti-PD-1 MAbs.(57) Initial work-up should include high-resolution CT scan, 
ruling out infection, and pulse oximetry. Pulmonary consultation is highly recommended.  
Hepatic function abnormalities (Hepatitis / transaminase increases) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies.(58)  Inflammatory hepatitis has been reported in 3% to 9% of subjects treated with 
anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of ipilimumab-
treated subjects included general weakness, fatigue, nausea and/or mild fever and increased 
liver function tests such as AST, ALT, alkaline phosphatase, and/or total bilirubin. Hepatic 
function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN and 
concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are those 
that derive from a single blood draw or from separate blood draws taken within 8 days of each 
other. Follow-up investigations and inquiries will be initiated promptly by the investigational site 
to determine whether the findings are reproducible and/or whether there is objective evidence 
that clearly supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with 
distended gallbladder) or an agent other than the investigational product.  Cases where a 
subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need to be reported as SAEs.  
These cases should be reported as SAEs if, after evaluation they meet the criteria for a Hy’s Law 
case or if any of the individual liver test parameters fulfill any of the SAE criteria. 
Neurotoxicity (Neuropathy / neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.   
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis/hypopituitarism, adrenal 
insufficiency, Type 1 diabetes mellitus, and hyper- and hypothyroidism.   
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as per current 
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Nephritis and increases in serum creatinine 
A consult with Nephrologist should be done as well as monitoring for signs and symptoms that 
may be related to changes in renal function (e.g. routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine output, 
proteinuria, etc.). Subjects should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, infections etc.). Steroids should be considered in the absence of clear 
alternative etiology even for low grade events (Grade 2), in order to prevent potential 
progression to higher grade event.   
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, (or labs suggestive of 
pancreatitis - increased serum lipase, increased serum amylase) 
Myocarditis 
Myocarditis, a rare but severe immune-mediated adverse event, presents with signs/symptoms 
such as decreased ejection fraction, arrhythmias, in particular occurrences of atrioventricular 
block. For subjects with suspected myocarditis, investigators should obtain a cardiology consult 
and institute full diagnostic work-up (that includes exclusion of other alternate causes such as 
infection). 
Myositis / Polymyositis 
Myositis or polymyositis should be suspected in subjects who present with proximal muscle 
weakness and the evaluation should include an examination of the skin, muscle enzyme 
measurement, antibody testing, any systemic disease manifestations and exclusion of other 
diseases including drug-induced myopathy. Cases of myositis have been reported with 
myocarditis in which immune infiltration has been described in skeletal and cardiac muscle (see 
IB). 
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, haematological and rheumatological events. 
Hypersensitivity and Infusion Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-
L1 and anti-PD-1 therapy.(58) As with the administration of any foreign protein and/or other 
biologic agents, reactions following the infusion of MAbs can be caused by various mechanisms, 
including acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid reactions against 
the MAb, and serum sickness. Acute allergic reactions may occur, may be severe, and may result 
in death. Acute allergic reactions may include hypotension, dyspnea, cyanosis, respiratory 
failure, urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, 
dizziness, fatigue, headache, hypertension, myalgia, vomiting and unresponsiveness. 
7.1.8.2 Additional AESI for ONCOS-102 
7.1.8.2.1 Fever 
Temporary fever was observed in all subjects after the ONCOS-102 administrations in the Phase 
1 study. The addition of durvalumab could theoretically exacerbate the fever. Paracetamol may 
be given at the discretion of the Investigator. 


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Guidelines for the management of subjects experiencing the toxicities for ONCOS-102 can be 
found in Section 8.4. 
If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
7.2 Administrative Sponsor Requirements 
7.2.1 Study Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Study Master File”) of all trial-related documentation that is suitable for inspection by the 
Sponsor and regulatory authorities.  Upon completion of the trial, the Investigator is required to 
submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor.  No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
7.2.2 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor.  The use of eCRFs encompasses electronic data 
entry, query management and sign-off.  Systems used for electronic data capture will be 
compliant with FDA regulations 21 CFR Part 11 and within the constraints of the applicable local 
regulatory agency guidelines (whichever provides the greatest protection to the integrity of the 
data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigator will sign and date the completed eCRF sections.  This signature will indicate a 
thorough inspection of the data in the CRF and will certify its content. 
7.2.3 Language 
The protocol is written in English.  All correspondence between the study site and the Sponsor 
should be maintained in English.  Case Report Forms must be completed in English.  All written 
material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood, and be in the language appropriate for the trial site. 
7.2.4 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
qualification, site initiation, routine monitoring and site close-out.  Clinical Monitors and/or 
other Sponsor staff will meet with the Investigator staff and require direct access to source 
data/documents.  Such access may also be required for Institutional Review Board review, and 
regulatory inspection/audits.  Direct access is defined as permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of the study.  All 
reasonable precautions within the constraints of the applicable regulatory requirement(s) to 
maintain the confidentiality of subjects’ identities and Sponsor’s proprietary information will be 
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It is the Clinical Monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
trial to verify adherence to the protocol, the completeness, accuracy and consistency of the 
data, and adherence to GCP guidelines.  The Clinical Monitor should have access to subject 
charts, laboratory reports, and other subject records needed to verify the entries on the CRFs 
(“source data verification”). 
7.2.5 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Institutional Review Board and, if required, the regulatory authorities.  Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals; however, in this case, approval must be obtained as soon as possible after 
implementation. Implementation of administrative amendments that do not affect the safety of 
the subjects usually do not require prior Institutional Review Board approval, just notification. 
When immediate deviation from the protocol is required to eliminate immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor, if circumstances permit, to discuss the 
planned course of action.  Any departures from the protocol must be fully documented in the 
source documentation. 
7.2.6 Premature Subject Withdrawal from Treatment or from Study 
A subject may withdraw from study treatment or from the study at any time for any reason 
without prejudice to his/her future medical care by the physician or at the study site.  Likewise, 
the Investigator and/or Sponsor have the right to withdraw subjects from treatment or from the 
study.  Specific subject withdrawal criteria are listed in Section 3.1.10.  Should a subject (or a 
subject’s legally authorized representative) decide to withdraw from study treatment or from 
the study, all efforts will be made to complete the required study procedures and report the 
treatment observations as thoroughly as possible. 
For all subject withdrawals, a complete final evaluation should be made at the time of 
withdrawal.  The appropriate form in the Case Report Form should be completed with an 
explanation of why the subject is withdrawing, and an attempt should be made to perform a 
follow-up evaluation. 
7.2.7 Early Trial Termination 
The Study Sponsor and Investigator have the right to terminate the study early.  Specific study 
stopping rules are listed in Section 3.1.14.  In such case, one party must notify the other in 
advance in writing about the intent of and the reasons for the termination.  The Investigator 
must also notify the appropriate Institutional Review Board accordingly. 
7.2.8 Study Drug Shipments and Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably, the site’s pharmacy.  The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 


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• 
date and quantity of drug dispensed 
• 
date and quantity of drug returned to the Investigator/pharmacy (if applicable; see Note 
for ONCOS-102) 
• 
date and quantity of accidental loss of drug (if any)  
These inventories must be made available for inspection by the Clinical Monitor.  The 
Investigator is responsible for seeing to it that all used and unused trial supplies are accounted 
for.  At the end of the study, the Clinical Monitor will also collect the original study drug 
dispensing records. 
At the end of the study, or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable.  Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed by a 
second person.  At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
Additional Note for ONCOS-102:   
During the course of the clinical trial, the ONCOS-102 remaining after dilution (i.e., used vials 
and unused extra vials) will be destroyed at the site according to hospital practice for Biosafety 
Level 2 agents or according to guidance provided by Targovax; the guidance will be provided to 
the sites by the Sponsor.  Please refer to the ONCOS-102 Handling Guideline for specific details 
regarding drug accountability and disposal.  The drug disposition log will be maintained as stated 
above.  
7.3 Regulatory, Legal and Ethical Requirements 
7.3.1 Good Clinical Practice (GCP), Laws and Regulations 
The Investigator must ensure that he/she and all authorized personnel for the study are familiar 
with the principles of Good Clinical Practice (GCP) and that the study is conducted in full 
conformity with the current revision of the Declaration of Helsinki, ICH Guidelines, and 
applicable local laws and regulations, with the understanding that local laws and regulations 
take precedence over respective sections in the Declaration of Helsinki and/or the ICH 
Guidelines. 
7.3.2 Informed Consent 
The Investigator must obtain witnessed (if applicable) written Informed Consent from the 
subject or the subject’s legally authorized representative after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any study 
procedures are performed.  The subject should be given a copy of the Informed Consent 
documentation.  The original signed and dated Informed Consent form must be retained in the 
study records at the study site, and is subject to inspection by representatives of the Sponsor, or 
representatives from regulatory agencies. 


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7.3.3 Institutional Review Board 
The Investigator must obtain written approval from the appropriate Institutional Review Board 
for the protocol and Informed Consent, and all amendments thereof, prior to recruitment of 
subjects and prior to shipment of investigational agents. 
The Investigator must report SAEs to the appropriate Institutional Review Board in accordance 
with the Institutional Review Board’s rules and guidelines (see also Section 7.1). 
The Investigator must assure that continuing review (at least once per year) of the study is 
performed by the Institutional Review Board throughout the duration of the study.  If so 
required by the Institutional Review Board, the Investigator must provide study reports on an 
annual basis and upon completion of the study. 
All correspondence with, and reports to, the Institutional Review Board must be maintained in 
the study files at the study site and copies must be sent to the Sponsor. 
7.3.4 Subject Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained.  A subject should only be 
identified by their initials, date of birth and subject number on the CRFs or other documents 
submitted to the Sponsor.  Documents that are not submitted to the Sponsor (e.g., signed 
Informed Consent form) should be kept in a strictly confidential section of the study file by the 
Investigator. 
The Investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study.  As 
part of the Informed Consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
 


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8 
Appendices 
8.1 Protocol Version History 
Original Issue 
Issue date: Final, 19-OCT-2016 
Summary of Changes: not applicable 
Original Issue 0.1 
Issue Date: Final, 01-NOV-2016 
Summary of Changes:  The IND # was added to the cover page. This was done as an 
administrative change. 
 
Amendment 1 
Issue Date: Final, 09-FEB-2017 
Summary of Changes: 
Per FDA request, clarification was provided for Inclusion Criterion #1. Other changes were made 
for consistency with the language in Inclusion Criterion #1. 
1. Synopsis and Section 3.1, Study Design: Paragraph 1 was changed 
FROM: “This is a two-part Phase 1/2 dose escalation and dose expansion study of the GMCSF-
encoding adenovirus, ONCOS-102, in combination with anti-programmed death ligand-1 (PD-L1) 
antibody, durvalumab, in adult subjects with peritoneal disease who have failed prior standard 
chemotherapy and have histologically confirmed platinum-resistant or refractory epithelial 
ovarian cancer or colorectal cancer.” 
TO: “This is a two-part Phase 1/2 dose escalation and dose expansion study of the GMCSF-
encoding adenovirus, ONCOS-102, in combination with anti-programmed death ligand-1 (PD-L1) 
antibody, durvalumab, in adult subjects with peritoneal disease who have histologically 
confirmed epithelial ovarian cancer or metastatic colorectal cancer and have failed prior 
standard therapies.” 
2. Synopsis: The following changes were made (changes in bold):   
Phase 2 of the study is the dose expansion phase, which will further explore the safety and anti-
tumor activity for the RCD in 2 expansion cohorts with peritoneal disease: 
• 
Platinum-resistant epithelial ovarian cancer  
• 
Metastatic Ccolorectal cancer 
3. Section 3.1, Study Design: The following changes were made (changes in bold): 
In Phase 2, there are The 2 expansion cohorts with peritoneal disease in Phase 2 are the 
following: 
• 
Cohort 1: Platinum-resistant epithelial ovarian cancer  
• 
Cohort 2: Metastatic Ccolorectal cancer 
4. Section 3.1.4, Subject Population was changed  
FROM: “Subjects with peritoneal disease who have failed prior standard chemotherapy and have 
histologically confirmed platinum-resistant or refractory epithelial ovarian cancer or colorectal 
cancer will be enrolled. Platinum resistance is defined as relapse within 6 months of last 
platinum-based chemotherapy or progression while on platinum-based therapy. Co-existing 
distant metastases and parenchymal organ metastases will be allowed. Details on subject 
eligibility are found in Section 5.” 


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TO: “Subjects with peritoneal disease who have histologic confirmation of epithelial ovarian 
cancer or metastatic colorectal cancer (CRC) will be enrolled. Subjects with ovarian cancer must 
have either received one line of platinum based therapy and have progressed within 6 months 
(defined as platinum resistant) or have received 2 or more lines of standard therapy. Subjects 
with CRC must have at least failed two lines of fluropyrimidine based therapies, oxaliplatin or 
irinotecan based therapies with or without anti-VEGF component, or for RAS wild-type, with or 
without anti-EGFR therapy. Co-existing distant metastases and parenchymal organ metastases 
will be allowed. Subjects may have received prior intraperitoneal therapy. Details on subject 
eligibility are found in Section 5.” 
5. Section 3.1.7.2, Dose Expansion Phase:  The following changes were made (changes in bold): 
The following cohorts will be enrolled: In Phase 2, there are 2 expansion cohorts with 
peritoneal disease: 
• 
Cohort 1: Platinum-resistant epithelial ovarian cancer  
• 
Cohort 2: Metastatic cColorectal cancer 
6. Section 5.1: Inclusion Criterion #1 was changed  
FROM: “Subjects with peritoneal disease who have failed prior standard chemotherapy and have 
histologic confirmation of platinum-resistant or refractory epithelial ovarian cancer or colorectal 
cancer will be enrolled. Platinum resistance is defined as relapse within 6 months of last 
platinum-based chemotherapy or progression while on platinum-based therapy. Co-existing 
distant metastases and parenchymal organ metastases will be allowed.” 
TO: “Subjects with peritoneal disease who have histologic confirmation of epithelial ovarian 
cancer or metastatic colorectal cancer (CRC) will be enrolled.  Subjects with ovarian cancer must 
have either received one line of platinum based therapy and have progressed within 6 months 
(defined as platinum resistant) or have received 2 or more lines of standard therapy. Subjects 
with CRC must have at least failed two lines of fluropyrimidine based therapies, oxaliplatin or 
irinotecan based therapies with or without anti-VEGF component, or for RAS wild-type, with 
or without anti-EGFR therapy. Co-existing distant metastases and parenchymal organ 
metastases will be allowed. Subjects may have received prior intraperitoneal therapy.” 
 
Amendment 2 
Issue Date: Final, 18-JAN-2018 
Summary of Changes: 
1. Section 1.3.2 (ONCOS-102): For Clinical Study ONCOS C1, a clarification was provided that the 
ONCOS injections were given intratumorally. In addition, paracetamol was deleted in the last 
paragraph, as acetaminophen is sufficient description for the US sites. 
2. Section 2.1.3 (Fixed dosing for Durvalumab): Based on Medimmune recommendations, a 
clarification was provided to indicate that: “If a subject’s body weight drops to ≤ 30 kg while 
on the study, the durvalumab dose will be weight based as long as the body weight remains 
≤ 30 kg.” This was changed from 600 mg Q4W fixed dose for subjects≤ 30 kg. A reference to 
Section 6.1.3 was provided for additional details.  
a. This change was also implemented in Sections 3.1 (Study Design), 3.1.7 (Treatment Arms 
and Treatment Schema), and 3.1.7.1 (Dose Escalation Phase). 
3. Section 3.1.7 (Treatment Arms and Treatment Schema): Treatment with ONCOS-102, third 
paragraph was modified to provide clarification for the ONCOS-102 infusion (changes in 
bold): 


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“After accessing the IP port and aspirating any ascites, if present, the reconstituted ONCOS-
102 will be infused in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) 
by gravity feed or per institutional procedures for IP infusions. The infusion should be given 
as soon as possible after preparation of the infusion solution. It is recommended that the 
total infusion time not exceed 2 hours.  over a period of approximately 1 hour. To ensure 
uniform distribution of ONCOS-102 in the peritoneal cavity during infusion, it is 
recommended that the subjects are rotated every 30 minutes, or institutional procedures 
may be followed. See Section 6.2.3 regarding administration of ONCOS-102.” 
a. This modification was also implemented in Section 6.2.3. 
4. Section 3.1.7.1 (Dose Escalation Phase) change from overnight stay to an observation period 
of 8 to 12 hours after each ONCOS-102 infusion was implemented.  
5. Section 3.1.9 (DLT and MTD/RCD): The following exception bullet was added to Point #3: 
“Grade 3 or 4 asymptomatic increases in amylase or lipase levels for which appropriate 
evaluation shows no clinical evidence of pancreatitis.” This was done to align with the 
amylase/lipase information in Section 8.3.1 dose modifications.” 
6. Section 3.1.16.1 (End of Study Visit): The following clarification was added to the first 
paragraph (changes in bold): “All subjects of childbearing potential who withdraw from study 
must have a serum pregnancy test done at the End of Study visit, unless it was done within 7 
days prior to the End of Study Visit. 
7. Section 3.2 (Flowchart): the following changes/additions were made based on updated 
recommendations from the Investigators and/or corrections: 
a. Previous Row 35 (Blood for Tumor markers in serum) was moved below Disease 
Assessment Row, and renamed as: “Blood for CA-125 for ovarian or CEA for CRC (must be 
at same time points as disease assessments; test will be performed by local lab)h” The 
assessment on Cycle1/Day1 was moved Screening/Baseline to correspond with the 
disease assessments. 
b. Day 1 of Cycles 3, 5, and 7- visit window was changed from ±2 to ±4.  
c. Window of ±1 month was added for Post Study Follow-up visits. Note: this window was 
also added to Section 3.1.16. 
d. Window of ±1 week was On Study Follow-up visits for disease assessments and tumor 
markers 
e. Footnote a was clarified changes in bold): “pre-dose (if applicable). Note: It is strongly 
recommended that test results are reviewed before dosing for hematology, chemistry 
(including amylase, lipase, and thyroid pre durvalumab) and pregnancy (when 
applicable).” 
f. Footnote b was updated to correspond with changes to observation period in Section 
6.4.2 (changes in bold): “pre-ONCOS-102 dose, 4-6 hours after ONCOS-102 dose, and 
prior to discharge the following morning. 
g. Footnote f was updated (changes in bold): “Six CPT tubes per time point (pre-dose)  -> 
PBMC isolation; used for banking PBMCs and plasma (* Only one CPT tube is required on 
Day 1 -> PBMC isolation for assessment of T regs) 
h. Footnote h was clarified (changes in bold): “Collected as part of together with routine lab 
assessment blood draw (pre-dose, if applicable) 
i. 
Footnote i was added for Cycle 1/Day 1 Physical Exam: “The physical exam on 
Cycle1/Day1 does not need to be repeated if it was performed on Day -1, prior to the 
cyclophosphamide injection.”   


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j. 
Footnote J was added for Cycle 1/Day1 for all routine lab procedures: “The Cycle1/Day 1 
lab assessments may be done on Day -1.” 
k. Row labeled Long Term Follow-up was corrected to Post Study Follow-up. 
l. 
The following routine lab procedures were deleted as they were inadvertently included in 
the previous versions: 
i. Thyroid tests on Cycle 5/Day1 
ii. Amylase/Lipase tests on Cycle 1/Days 8 and 22, Cycle 2/Days 1 and 8, Cycle 3/Day 1, 
Cycle 5/Day 1, and Cycle 7/Day 1. 
iii. Coagulation for Cycles 3 to 12 and 2nd/3rd on study follow-up visits. (For durva, coag is 
needed at screening and as clinically indicated; however, it is required during ONCOS-
102 administration.) 
8. Section 4.3.1 (Biological Activity, Endpoints and Assessment Methods): Table 2 was changed 
as follows to provide clarification of intended meaning (changes in bold): 
a. Fifth row: Pre-treatment and on treatment serum plasma (from PBMC collection tubes) 
b. New sixth row was added: “Blood for cytokines in serum” 
c. Last row: “Blood for CA-125 for ovarian or CEA for CRC (must be collected at same time 
points as disease assessments; test will be performed by local lab). Tumor markers – 
part of routine lab assessment blood draw. 
9. Section 5.1 (Inclusion Criteria): 
a. Criterion #1. The following note was added for clarification: “Note: the CRC cohort may 
include subjects with cancer originating from the appendix.” Rationale: The treatment 
paradigm for appendiceal cancer is essentially the same as CRC; in many studies, they are 
grouped together. 
o This note was also added to the description of the population in the Synopsis. 
b. Criterion #1, the CRC paragraph was modified as follows (changes in bold): ”Subjects 
with CRC must have at least failed two lines of therapy (e.g., fluropyrimidine based 
therapies, oxaliplatin or irinotecan based therapies with or without anti-VEGF 
component, or for RAS wild-type, with or without anti-EGFR therapy.) 
c. Previous Inclusion Criterion #4 was changed as follows for clarification of the intended 
meaning (changes in bold): “Subjects should have failed prior treatment Previously 
treated for advanced cancer and deemed by the Investigator to no longer be eligible for 
or have reasonable standard of care alternatives, which are felt to have a clinically 
meaningful impact on their with no additional therapy options available known to 
prolong survival.”  
d. The re-worded criterion 4 was added to text of Inclusion criterion #1.  All other inclusion 
criteria were re-numbered, as appropriate. 
e. The changes made to inclusion criterion #1 were also made to Section 3.1.4 (Subject 
Population). 
10. Section 6 (Study Drug Preparation an Administration): The following change was made to 
provide clarification of the intended meaning (changes in bold): “When durvalumab and 
ONCOS-102 are administered on the same day, durvalumab is administered first, and there 
should be at least 1 hour between the end of infusion of the durvalumab and the start of 
the infusion of ONCOS-102.  
11. Section 6.1 (Durvalumab):  
a. The entire section and sub-sections were updated and reorganized according to current 
language from Medimmune. 
b. In Section 6.1.3 (Durvalumab Preparation): 


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i. The following note was added based on current Medimmune recommendations: “NOTE: 
if a subject’s body weight drops to ≤ 30 kg while on the study, the subject will receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab as long as the body weight 
remains ≤ 30 kg (e.g., a 30 kg subject would receive a 600 mg dose; a 25 kg subject would 
receive a 500 mg dose; etc.). When the weight improves to >30 kg, the subject may 
return to fixed dosing of durvalumab 1500 mg.”  The note stating that the fixed dosing for 
subjects who weigh ≤ 30 kg will be 600 mg Q4W was deleted. 
ii. The following clarification was added for sub-section Dose preparation (changes in bold): 
“Durvalumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 
5% (w/v) dextrose, and delivered through an IV administration set with a 0.2 or 0.22 
µm in-line filter. A volume of diluent equal to the calculated volume of durvalumab to 
be added to the IV bag must be removed from the bag prior to addition of durvalumab. 
The calculated volume of durvalumab is then added to the IV bag, and the bag is mixed 
by gentle inversion to ensure homogeneity of the dose in the bag.” 
12. Section 6.2.1 (ONCOS-102 Study Drug Information): Stability of diluted solution was updated 
based on current recommendations from updated IB (changes in bold):  
 
Stability after 
reconstitution addition to 
the infusion bag 
5 8 (changed from 5 to 8) hours at 0 +15 to +25 °C  
Note: this is from the time the ONCOS-102 is added to the 
infusion bag to the end of infusion. 
Note: term “reconstitution” was changed to “dilution or preparation” throughout the 
document, as it more accurately reflects the preparation of ONCOS-102. 
13. Section 6.2.2 (ONCOS-102 Preparation): The fifth paragraph was modified to reflect the 
changes noted above for stability of the diluted ONCOS-102 (changes in bold): “The dose of 
ONCOS-102 will be reconstituted diluted with saline in a 500-mL infusion bag prior to 
administration. The reconstituted diluted product is stable for treatment at a temperature of 
+2+15 to +25°C for a maximum of 5 8 hours (from the time the ONCOS-102 is added to the 
infusion bag to the end of infusion). The reconstitution dilution must be performed within a 
biosafety cabinet with a Closed System Transfer Device to reduce the risks posed by the 
possibility of generation and inhalation of aerosols.” 
14. Section 6.2.3 (ONCOS-102 Administration): the section was updated based on updated 
recommendations from the Investigators (changes in bold): “ONCOS-102 will be delivered by 
intraperitoneal (IP) infusion via a peritoneal Hickmann catheter (or institutionally preferred 
alternative). Reconstituted The ONCOS-102 will be infused in a total volume of 500 mL saline 
(0.9 mg/mL NaCl in water for injection) over a period of approximately 1 hour by gravity 
feed or per institutional procedures for IP infusions. The infusion should be given as soon as 
possible after preparation of the infusion solution. It is recommended that the total 
infusion time not exceed 2 hours. To ensure uniform distribution of ONCOS-102 in the 
peritoneal cavity during the infusion, it is recommended that the subjects are rotated every 
30 minutes, or institutional procedures may be followed. ONCOS-102 will be administered 
weekly for a total of 6 weeks (see separate ONCOS-102 Handling Guideline for additional 
details). 
15. Section 6.4.2 (Monitoring for ONCOS-102 Administration): the following changes were made 
based on updated recommendations and/or clarifications. (changes in bold): “All subjects in 
the dose escalation phase will remain in the facility overnight for observation for 8 to 12 
hours after each ONCOS-102 infusion. This is not a 24-hour stay, as they can leave the 


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following morning. During this period, subjects should be monitored according to 
institutional policy. Further guidance is provided below. 
It is suggested that vital signs and temperature are taken every 4 hours. Discharge or 
admission for further observation are at the discretion of the Investigator. Subjects are 
expected to develop fever. Fever without associated other symptoms, such as 
hemodynamic instability, is generally not a reason for admission. 
The following suggested guidelines may be used for the management of ONCOS-102-
related toxicities: (1) Isolated fever or pain may be treated with acetaminophen, NSAIDS, 
opioids, or as determined by the Investigator. (2) For more severe reactions, aggressive 
symptomatic treatment may be administered, which may include fluids, oral or IV 
antihistamine, anti-pyretics, bronchodilators, pressors, and oxygen as indicated. 
Glucocorticoids may be administered for refractory symptoms according to the judgment of 
the Investigator.  
All adverse events (AEs), including clinically significant changes in vital signs and 
temperature, that occur during this observation period should be documented in the 
source and eCRF. Refer to Section 7.1.5 for details on reporting AEs and Section 7.1.6 for 
details on reporting serious AEs. 
Based on the safety data from the dose escalation phase, the internal data safety monitoring 
panel (as defined in Section 3.1.14) will decide if an overnight stay observation period will be 
required for the expansion phase.” 
a. The change from overnight stay to an observation period of 8 to 12 hours was also 
implemented in Section 3.1.7.1 (Dose Escalation Phase). 
16. Section 7.1.8.1 (AESIs for Durvalumab):  The entire section was updated and reorganized 
based on updated recommendations from Medimmune in the updated IB. Specifically, the 
following changes or additions were implemented (changes in bold): 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis/hypopituitarism, adrenal 
insufficiency, Type 1 diabetes mellitus, and hyper- and hypothyroidism.  
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as per 
current established toxicity management guidelines. 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, (or labs suggestive of 
pancreatitis - increased serum lipase, increased serum amylase) and lipase/amylase 
elevation 
Myocarditis 
Myocarditis, a rare, but severe immune-mediated adverse event, presents with 
signs/symptoms such as decreased ejection fraction, arrhythmias, in particular occurrences 
of atrioventricular block. For subjects with suspected myocarditis, investigators should 
obtain a cardiology consult and institute full diagnostic work-up (that includes exclusion of 
other alternate causes such as infection). 
Myositis / Polymyositis 
Myositis or polymyositis should be suspected in subjects who present with proximal muscle 
weakness and the evaluation should include an examination of the skin, muscle enzyme 
measurement, antibody testing, any systemic disease manifestations and exclusion of 
other diseases including drug-induced myopathy. Cases of myositis have been reported 


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with myocarditis in which immune infiltration has been described in skeletal and cardiac 
muscle (see IB). 
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and 
other events involving the eye, skin, haematological and rheumatological events. 
17. Section 8.3.1 (Durvalumab dose modification due to toxicity): Immune-related AEs were 
updated based on updated Toxicity Mgt Guidelines from Medimmune (Dated 01Nov2017). 
Specifically, myocarditis, myositis/polymyositis were added; Diarrhea/colitis and 
endocrinopathies were updated.  
18. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
Amendment 2.1 
Issue Date: Final, 05-MAR-2018 
Summary of Changes:  
Inclusion Criterion for laboratory parameters was updated to remove the requirement that the 
lymphocyte count should be ≥ LLN.  Rationale: A follow-up discussion indicated that a specific 
target of LLN for lymphocyte count has not been found to be associated with response to 
checkpoint inhibitors. Thus, the decision was made to remove the criterion. 
This discussion occurred after Amendment 2 was finalized but before it was distributed to the 
sites. A temporary change (TC-2018-02) was written to allow the notation of Amendment 2.1 for 
the updated amendment. 
 
Amendment 3 
Issue Date: Final, 04-MAY-2018 
Summary of Changes: 
1. Synopsis; The following sentence in the last paragraph was edited for clarification (changes in 
bold): “Simon’s 2-Stage MINIMAX Design will be used in Phase 2 for Expansion Cohorts 1 and 
2 (see Section 3.1.6 for sample size considerations). In the first stage, 18 subjects will be 
enrolled in Cohort 1 and 13 subjects in Cohort 2 (including the 6 subjects at the RCD from 
the dose escalation phase). This clarification was also added to Section 3.1.2 (Enrollment). 
2. Section 3.1 (Study Design), Phase 1: The following note was added for Cohort A: 
“(NOTE: Upon agreement between Investigator and Sponsor, if a subject in Cohort A has 
tolerated the ONCOS treatment well but is starting to get symptomatic, the first dose of 
durvalumab may be given on Day 43 (Cycle 2/Day15); durvalumab dosing will then continue 
per flowchart in Section 3.2).”  
Rationale: This was based on an exception that was provided per Note to FILE, LUD2015-
008_017_Correspondence_12Apr2018_017-002-YRE Durvalumab Start_revised. 
References to this note were added to Section 3.1.2 (Enrollment); Section 3.1.7.1 (Dose 
escalation phase), Table 1 and Figure 3. 
3. Section 5.1 (Inclusion Criteria): The following criterion was added as #3: 
“Availability of microsatellite instability (MSI) status for all subjects (OC and CRC) 
Availability of KRAS and NRAS status for subjects with CRC.” 
Subsequent inclusion criteria were re-numbered, as appropriate. 
4. Section 5.2 (Exclusion Criteria): 


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a. # 19 was changed FROM: “Other invasive malignancy within 5 years except for 
noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous 
carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been 
surgically cured.” TO: “Active or prior malignancy except for history of other prior 
malignancy treated with curative intent which, in the opinion of the treating investigator 
and the Sponsor, has minimal risk of interfering with safety or efficacy endpoints of the 
study.” 
Rationale: The language was updated to be consistent with current standards. 
b. #21 was clarified as follows (changes in bold): 
Any condition that, in the clinical judgment of the treating physician, is likely to interfere 
with the interpretability of the data or prevent the subject from complying with any 
aspect of the protocol or that may put the subject at unacceptable risk. 
5. Section 8.8 (Abbreviations): MSI was added 
6. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
Amendment 4 
Issue Date: Final, 08-JAN-2019 
Summary of Changes: 
 
1. The requirement for a 4-week waiting period between the first study drug administration for 
the first and second subjects in Cohort C in the dose escalation phase was removed.  
This was based on the completion of the safety reviews for Cohort B (ONCOS-102 1x1011 VP 
+1500 mg durvalumab) and Cohort A (ONCOS-102 1x1011 VP +delayed 1500 mg durvalumab 
which started after completion of the 6 weekly doses of ONCOS-102).  
Changes are reflected in Section 3.1.2 (Enrollment) and Section 3.1.7.1 (Dose Escalation 
Phase). 
2. Section 5.1 (Inclusion Criteria) 
a. #1 – the second paragraph was clarified as follows: 
 
b. #3 was clarified as follows: 
 
This clarification was also added as footnote K to the Flowchart in Section 3.2. 
3. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable 
 


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Amendment 5 
Issue Date: Final, 19-JUN-2019 
Summary of Changes: 
1. Optional durvalumab treatment extension beyond the initial 12-cycle treatment period (Core 
Study) was added. Sections impacted were as follows: 
a. Synopsis, Section 3.1.7 (Treatment Arms and Treatment Schema), Section 3.1.12 
(Optional Study Treatment Extension) .  The following paragraph was added: 
“Per Amendment 5, optional durvalumab treatment extension beyond the initial 12-cycle 
treatment period (Core Study) will be available for subjects who complete the Core Study 
with Stable Disease or better. The optional treatment extension will be permitted upon 
agreement with subject, Sponsor and Investigator, and it may continue until confirmed 
disease progression, unless there is unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met.  See Section 8.8 for details.” 
b. Section 3.1.15 (Duration of Study) and Section 3.1.16 (On Study and Post Study Follow-
up). The following statement was added: “See Section 3.1.12 for optional durvalumab 
treatment extension.” 
c. Section 8.8 (Details for Subjects who Continue Durvalumab Treatment Beyond the Core 
Study) was added (including flowchart). 
2. Section 3.1.10.1 (Treatment Beyond Progression). The second paragraph was clarified to 
indicate that irRECIST would be used to assess progression in agreement with other ongoing 
protocols. Changes in bold.  
“Subjects meeting criteria for progression by irRECIST RECIST 1.1 (Section 8.5) will be allowed 
to continue on therapy until confirmation of progression by irRECIST if the subject agrees and 
signs an appropriate informed consent form regarding continuation of treatment and as long 
as the following criteria are met at the discretion of the Investigator: 
• 
Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression; 
• 
No significant decline in ECOG performance status; 
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention.” 
3. The observation period post ONCOS-102 was shortened for the expansion phase. Sections 
impacted were as follows: 
a.  Section 3.1.7.1 (Dose Escalation Phase). Last paragraph was updated (changes in bold): 
“Based on the safety data from the dose escalation phase, the internal data safety 
monitoring panel (as defined in Section 3.1.14) will decide if an observation period will 
be required for the expansion phase. The safety review for the dose escalation phase 
was conducted, and it was agreed that the observation period would be shortened for 
the expansion phase. See note below for expansion phase requirements, per 
Amendment 5.  
Note: Per Amendment 5, all subjects in the expansion phase will remain in the facility 
for observation for a minimum of 6 hours after the first dose of ONCOS-102 infusion; 
for subsequent doses, the observation period will be a minimum of 4 hours, but it may 
be longer based on Investigator’s discretion. See Section 6.4.2 for additional details.” 
b. Section 3.1.7.2 (Dose Expansion Phase). The following statement was added “See 
Section 6.4 for monitoring details before/during/after drug administration.” 
c. Section 6.4.2 (Monitoring for ONCOS-102 Administration). The following note was added 
after the first paragraph: “NOTE: Per Amendment 5, all subjects in the expansion phase 


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will remain in the facility for observation for a minimum of 6 hours after the first dose of 
ONCOS-102 infusion; for subsequent doses, the observation period will be a minimum of 
4 hours, but it may be longer, based on Investigator’s discretion. 
d. Section 6.4.2 (Monitoring for ONCOS-102 Administration). The last paragraph was 
updated (changes in bold): “Based on the safety data from the dose escalation phase, 
the internal data safety monitoring panel (as defined in Section 3.1.14) will decide if an 
observation period will be required for the expansion phase. The safety review for the 
dose escalation phase was conducted, and it was agreed that the observation period 
would be shortened for the expansion phase.  See note above for expansion phase 
requirements, per Amendment 5.” 
e. Section 3.2 (Study Flowchart). For Footnote b, the following note was added: “(Note: the 
cytokine collection prior to discharge is for dose escalation phase only). 
 
Amendment 6, dated 14-JAN-2022, was not issued. The following clarification was made, and all 
changes were incorporated into Amendment 6.1 (changes in bold): 
“By the date of implementation of this amendment, all subjects will have completed treatment 
and applicable On Study Follow-up, with the exception of one subject in optional treatment 
extension who will complete treatment and On Study Follow-up by 30 June 2022 or before. This 
amendment provides that the Post Study Follow-up for the collection of survival data will be 
discontinued as of 30 June 2022, and the study will be completed.” 
 
Amendment 6.1 
Issue Date: Final, 10-MAR-2022  
Summary of Changes: 
1. By the date of implementation of this amendment, all subjects will have completed 
treatment and applicable On Study Follow-up, with the exception of one subject in optional 
treatment extension who will complete treatment and On Study Follow-up by 30 June 2022. 
This amendment provides that the Post Study Follow-up for the collection of survival data 
will be discontinued as of 30 June 2022, and the study will be completed. (The preceding 
note was added to the Synopsis and Section 8.8 [Details for Subjects Continuing Durvalumab 
Treatment Beyond the Core Study].) 
a. The following note was added to Sections 3.1.15 (Duration of Study), 3.1.16 On Study and 
Post Study Follow-up), and 4.2.1.5 (Overall Survival): “NOTE: Per Amendment 6.1, all post 
study follow-up for the collection of survival data will be discontinued as of 30 June 2022 
(see rationale in Section 8.1, Amendment 6.1). 
b. Section 3.2 (Study Flowchart) and Section 8.8.1 (Study Flowchart for Subjects Who 
Continue Durvalumab Treatment Beyond the Core Study): Footnotes L and e, 
respectively, were added, “Per Amendment 6.1, all post study follow-up for the collection 
of survival data will be discontinued as of 30 June 2022 (see Section 8.1, Amendment 
6.1)” 
2. AstraZeneca provided updated language for Section 7.1.2 (Additional expedited reporting 
requirements for this study). Section 7.1.2.4 (New Cancers) and Section 7.1.2.5 (Deaths) were 
added. 
3. Section 7.1.6 (Expedited SAE Reporting Requirements): updated address for Drug safety 
Contact and Primary Sponsor Contact due to office move, and updated the title of the 


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primary Sponsor Contact. 
 
 
8.2 Participating Study Sites, Investigators and Staff, Laboratories, and 
Sponsor Information 
This information is maintained in the Clinical Study File 
 


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8.3 Dose Adjustments and Delays for Durvalumab 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3. or 8.4, 
and the toxicity causing agent can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing agent cannot be identified, then the more conservative guideline 
should be followed. 
8.3.1 Durvalumab (MEDI4736) Dose Modification Due to Toxicity 
Durvalumab administration may be modified or discontinued as a result of toxicities as 
described in the table below.  
Additional information and guidance regarding dose modification due to toxicity are provided 
from Medimmune in the following guideline:  
“Medimmune’s Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 (durvalumab) 
Monotherapy or Combination therapy with Tremelimumab or Tremelimumab monotherapy)”. 
Dose modifications will not be required for AEs that are clearly not attributed to durvalumab 
(such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant. 
Durvalumab (D) Dose Modification Due to Toxicity 
Note: If D dosing is held temporarily until resolution of the event as per instructions below, 
treatment should resume at the next scheduled treatment date. 
Immune-related Adverse Events (irAEs) 
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) in 
the absence of a clear alternative etiology. Maximum supportive care, including 
immunosuppressive medications, such as high dose steroids, is allowed to induce resolution 
of the event. However, infliximab should not be used for management of immune-related 
hepatitis. 
In addition to the criteria for permanent discontinuation of D depicted below, permanently 
discontinue D also for:  
• Any Grade rash with bullous skin formations. 
• Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose of study drug/regimen. 
• Recurrence of a previously experienced Grade 3 treatment-related AE following 
resumption of dosing. 
• Any Grade biopsy-proven immune-mediated myocarditis. 
Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease and myocarditis, consider holding D dosing as clinically 
appropriate and during diagnostic work-up for other etiologies. 


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Grade 2 
• 
In general, hold D until resolution to ≤ Grade 1 and after the end of any steroid taper, and 
discontinue D permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities). Criteria for temporary hold or permanent discontinuation of D may differ by event 
as detailed below. 
• 
For myositis/polymyositis, hold D until resolution to ≤ Grade 1; permanently discontinue D if it 
does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory insufficiency. 
• 
For pneumonitis/interstitial lung disease and myocarditis, the decision to reinitiate D upon 
resolution shall be based upon treating physician’s clinical judgment (as long as the event does not 
meet DLT criteria). 
• 
For peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis, follow 
general instructions above, but always discontinue D permanently if there are signs of respiratory 
insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism and isolated Type 1 diabetes mellitus, 
follow general instructions above, but subjects may be retreated if the endocrinopathy is 
controlled and the subject is clinically stable while requiring steroid doses of ≤ 10 mg/day 
prednisone equivalent. 
• 
For isolated hypothyroidism managed with hormone replacement therapy, isolated Type 1 
diabetes mellitus treated with appropriate diabetic therapy, and for sensory 
neuropathy/neuropathic pain, holding D is at the discretion of the Investigator. 
• 
For elevated creatinine or rash, D should be held until resolution to ≤ Grade 1 or baseline and after 
completion of steroid taper. 
• 
For vitiligo, no dose modification required. 
Grade 3 
• 
In general, hold D until resolution to ≤ Grade 1, and after the end of any steroid taper, and 
discontinue D permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities and rash). Criteria for permanent discontinuation of D may differ by event as 
detailed below. 
• 
For myositis/polymyositis, follow Grade 2 instructions above. 
• 
For peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), apply 
respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For diarrhea/colitis, permanently discontinue D if toxicity does not improve to ≤ Grade 1 within 
14 days. 
• 
For pneumonitis/interstitial lung disease, myocarditis, and elevated serum creatinine (e.g., 
nephritis or renal dysfunction), always discontinue D permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold D, and if complete work up shows no 
evidence of pancreatitis, D may be continued. 
• 
For hepatitis, discontinue D permanently for (1) transaminases or bilirubin not resolving to ≤ Grade 
1 or baseline within 14 days, (2) transaminases > 8 × the upper limit of normal (ULN) or bilirubin > 
5 × ULN, or (3) any case meeting Hy’s law criteria (as defined in FDA Guidance Document “Drug-
Induced Liver Injury”). 
• 
For rash, D should be held until resolution to ≤ Grade 1 or baseline. 
Grade 4 
• 
In general, discontinue D permanently. 


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Durvalumab (D) Dose Modification Due to Toxicity 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold D, and if complete work up shows no 
evidence of pancreatitis, D may be continued.  
Infusion-related Reactions 
Grade 1 
• 
The infusion rate of D may be decreased 50% or temporarily interrupted until resolution of the 
event. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards at the 
discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤ Grade 2 infusion reactions. 
Grade 2: 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion rate. 
Grade 3 and 4: 
• 
The infusion must be stopped immediately and treatment permanently discontinued. 
• 
Manage severe infusion-related reactions per institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2  
• 
Hold D until resolution to ≤ Grade 1 or baseline, and discontinue D permanently if such resolution 
does not occur within 60 days. 
Grade 3 
• 
Hold D. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 14 
days, resume D administration at next scheduled dose. Otherwise, discontinue D permanently. 
Grade 4 
• 
In general, discontinue D permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment and in consultation with the Sponsor. 
 
8.3.2 Durvalumab Dose Modification Not Due to Treatment-related Toxicities 
Durvalumab administration may be modified or discontinued as a result of events other than 
toxicity, e.g., intercurrent illness or logistical/administrative reasons, whereby the following 
rules should apply: 
1. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may 
be made only for individual dosing days, whereby the interval between any two doses 
shall be no less than 21 days. All resulting protocol deviations should be documented. 


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2. If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
3. If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
4. If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
 
 


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8.4  Dose Modifications and Delays for ONCOS-102  
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3. or 8.4, 
and the toxicity causing agent can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing agent cannot be identified, then the more conservative guideline 
should be followed. 
8.4.1 Dose Modifications 
With a rapidly replicating virus, dose modifications are unlikely to be relevant or have any 
significant impact on the resulting production of virus particles. Thus, intra-subject dose 
reductions are not permitted. If a subject has an ONCOS-102 related toxicity, the subject should 
discontinue treatment.  
Subjects must be discontinued from ONCOS-102 treatment for deterioration of serum bilirubin, 
international normalized ratio (INR), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or creatinine by an increase of National Cancer Institute, common 
terminology criteria for adverse events (NCI CTCAE) toxicity Grade ≥2 from the baseline value: 
Laboratory variable 
Baseline value 
(predose on Day 1) 
CTCAE Grade after 
Day 1 - continue to 
treat 
CTCAE Grade after 
Day 1 - withdraw from 
treatment 
Bilirubin, INR 
Normal 
Grade 1 
Grade 2 or higher 
AST, ALT, creatinine 
Normal 
Grade 1 
Grade 2 or higher 
Grade 1 
Grade 2 
Grade 3 
 
8.4.2 Dose Delays Not Due to Toxicities 
For the administration of ONCOS-102, there will be a dosing window of ±2 days. If there is a 
delay of > 2 days, the dose should be skipped and the next scheduled drug administration 
should be performed. The respective protocol deviation should be documented. 
 
 


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8.5 Guidelines for RECIST 1.1 and irRECIST 
The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines were revised in 2009 as 
RECIST 1.1.(59) These guidelines have been the widely accepted criteria to assess response and 
progression in solid tumors; however, limitations have been noted in the use of RECIST 1.1 for 
immunotherapy trials. With immunotherapeutic agents, clinical trials have shown that complete 
response, partial response, or stable disease status can still be achieved after an initial increase 
in overall tumor burden, and regression of initial lesions may occur despite development of new 
lesions. The Immune-related Response Criteria (irRC) were developed to address the need for 
response criteria in an immunotherapy setting.(54)  The main difference with irRC was that it 
considered the subject's total tumor burden at each subsequent assessment and required 
confirmation of suspected disease progression with subsequent imaging, approximately four 
weeks later.  In addition, a greater number of lesions (10 vs. 5) were measured in a 
bidimensional manner instead of unidimensionally as in RECIST 1.1.  In 2013, Nishino et al. 
demonstrated that immune-related response criteria using unidimensional measurements were 
highly concordant with the bidimensional results of irRC, but with less measurement 
variability.(60)  Based on these findings and in order to utilize both the established criteria of 
irRC and RECIST 1.1, the two systems have been adapted, modified, and combined into the 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).(61)  The adapted 
irRECIST criteria are modifications to the irRC, incorporating the findings of Nishino et al. and the 
advantages of RECIST 1.1 while overcoming the shortcomings of each of the other guidelines.   
The guidelines for RECIST 1.1 are summarized below, followed by a summary for irRECIST. 
RECIST 1.1 
The following section outlines the RECIST 1.1 guidelines as published (59) and as summarized by 
National Cancer Institute for CTEP-involved clinical trials.   
I. 
Disease Parameters for RECIST 1.1 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria. 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
NOTE for irRECIST: During target lesion selection the radiologist will consider information on 
the anatomical sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, 
surgery, etc.). Lesions undergoing prior intervention will not be selected as target lesions 
unless there has been a demonstration of progress in the lesion. 


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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same subject, these are preferred for selection 
as target lesions. 
NOTE for irRECIST:  
Lesions that are partially cystic or necrotic can be selected as target lesions. The longest 
diameter of such a lesion will be added to the Total Measured Tumor Burden (TMTB) of all 
target lesions at baseline. If other lesions with a non-liquid/non-necrotic component are 
present, those should be preferred. 
Brain lesions detected on brain scans can be considered as both target or non-target lesions 
depending on the protocol definition. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any non-measureable as well 
as measurable lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  


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II. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans.  Body 
scans should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation by 


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CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published.(62-64)  In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer.(65)  
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If 
the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
3. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 


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III. 
Response Criteria for RECIST 1.1 
A. Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.   
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study 
B. Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single 
lesion increase.   
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
C. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


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1. For Subjects with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document the objective progression even after discontinuation of 
treatment. 
 
2. For Subjects with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an end-
point for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised. 
 
D. Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 


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irRECIST 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. (61) are presented 
below. 
I. 
Baseline Assessments in irRECIST 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1.  One new definition is 
added: If a subject has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-up time 
points unless new measurable lesions are identified and contribute to the total measured tumor 
burden (TMTB).  irND is a valid assessment in studies with adjuvant setting where the protocol 
and study design allow the inclusion of subjects with no visible disease 
II 
Follow-up Assessments in irRECIST 
A. Follow-up recording of target and new measurable lesions 
A key difference in irRECIST is that the appearance new lesions does not automatically 
indicate progression.  Instead, all measured lesions (baseline-selected target lesions and new 
measurable lesions) are combined into the total measured tumor burden (TMTB) at follow up.  
Baseline-selected target lesions and new measurable lesions are NOT assessed separately. 
Measurements of those lesions are combined into the TMTB, and one combined assessment 
provided. 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per 
time point), new lesions must meet criteria as defined for baseline target lesion selection and 
meet the same minimum size requirements of 10 mm in long diameter and minimum 15 mm in 
short axis for new measurable lymph nodes. New measurable lesions should be prioritized 
according to size, and the largest lesions elected as new measured lesions.  
B. Follow-up non-target assessment 
RECIST 1.1 definitions for assessment of non-target lesions apply.  The response of non-target 
lesions primarily contributes to the overall response assessments of irCR and irNon-CR/Non-PD 
(irNN). Non-target lesions do not affect irPR and irSD assessments. Only a massive and 
unequivocal worsening of non-target lesions alone, even without progress in the TMTB is 
indicative of irPD.  In alignment with RECIST 1.1, baseline selected non-target lesions can never 
convert to measurable lesions, not even if they increase in size at subsequent time points and 
become measurable. Only true new lesions can be measured and contribute to the TMTB. 
C. Follow-up for New Non-Measurable Lesions  
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only a massive and unequivocal progression of new non-
measurable lesions leads to an overall assessment of irPD for the time point. Persisting new 
non-measurable lesions prevent irCR.  


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III 
Overall Assessments for irRECIST 
The irRECIST overall tumor assessment is based on TMTB of measured target and new lesions, 
non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment (TA), the SumD 
of the target lesions and of new, measurable lesions (up to 2 new lesions per organ, total 5 new 
lesions) are added together to provide the total measurable tumor burden (TMTB). 
Overall Assessments by irRECIST 
Complete Response 
(irCR) 
Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. 
Partial Response 
(irPR) 
Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions 
• 
If new measurable lesions appear in subjects with no target lesions at 
baseline, irPD will be assessed. That irPD time point will be considered a 
new baseline, and all subsequent time points will be compared to it for 
response assessment. irPR is possible if the TMTB of new measurable 
lesions decreases by ≥ 30% compared to the first irPD documentation 
• 
irRECIST can be used in the adjuvant setting, in subjects with no visible 
disease on CT/MRI scans. The appearance of new measurable lesion(s) 
automatically leads to an increase in TMTB by 100% and leads to irPD. 
These subjects can achieve a response if the TMTB decreases at follow-up, 
as a sign of delayed response. 
• 
Based on the above, sponsors may consider enrolling subjects with no 
measurable disease and/or no visible disease in studies with response 
related endpoints. 
Stable Disease 
(irSD) 
Failure to meet criteria for irCR or irPR in the absence of irPD 
Progressive Disease 
(irPD) 
Minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first 
irPD assessment. An irPD confirmation scan may be recommended for subjects 
with a minimal TMTB %-increase over 20% and especially during the flare time-
window of the first 12 weeks of treatment, depending on the compound 
efficacy expectations, to account for expected delayed response. 
• 
In irRECIST a substantial and unequivocal increase of non-target lesions is 
indicative of progression. 
• 
IrPD may be assigned for a subject with multiple new non-measurable 
lesions if they are considered to be a sign of unequivocal massive 
worsening 
Other 
irNE: used in exceptional cases where insufficient data exist.  
irND: in adjuvant setting when no disease is detected 
irNN: no target disease was identified at baseline, and at follow-up the subject 
fails to meet criteria for irCR or irPD 
 


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8.6 ECOG Performance Status 
ECOG Performance Status: Developed by the Eastern Cooperative Oncology Group, Robert L. 
Comis, MD, Group Chair.(66) 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
 


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8.7 Exploratory Assessment of Correlative Immunologic Research 
Please refer to Section 4.3 for information on correlative testing and refer to the Study Laboratory 
Manual for instructions on specimen handling and logistics. 
 
 


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8.8 Details for Subjects who Continue Durvalumab Treatment beyond 
the Core Study 
According to Section 3.1.12, optional durvalumab treatment extension beyond Core Study is 
available for subjects who complete the Core Study with Stable Disease or better. The optional 
treatment extension will be permitted upon agreement with the subject, Sponsor and 
Investigator, and it may continue until confirmed disease progression, unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.  
The flowchart for optional treatment extension in Section 8.8.1 will be followed. 
Preparation and administration of durvalumab will proceed according to Section 6.1.   
Collection and reporting of AEs/SAEs will be performed according to the protocol requirements 
(Section 7.1 ) and until disease progression is documented.  For AEs/SAEs that may be ongoing 
at the time of disease progression, follow-up will be performed until resolution or stabilization 
of the events or up to 90 days after the last dose of durvalumab. 
 
Per Amendment 6.1: 
By the date of implementation of this amendment, all subjects will have completed treatment 
and applicable On Study Follow-up, with the exception of one subject in optional treatment 
extension who will complete treatment and On Study Follow-up by 30 June 2022. This 
amendment provides that the Post Study Follow-up for the collection of survival data will be 
discontinued as of 30 June 2022, and the study will be completed. 
 
 
 


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8.8.1 Study Flowchart for Subjects who Continue Durvalumab Treatment beyond 
the Core Study 
 
 
 
Post Study 
Follow-upe
Durvalumab  (IV) 
Tumor and Disease Assessments
Disease Assessment by RECIST 1.1/irRECIST (see 
Sections 4.2 and 8.5 for details on scans and 
confirmation)
Blood for CA-125 for ovarian or CEA for CRC (must 
be at same time points as disease assessments; 
test will be performed by local lab)c
Physical Exam (incl. weight and ECOG Perf Status)
x
x
x
12-Lead ECGa
x
Vital Signs (T, HR, BP, RR) - pre dose 
x
x
x
Concomitant Medication / Procedure  (name, 
indication, dose, route, start & end dates)
x
x
x
Adverse Events (starting or worsening after IC)b
x
x
x
Blood Hematology (CBC, differential, platelets)a
x
x
x
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca, 
Mg, protein, alb, TBili, AST, ALT,  ALP, LDH)a
x
x
x
Chemistry Cont. (Free  T3, Free T4, TSH)a
x
x
x
Chemistry Cont. (amylase, lipase)a
x
x
x
Urinalysisa
x
x
x
Coagulation parameters (PT, aPTT, INR)a
x
Serum pregnancy test a
x
x
Blood for PBMC Collection and Bankingd
x
Blood for Th1/Th2/Th17 cytokines in serum
x
Overall Survival
xe
Progression Free Survival
xe
a - Collected pre-dose (if applicable). Note: It is strongly recommended that test results are reviewed before dosing for hematology, 
      chemistry (including amylase, lipase, and thyroid pre durvalumab) and pregnancy (when applicable). 
b - See section 7.1.5 of protocol  for details regarding collection of AEs for 90 days after last study drug administration
c - Collected together with routine lab assessment blood draw (pre-dose, if applicable)
d - Six CPT tubes per time point (pre-dose if applicable)  -> PBMC isolation; used for banking PBMCs and plasma 
e - Per Amendment 6.1, all post study follow-up for the collection of survival data will be discontinued as of 30 June 2022 (see Section 8.1, Amendment 6.1)
Q4W = every 4 weeks; Q12W = every 12 weeks; SOC = standard of care
Q4W
At first optional treatment visit, then every 6 months
At first optional treatment visit, then every 6 months
At first optional treatment visit, then every 6 months
Q4W
Q4W
Q4W
Post Study Follow-upe
Specimens for Routine Laboratory Procedures
Specimens for Biological Markers and Correlative Studies
At first optional treatment visit, then Q12W
At first optional treatment visit, then Q12W
At first optional treatment visit, then Q12W
At first optional treatment visit, then Q12W
At first optional treatment visit, then Q12W
At first optional treatment visit, then every 6 months
At first optional treatment visit, then Q12W
Every 6 months (± 
1 month)  for 3 
years from 
initiation of 
treatment
SOC
Study Drug Administration 
Study Procedures and Examinations
On Study Follow-up
If subject has not progressed, one 
tumor/disease assessment should be 
done, either at treatment  
discontinuation or at some point during 
on study follow-up
LUD2015-008 - Study Flowchart for 
Subjects who Continue Optional 
Durvalumab Treatment 
after Core Study
Optional Study Treatment
(Q4W following Cycle 12 study treatment dose)
Last Study 
Drug Dose 
+28 (+3) days
Last Study 
Drug Dose 
+56 (+7) days
 Last Study 
Drug Dose 
+91 (+7) days  
End of  Study
If subject has not progressed, one 
tumor/disease assessment should be 
done, either at treatment  
discontinuation or at some point during 
on study follow-up
1500 mg Q4W
SOC


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8.9 List of Abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATAP 
Advanced Therapy Access Program 
AUC 
area under the concentration time curve 
BSA 
Body surface area 
BSL-2 
Biosafety level 2  
CBC 
Complete Blood Count 
CB 
Clinical benefit 
CD 
Cluster of differentiation 
Cmax 
peak concentration 
Cmin 
trough concentration  
CPO 
cyclophosphamide  
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-Lymphocyte Antigen 4 
DCB 
Durable clinical benefit 
DL 
Dose level (or starting dose level) 
DLT 
Dose-limiting Toxicity 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GMCSF 
granulocyte-macrophage colony stimulating factor 
GMM 
genetically modified micro-organism  
HLA 
Human Leukocyte Antigen 
IB 
Investigator's Brochure 
ICD 
Immunogenic cell death 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IgG2 
immunoglobulin G2  
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
irAE 
Immune-related Adverse Events 
irCR 
Immune-related Complete Response 
irPD 
Immune-related Progressive Disease 


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irPR 
Immune-related Partial Response 
irRECIST 
Immune-related Response Evaluation Criteria In Solid Tumors 
irSD 
Immune-related Stable Disease 
ITT 
Intent to treat 
IV 
intravenous 
LICR 
Ludwig Institute for Cancer Research 
LLN 
Lower limit of normal 
mAb 
Monoclonal antibody 
MDSC 
Myeloid derived suppressor cells  
MSI 
Microsatellite instability 
NCI CTCAE 
National Cancer Institute, common terminology criteria for adverse events  
ORR 
Objective response rate 
OS 
Overall survival 
OV 
Oncolytic virus 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-1 
programmed cell death-1  
PD-L1 
programmed cell death ligand-1  
PFS 
Progression-free survival 
PP 
Per protocol 
PR 
Partial response 
PSDSS 
peritoneal surface disease severity score  
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
RCD 
Recommended combination dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable disease 
TEAE 
treatment-emergent adverse events  
T-VEC 
talimogene laherparepvec  
TMTB 
Total measured tumor burden 
ULN 
Upper limit of normal 
VP 
Viral particle 
WFI 
Water for injection 
w/v 
Weight/volume 
 
 


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Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety and 
Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant 
Ovarian Cancer. J Clin Oncol. 2015;Sep 8. pii: JCO.2015.62.3397. [Epub ahead of print]. 
52. 
Disis M, Patel M, Pant S, Infante J, et al.  Avelumab (MSB0010718C), an anti-PD-L1 
antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, 
open-label expansion trial. J Clin Oncol 2015;33:(suppl; abstr 5509). 
53. 
Varga A, Piha‐Paul S, Ott P, Mehnert J, et al.  Antitumor activity and safety of 
pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results 
from a phase Ib study. J Clin Oncol  2015;33:suppl; abstr 5510. 
54. 
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2009;15(23):7412-20. 
55. 
Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, et al. A clinical 
development paradigm for cancer vaccines and related biologics. Journal of immunotherapy. 
2007;30(1):1-15. 
56. 
Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, et al. Improved 
endpoints for cancer immunotherapy trials. Journal of the National Cancer Institute. 
2010;102(18):1388-97. 
57. 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of 
medicine. 2012;366(26):2443-54. 
58. 
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. The New England journal of medicine. 
2012;366(26):2455-65. 
59. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European 
journal of cancer. 2009;45(2):228-47. 
60. 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya N, Hodi FDaclftrtii-
rrcuumCCR-. Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clinical cancer research : an 
official journal of the American Association for Cancer Research. 2013;19(14):3936-43. 
61. 
Bohnsack O, Ludajic K, A H. Adaptation of the immune-related response criteria: 
irRECIST. ESMO 2014 Poster. Annals of Oncology. 2014;25(Suppl 4): iv361-iv72. 
62. 
Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. Re: New 
guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). Journal of the 
National Cancer Institute. 2004;96(6):487-8. 
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Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. Eligibility 
and response guidelines for phase II clinical trials in androgen-independent prostate cancer: 


C O N F I D E N T I A L  
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recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 
1999;17(11):3461-7. 
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Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and 
end points of clinical trials for patients with progressive prostate cancer and castrate levels of 
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Oncol. 2008;26(7):1148-59. 
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Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, et al. 
Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. 
Gynecologic Cancer Intergroup. Journal of the National Cancer Institute. 2000;92(18):1534-5. 
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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
 

SAP_001.pdf: 
 
 
 
Template #: ST-T-002A  Ver.: 2.0                                     Effective Date: 11 DEC 2017  
CONFIDENTIAL EXCLUSIVE PROPERTY OF ADVANCED CLINICAL, LLC  Page 1 of 26 
 
 
Ludwig Institute for Cancer Research (LICR) 
 
 
Statistical Analysis Plan 
 
Protocol Number: LUD2015-008 
Amendment 5 (19-June-2019)  
 
A Phase 1/2 dose escalation study with expansion cohorts to investigate the safety, 
biologic and anti-tumor activity of ONCOS-102 in combination with durvalumab in 
subjects with advanced peritoneal malignancies 
 
SPONSOR 
Ludwig Institute for Cancer Research Ltd.  
New York, NY 
Version 4.0 
26-FEB-2021 


  
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TABLE OF CONTENTS 
1 
Introduction ........................................................................................ 6 
2 
Overall Study Design and Objectives .................................................. 6 
2.1 
Study Objectives .................................................................................................. 6 
2.1.1 
Primary Objectives ........................................................................ 6 
2.1.2 
Secondary Objectives .................................................................... 6 
2.2 
Trial Design and Study Procedures...................................................................... 7 
2.2.1 
Study Design ................................................................................. 7 
2.2.2 
Treatments and Assignment to Treatments ................................... 7 
2.3 
Determination of Sample Size ............................................................................. 8 
3 
General Analysis Conventions ............................................................. 8 
3.1 
Study Periods ....................................................................................................... 8 
3.2 
Visit Windows ..................................................................................................... 8 
3.3 
Baseline ................................................................................................................ 9 
3.4 
Coding dictionaries .............................................................................................. 9 
4 
Analysis Populations ........................................................................... 9 
4.1 
Intent to Treat Population for Clinical Efficacy .................................................. 9 
4.2 
Per Protocol Population for Clinical Efficacy ................................................... 10 
4.3 
Per Protocol Population for DLT Assessment ................................................... 10 
4.4 
Safety Population ............................................................................................... 10 
5 
Protocol Deviations ........................................................................... 10 
6 
Subject Disposition ........................................................................... 10 
7 
Demographics and Baseline Characteristics ..................................... 11 
7.1 
Demographic Characteristics ............................................................................. 11 
7.2 
Medical History ................................................................................................. 11 
7.3 
Oncological Treatment History.......................................................................... 12 
8 
Efficacy Analysis ............................................................................... 12 
8.1 
Primary Efficacy Analysis for the Expansion Phase ......................................... 12 
8.2 
Secondary Efficacy Analysis ............................................................................. 12 
8.2.1 
Objective Response Rate (ORR) ................................................. 12 


  
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8.2.2 
Durable Clinical Benefit (DCB) .................................................. 13 
8.2.3 
Progression-free Survival (PFS) .................................................. 13 
8.2.4 
Overall Survival (OS) .................................................................. 14 
8.2.5 
Duration of Response (DoR) ....................................................... 14 
8.2.6 
Analysis of Time to Event (TTE) Variables ............................... 14 
9 
Statistical/Analytical Issues ............................................................. 15 
9.1 
Handling of Dropouts or Missing Data .............................................................. 15 
9.2 
Multiple Comparisons/Multiplicity ................................................................... 15 
9.3 
Examination of Subgroups ................................................................................. 15 
9.4 
Interim Analysis ................................................................................................. 16 
9.5 
Safety Monitoring and Study Stopping Rules ................................................... 16 
10 
Safety Analysis .................................................................................. 16 
10.1 
Study Drug Exposure ......................................................................................... 16 
10.2 
Adverse Events .................................................................................................. 16 
10.2.1 
Treatment Related Adverse Events ............................................. 17 
10.2.2 
Adverse Events TEAEs Leading to Study Drug Withdrawal ..... 17 
10.2.3 
DLTs ............................................................................................ 17 
10.2.4 
Serious Adverse Events ............................................................... 17 
10.3 
Clinical Laboratory Data.................................................................................... 17 
10.4 
Vital Signs .......................................................................................................... 19 
10.5 
ECOG performance status ................................................................................. 19 
10.6 
Prior and Concomitant Medications and Procedures ......................................... 19 
11 
Quality Control .................................................................................. 19 
12 
Tables and Listings Conventions ....................................................... 20 
12.1 
Statistical Table Conventions ............................................................................ 21 
12.2 
Data Listing Conventions .................................................................................. 21 
13 
References ........................................................................................ 21 
14 
List of Statistical Tables, Listings and Figures to Be Programmed .... 21 
14.1 
Statistical Tables ................................................................................................ 21 
14.2 
Figures................................................................................................................ 23 


  
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14.3 
Data Listings ...................................................................................................... 24 
15 
Change history .................................................................................. 26 
 


  
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ACRONYMS 
Below is the list of acronyms that will be used throughout this document. 
Abbreviation 
Definition 
AE 
Adverse Event 
ATC-4 
Anatomical Therapeutic Chemical level 4 
CB 
Clinical Benefit 
CP 
Clinical Progression 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DCB 
Durable Clinical Benefit 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
IP 
Intraperitoneally 
irRECIST 
Immune-related Response Evaluation Criteria in Solid 
Tumors 
ITT 
Intent to Treat 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PP 
Per Protocol 
Q4W 
Once every four weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
VPs 
Viral particles 
WHO 
World Health Organization 
 


  
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1 
Introduction 
This SAP describes the methods to be used in the analysis of study data from clinical 
protocol LUD2015-008 in order to answer the study objectives, and is based on 
Amendment 5 of the study protocol, dated 19June2019. 
Populations for analysis, data handling rules, statistical methods, and formats for data 
presentation are described within this document. The statistical analyses and summary 
tabulations described in this SAP will provide the basis for the results sections of the 
CSR for this trial. The SAP outlines any differences in data analysis methods relative to 
those planned in the study protocol. Any changes to the data analysis methods after the 
SAP is finalized will be described in the CSR. 
2 
Overall Study Design and Objectives 
2.1 
Study Objectives 
2.1.1 
Primary Objectives 
Dose Escalation Phase: 
Safety and Tolerability including: 
• Recommended combination dose (RCD) of durvalumab and ONCOS-102 
• Dose Limiting Toxicities (DLTs) according to Common Terminology Criteria for 
Adverse Events (CTCAE) 4.03 
Expansion Phase:   
• Clinical Benefit (CB) by Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1, defined as the percentage of subjects who are not in progression at end of Week 
24 
2.1.2 
Secondary Objectives 
Dose Escalation and Expansion Phases (all subjects): 
• Safety and Tolerability per AEs, SAEs, laboratory data, and vital sign data 
• Clinical Efficacy by RECIST 1.1/ Immune-related Response Evaluation Criteria in 
Solid Tumors (irRECIST) 
o Durable Clinical Benefit (DCB), defined as the percentage of subjects meeting 
criteria of Stable Disease (SD), partial response (PR), or complete response (CR) 
over a period of at least 24 weeks 
o Overall Response Rate (ORR) after 8 and 24 weeks 
o Progression Free Survival (PFS) 
o Overall Survival (OS) 


  
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2.2 
Trial Design and Study Procedures 
2.2.1 
Study Design 
This is a two-part Phase 1/2 dose escalation and dose expansion study of the GMCSF-
encoding adenovirus, ONCOS-102, in combination with anti-programmed death ligand-1 
(PD-L1) antibody, durvalumab, in adult subjects with peritoneal disease who have 
histologically confirmed epithelial ovarian cancer or metastatic colorectal cancer and 
have failed prior standard therapies. 
ONCOS-102 will be administered intraperitoneal (IP) infusion at weekly intervals for 6 
weeks. A bolus dose of 300 mg cyclophosphamide will be administered intravenously 
(IV) 1 to 3 days before the first infusion of ONCOS-102.  Durvalumab will be 
administered by IV infusion once every four weeks (Q4W) for a total of 12 four-week 
cycles.  
Phase 1 of the study is a dose escalation phase, which will use a 3+3 design to evaluate 
the safety of ONCOS-102 monotherapy before initiation of durvalumab and to identify 
the RCD of ONCOS-102 when given with a fixed dose of durvalumab (1500 mg).  Two 
dose levels of ONCOS-102 will be used: 1 x 1011 viral particles (VPs) and 3 x 1011 VPs. 
Phase 2 of the study is the dose expansion phase, which will further explore the safety 
and anti-tumor activity for the RCD in 2 expansion cohorts with peritoneal disease: 
• Cohort 1 (OC): Platinum-resistant epithelial ovarian cancer  
• Cohort 2 (CRC): Metastatic colorectal cancer  
Simon’s 2-Stage MINIMAX Design will be used in Phase 2 for Expansion Cohorts 1 
(OC) and 2 (CRC). In the first stage, 18 subjects will be enrolled in Cohort 1 (OC) and 13 
subjects in Cohort 2 (CRC), including the subjects who received RCD in Phase 1. If 5 or 
more subjects in Cohort 1 (OC), or one or more subjects in Cohort 2 (CRC), demonstrate 
clinical benefit (defined as percentage of subjects who are not in progression at end of 
Week 24), 15 additional subjects will be enrolled in Stage 2 of Cohort 1 (OC), and 14 
additional subjects will be enrolled in Stage 2 of Cohort 2 (CRC).  
2.2.2 
Treatments and Assignment to Treatments 
All subjects in the study will receive ONCOS-102 and durvalumab. A single dose of 
cyclophosphamide will be given prior to the first dose of ONCOS-102.  
In the Phase 1, subjects will be enrolled and assigned treatment in parallel in a non-
randomized, sequential manner, with competitive enrollment between study sites.  The 
treatments for the 3 Phase 1 cohorts are defined as follows: 
• Cohort A: ONCOS-102, 1 x 1011 viral particles (VPs) monotherapy for 6 weeks, 
followed by durvalumab 1500 mg starting on Day 71.  
• Cohort B: ONCOS-102, 1 x 1011 VPs + durvalumab 1500 mg. 


  
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• Cohort C: ONCOS-102, 3 x 1011 VPs + durvalumab 1500 mg. 
NOTE: if a subject’s body weight drops to ≤ 30 kg while on the study, the durvalumab 
dose will be 20mg/kg Q4W as long as the body weight remains ≤ 30 kg. 
Phase 2 will use the RCD of ONCOS-102 + durvalumab 1500 mg found in Phase 1. 
2.3 
Determination of Sample Size  
The dose escalation phase will utilize a standard 3+3 design for 3 cohorts, which will 
result in the enrollment 12 to 18 subjects. 
In the expansion phase, up to 33 subjects will be enrolled in Cohort 1 (OC), and up to 27 
subjects will be enrolled in Cohort 2 (CRC), for a total of up to 60 subjects.   
The sample size rationale for Cohorts 1 (OC) and 2 (CRC) of the expansion phase is 
based on Simon’s 2-Stage MINIMAX Design with a Type I error rate of 0.05 and 80% 
power.  
For Cohort 1, the null hypothesis for the clinical benefit rate (number of subjects who are 
not in progression) at end of Week 24 for Cohort 1 (OC) will be 20%, which will be 
tested against a one-sided alternative of 40%. In the first stage, 18 subjects will be 
accrued to Cohort 1 (OC). If clinical benefit at end of Week 24 is seen in <5 of these 
subjects, the study of Cohort 1 (OC) will be stopped. If 5 or more subjects demonstrate 
clinical benefit at end of Week 24, an additional 15 subjects will be accrued to a total of 
33. The null hypothesis will be rejected if 11 or more subjects experience clinical benefit 
at end of Week 24. 
For cohort 2 (CRC), the null hypothesis for the clinical benefit rate at end of Week 24 
will be 5%, which will be tested against a one-sided alternative of 20%. In the first stage, 
13 subjects will be accrued to Cohort 2 (CRC). If clinical benefit at end of Week 24 is 
seen in <1 of these subjects, the study of Cohort 2 (CRC) will be stopped. If 1 or more 
subjects demonstrate clinical benefit at end of Week 24, an additional 14 subjects will be 
accrued to a total of 27. The null hypothesis will be rejected if 4 or more subjects 
experience clinical benefit at end of Week 24.  
3 
General Analysis Conventions 
3.1 
Study Periods 
The study will include screening, a treatment period for up to 12 cycles, On Study 
Follow-up phase for 90 days after the end of study drug administration, and Post Study 
Follow-up phase for up to 3 years from the start of treatment. 
3.2 
Visit Windows 
The protocol visit windows are defined as shown in Table 1. Visits will be analyzed per 
the eCRF collection.   


  
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Table 1 
Visit Windows 
Visit 
Window 
Screening 
Day -28 to -1 
Cycle 1, Days 8, 15, 22 
Cycle 2, Days 1, 8 
+/- 2 day 
Day 15 of Cycles 2, 3 
+/- 3 days 
Day 1 of Cycles 3, 5, 7 
+/- 4 days 
Day 15 of Cycles 4 - 12 
+/- 7 days 
On Study Follow-up 
28 (+/-3) days post last dose 
56 (+/-7) days post last dose 
91 (+/-7) days post last dose 
Post Study Follow-up 
+/- 1 month 
          Note: Visit days are defined from baseline (Cycle 1, Day 1 visit). 
It should be noted that summary tables will present only planned study visits, 
Unscheduled visit will not appear in the summary tables.  However, all Unscheduled 
visits will appear in the listings.  Also, if multiple assessments are performed during the 
same visit (i.e. multiple vital signs collected, repeat laboratory assessment taken) the first 
collection will be presented in summary tables but all data will be presented in listings. 
3.3 
Baseline 
Unless specified otherwise, baseline measurements will be the most recent value prior to 
receiving the first dose of study medication.   
3.4 
Coding dictionaries 
Medical history, adverse events, and concurrent procedures will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), Version 19 and Prior and concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
Version WhoDrug_DDE_B2_201603. 
4 
Analysis Populations 
4.1 
Intent to Treat Population for Clinical Efficacy 
The Intent-To-Treat (ITT) Population for Clinical Efficacy is defined as all subjects who 
receive at least one dose of durvalumab or ONCOS-102. All efficacy analysis will be 
performed on the ITT Population for Clinical Efficacy unless noted.  Please note: the ITT 
population is identical to the Safety population as defined below. 


  
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4.2 
Per Protocol Population for Clinical Efficacy 
The Per-Protocol (PP) Population for Clinical Efficacy of the combination therapy is 
defined as all subjects who receive at least 60% of the scheduled doses of ONCOS-102 
and at least 1 dose of durvalumab (Cohorts B and C only in escalation and both cohorts in 
expansion) over the first 2 cycles, as well as respective disease assessments, without 
major protocol violations.  All efficacy analysis will be performed on the PP Population 
for Clinical Efficacy unless noted. 
4.3 
Per Protocol Population for DLT Assessment 
The Per-Protocol (PP) Population for DLT Assessment is defined as all subjects who 
meet one of the two criteria: 
• Experienced a DLT at any time during the DLT Evaluation Period. 
• No DLT and received at least 60% of the scheduled doses of ONCOS-102 and at least 
1 dose of durvalumab (Cohorts B and C only) as well as respective safety assessments 
without major protocol deviations during the DLT Evaluation Period. The sponsor 
will define and provide all major protocol deviations that occur. 
For Cohort A, the DLT Evaluation Period is the period from Day 1 of the study up to and 
including the Week 9 (Cycle 3 Day 1) study assessments.  
For Cohorts B and C, the DLT Evaluation Period is the period from Day 1 of the study up 
to and including the Week 11 (Cycle 3, Day 15) pre-dose study assessments. 
4.4 
Safety Population 
The Safety Population is defined as all subjects who receive at least one dose of 
durvalumab or ONCOS-102. The Safety population will be used for AEs, SAEs, 
laboratory data, and vital sign data.   
5 
Protocol Deviations 
Protocol deviations are recorded in a written log. Any major protocol deviations will be 
described in the study report.   
6 
Subject Disposition  
Subject disposition will be presented by cohort and overall. The number of subjects 
enrolled in each analysis population will be presented. 
The following will be summarized: 
• Number and percentage of Safety population 
• number and percentage of PP for DLT Assessment subjects experiencing a DLT by 
cohort 
• number and percentage of ITT for Clinical Efficacy subjects  


  
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• number and percentage of PP for Clinical Efficacy subjects  
• number and percent of subjects discontinuing treatment (this would be < 12 cycles of 
therapy) 
• Reasons for treatment discontinuation.  
• Number and percentage of subjects completing study (completion is 12 months of 
therapy and on study follow-up) 
• Reasons for study discontinuation 
Descriptive statistics will also be presented for duration of time in study for subjects (start 
of therapy to last visit of follow-up).  In addition to this, the duration of follow-up will be 
presented for overall survival in two ways using Kaplan-Meier methods: the first will be 
using the traditional “censor” and “event” flags as described in Section 8.2.4; the second 
will be constructed by reversing the “censor” and “event” flags (e.g. reverse Kaplan-
Meier) to assess the length and completeness of follow-up.  
7 
Demographics and Baseline Characteristics 
7.1 
Demographic Characteristics 
Demographic and baseline characteristics at study entry will be summarized for the 
Safety population, ITT for Clinical Efficacy Population and PP for Clinical Efficacy 
Population by cohort (within Phase 1 and Phase 2) and all cohorts overall.  
Demographic and baseline variables to be summarized are: 
• Continuous variables 
- Age (years) at time of consent 
- Height (cm) 
- Weight (kg) 
• Categorical variables  
- Gender 
- Race 
- Ethnicity 
- Disease staging at initial diagnosis and study entry; MSI, MMR, KRAS 
NRAS status 
7.2 
Medical History 
The number and percentage of subjects having a non-oncological medical condition in 
each MedDRA preferred term and lower level term as reported on the eCRF will be 


  
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summarized for the Safety population.  Non-oncological medical history will be 
presented in a subject listing. 
7.3 
Oncological Treatment History  
Frequencies and percentages will be tabulated for prior anti-cancer treatment use by lines 
of therapy for the Safety population overall.  In addition, these summaries will be 
displayed by Phase 2 cohort (Ovarian and CRC). Prior oncological treatment, radiation 
and surgical history will be presented in subject listings. 
8 
Efficacy Analysis 
8.1 
Primary Efficacy Analysis for the Expansion Phase 
The primary efficacy endpoint for the expansion phase is the Progression Free Survival  
rate at Week 24 (PFS 24) defined as percentage of subjects who are not in disease 
progression at the end of Week 24. 
For Phase 2, the primary endpoint analyses of PFS 24 will be conducted as follows on the 
ITT and PP populations using RECIST 1.1: 
• Cohort 1:  The null hypothesis of PFS 24 = 20% will be tested against a one-sided 
alternative of PFS 24 = 40% at 0.05 level of significance based on Simon 2-stage 
Minimax criterion. The null hypothesis will be rejected if 11 or more of 33 subjects 
experience clinical benefit at end of Week 24. 
• Cohort 2:  The null hypothesis of PFS 24 = 5% will be tested against a one-sided 
alternative of PFS 24 = 20% at 0.05 level of significance based on Simon 2-stage 
Minimax criterion. The null hypothesis will be rejected if 4 or more of the 27 subjects 
experience clinical benefit at end of Week 24.   
The number and percentage of subjects without progression will be presented. A 95% CI 
based on binomial distribution will be constructed for the estimated PFS 24.  
The analysis of PFS 24 will be repeated using irRECIST for both the ITT and PP 
populations without the hypothesis testing. 
8.2 
Secondary Efficacy Analysis 
8.2.1 
Objective Response Rate (ORR) 
ORR is defined as the percentage of subjects meeting criteria of Complete Response 
(CR) or Partial Response (PR). CR or PR must be confirmed at least 4 weeks after the 
date of the original CR or PR. For ovarian cancer subjects if the CA-125 is initially above 
the upper limit, the CA-125 value must normalize for a subject to be considered in CR for 
RECISIT 1.1. The number and percentage of these response categories will be presented. 


  
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The ORR rate at 8 and 24 weeks will be reported along with a 95% CI based on the exact 
binomial distribution. The ORR at 8 and 24 weeks will be based on the disease 
assessment scheduled at Week 9 and Week 25, respectively, with confirmation of 
response at least 4 weeks after the assessment. Subjects who drop out without a disease 
assessment will be considered a non-responder at the corresponding time point. These 
subjects will be included in the denominator when calculating the ORR. 
Best Overall Response (BOR) will also be presented. In the determination of BOR, any 
subsequent scans on or after the date of a clinical progression will be ignored. .  
The analysis will be performed on both the ITT and PP populations and using both 
RECIST 1.1 and irRECIST. 
8.2.2 
Durable Clinical Benefit (DCB) 
DCB is defined as the percentage of subjects meeting criteria of stable disease (SD), 
partial response (PR), or complete response (CR) over a period of at least 24 consecutive 
weeks. Visits with a non-evaluable assessment (or non-confirmed progression for 
irRECIST) will be not considered a break in the 24 consecutive weeks required for DCB 
as long as the assessment prior and after are SD or better. If a subject had clinical 
progression (CP), any recorded response (CR or PR) after the date of CP will be 
considered invalid. 
The estimated DCB will be reported along with a 95% CI based on the exact binomial 
distribution. 
The analysis will be performed on both the ITT and PP populations and using both 
RECIST 1.1 and irRECIST. 
8.2.3 
Progression-free Survival (PFS) 
PFS is defined as the interval between the date of first dose to the date of earliest 
determination of progressive disease (PD), clinical progression (CP) or death whichever 
comes first. If progression or death did not occur, subjects will be censored at start of 
alternative therapy or the last available tumor assessment.  
Descriptive analyses of PFS will include the following: 
• Number and percentage of subjects that died or had a progressive disease or clinical 
progression, 
• Number and percentage of subjects censored: 
o Number and percentage of subjects lost to follow up (unknown survival 
and/or progression status)  
o Number and percent of subjects survived without progression 
o Number and percentage of subjects missing tumor response assessment.  


  
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o Number and percentage of subjects who were offered alternative therapy  
The analysis will be performed on both the ITT and PP populations and using both 
RECIST 1.1 and irRECIST. 
8.2.4 
Overall Survival (OS) 
OS is defined as the time from date of first dose until date of death. The number and 
percentage of subjects who died, who were lost to follow up, and who survived will be 
summarized. Subjects who survived will be censored at the date of last contact/last data 
point collected in the CRF. 
OS Rate and the corresponding 95% confidence intervals at 6 months and 12 months will 
be calculated based on Kaplan-Meier product limit estimates and will be displayed along 
with the corresponding number of subjects at risk at each time point.  
The analysis will be performed on both the ITT and PP populations and using both 
RECIST 1.1 and irRECIST. 
8.2.5 
Duration of Response (DoR) 
Duration of response (DOR) is defined as the time from the first documentation of 
RECIST- defined confirmed response (CR or PR) to the first date that recurrent or 
progressive disease is objectively documented, clinical progression or death whichever 
comes first.  Censoring will be at the last available tumor scan if PD, CP or death did not 
occur.  
 
The DoR analysis will be performed on only those subjects with a confirmed response 
(CR, PR). The analysis will be performed on both the ITT and PP populations and using 
both RECIST 1.1 and irRECIST. 
8.2.6 
Analysis of Time to Event (TTE) Variables 
Progression Free Survival (PFS), OS and DoR will be analyzed using the Kaplan-Meier 
method. The Duration of follow-up (in months) will be analyzed using the Reverse 
Kaplan-Meier product limit estimation method.  
For all time to event analysis the number of events, number censored, 25th percentile, 
median, 75th percentile, corresponding 95% CIs as well as the minimum and maximum 
survival time will be presented in tables. In addition, survival curves will be presented 
graphically.  


  
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9 
 Statistical/Analytical Issues 
9.1 
Handling of Dropouts or Missing Data 
Algorithms for imputing partial or missing dates are shown below for adverse event (AE) 
start dates and defining concomitant medication based on missing start or stop dates. No 
other missing data will be imputed.   
The following imputation rules will be used for missing or incomplete AE start dates:  
• Missing AE start day:  
o If the partial date contains a different month from the date of first study dose, then 
impute it as the first day of the month.  
o If it contains the same month as the date of first dose, then impute it as date of 
first dose.  
• Missing AE start day and month:  
o If the partial date contains a different year from the date of first dose, then impute 
the missing day and month as Dec 31.  
o If it contains the same year as the date of first dose, then impute the missing day 
and month as day and month of first dose.  
• Completely missing AE date:  
o Impute the missing date as the date of first dose.  
Defining concomitant medications for medications with missing start or stop dates: 
• if both the start and stop dates of a particular medication are missing, that medication 
will be considered concomitant; 
• if the start date of a medication is missing and the stop date of that medication falls on 
or after the first dose date, that medication will be considered concomitant; 
• if the start date of a medication is missing and the stop date of the medication is prior 
to the first dose date, that medication is considered not concomitant; 
• If the start date of a medication is prior to the first dose date and the stop date of the 
medication is missing, that medication is considered concomitant. 
9.2 
Multiple Comparisons/Multiplicity 
There will be no adjustment for multiplicity. 
9.3 
Examination of Subgroups 
No analysis of subgroups is planned. 


  
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9.4 
Interim Analysis  
Interim analyses will be performed at the end of Simon Stage 1 for Cohorts 1 and 2 as 
described in Section 8. Safety analyses will be performed to assess DLTs in the dose 
escalation cohorts. 
9.5 
Safety Monitoring and Study Stopping Rules 
Safety Monitoring will be performed by an internal data safety monitoring panel, 
consisting of the Principal Investigators (and co-investigators as needed), the Sponsor’s 
Medical Monitor/Clinical Advisor, and drug safety personnel from Medimmune 
(AstraZeneca)/ TARGOVAX, providers of the study drugs.  Additional investigators and 
staff, or additional Sponsor personnel and consultants, shall participate in reviews, if 
indicated.  The internal data safety-monitoring panel will communicate by phone and/or 
email on a regular basis, and in particular, to review the safety of individual cohorts for 
the purpose of dose escalation. 
An Independent Data Monitoring Board will not be utilized for this open-label study. 
10 
Safety Analysis 
10.1 
Study Drug Exposure  
For each subject, treatment duration and the total number of cycles treated will be 
calculated based on the expected treatments for that subject in accordance with their 
assigned cohort. Treatment duration (weeks) will be calculated for each subject as: ([date 
of last dose of any study drug received – date of first dose of any study drug received 
+1]/7).  
Descriptive statistics for treatment duration and the total number of treatment cycles will 
be displayed. The number of doses and cumulative dose received will be summarized for 
durvalumab and ONCOS-102. Study drug administration will be presented in a by subject 
listing. 
10.2 
Adverse Events 
All tables will only include treatment emergent adverse events (TEAEs), where TEAEs 
are defined as any AE that occurs on or after the day of the first dose of study drug and 
up to 90 days after the last dose of study drug or administration of alternate therapy. 
Listings will include all reported AEs flagging events that were TEAEs. 
All adverse events will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA) and will be classified by MedDRA system organ class (SOC) and preferred 
term (PT).   
The number and percentage of subjects who experienced at least one TEAE by PT as 
well as the number and percentage of subjects who experienced at least one TEAE within 
each specific SOC and PT will be presented overall and by Phase 2 tumor type and Phase 


  
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1 cohort. For the presentation of AE incidences, the SOCs will be sorted alphabetically, 
and within SOC, the preferred term (PT) will be presented by decreasing total frequency.  
Adverse event toxicity grade will be classified using NCI-CTCAE Version 4.03 criteria. 
TEAEs will be presented by maximum CTCAE grade for each PT by cohort. For this 
analysis, if a subject has more than one occurrence of the same PT, then the PT will be 
counted only once for that subject under the maximum grade at which it was experienced. 
A missing toxicity grade will not be imputed.  
10.2.1 
Treatment Related Adverse Events 
Adverse events with a relationship to study drug of “possibly,” “probably” or “definitely” 
related will be classified as treatment related.  The incidences of adverse events related to 
cyclophosphamide, durvalumab, ONCOS-102, and any of the study therapies will be 
summarized by SOC and PT. 
10.2.2 
Adverse Events TEAEs Leading to Study Drug Withdrawal 
TEAEs leading to study drug withdrawal of durvalumab, ONCOS-102 or both will be 
presented by SOC and PT and will also be presented in a listing. 
10.2.3 
  DLTs  
DLTs will be presented in subject listings. 
10.2.4 
  Serious Adverse Events 
The incidences of serious adverse events will be summarized by SOC and PT and also 
will be presented in a listing. 
10.3 Clinical Laboratory Data 
Clinical Laboratory data (chemistry, hematology, coagulation, and urinalysis) will be 
collected as specified in the study flowchart in section 3.2 of the protocol. The Clinical 
lab tests are summarized in Table 2 below. 
For each continuous laboratory  parameter, results will be categorized as low, normal, or 
high based on the laboratory normal ranges.  Frequencies and percentages will be 
presented by Phase 2 tumor types and overall Safety population for the shifts in these 
categories from baseline to selected post-treatment assessment time points (e.g., low to 
normal, low to high, high to low). Percentages for the shift tables will be calculated based 
on the number of subjects who had results for both baseline and the corresponding post-
treatment assessment time point. Additionally, for continuous laboratory parameters, 
descriptive statistics will be presented for the changes from baseline to each selected 
post-treatment assessment time point.   
 
The clinical lab data will be presented in tables and listings as follows:  
• All laboratory results will be presented in the listings.  


  
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• Abnormal laboratory values with their clinical significance status will be 
presented in a listing.  
• Urinalysis data, differentials (%), and RDW will be presented in listings only 
• Magnesium, MCV, MCH, MCHC, MPV, differentials (absolute count), aPTT, 
PT, and INR will be presented in listings and summary tables but NOT in shift 
tables. 
• The remaining analytes will be presented in listings, summary tables and shift 
tables 
 
Table 2. Safety Laboratory Tests 
Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
Glucose 
Blood urea nitrogen 
(BUN) 
Creatinine 
Sodium 
Potassium 
Chloride 
Carbon Dioxide (CO2 ) 
Calcium 
Magnesium 
Total protein 
Albumin 
Total bilirubin 
Aspartate 
aminotransferase 
(AST) 
Alanine 
aminotransferase 
(ALT) 
Alkaline phosphatase 
Lactate dehydrogenase 
(LDH) 
Amylase 
Lipase 
Free T3 
Free T4 
Hemoglobin 
Hematocrit 
Platelets 
White blood cell 
(WBC) count 
Red blood cell 
(RBC) count 
Mean cellular 
volume (MCV) 
Mean corpuscular 
hemoglobin (MCH) 
Mean corpuscular 
hemoglobin 
concentration 
(MCHC) 
Mean Platelet 
Volume (MPV) 
RBC Distribution 
Width (RDW) 
 
Differential (% and 
absolute count for 
each): 
• Eosinophils 
• Basophils 
• Neutrophils  
• Lymphocytes 
Activated partial 
thromboplastin 
time (aPTT) 
Prothrombin time 
(PT) 
INR 
Albumin 
Bilirubin  
Blood/Hemoglobin 
Glucose 
Ketones 
White Blood Cells 
Nitrite 
pH 
Protein 
Red Blood Cells 
Specific gravity 
Urobilinogen 
Color  
Turbidity 


  
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Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
TSH 
CEA 
CA125 
 
• Monocytes 
 
10.4      Vital Signs  
Vital signs summaries will include temperature, heart rate, blood pressure, respiratory 
rate, and weight taken on the days ONCOS dosing is planned. Descriptive statistics will 
be presented for the changes in vital signs from baseline to each post-treatment 
assessment time point. Vital sign data will be presented in a listing.   
10.5 ECOG performance status 
ECOG performance status data will be presented in a listing.   
10.6    Prior and Concomitant Medications and Procedures 
A concomitant medication is defined as any drug or substance administered between the 
time of the first dose of study treatment and the time of the last study visit.  This includes 
medications that were started prior to screening, if their use continued during or after 
dosing. 
Concomitant medication use will be classified by Anatomical Therapeutic Class (ATC) 
level 4 and PT.  For the presentation of concomitant medications, the ATC level 4 terms 
will be sorted alphabetically, and within ATC level 4 term, the PT will be used and 
presented by decreasing total frequency overall. 
Frequencies and percentages of subjects using each concomitant medication will be 
presented for the Safety population overall as well as the Phase 2 cohorts (Ovarian and 
CRC). Prior and concomitant medications and concomitant procedures/surgeries will be 
presented in subject listings. 
11 
Quality Control 
All data displays and analyses will adhere to the International Conference on 
Harmonisation (ICH) Harmonized Tripartite Guideline: Structure and Content of Clinical 
Study Reports (ICH Topic E3). 
The sponsor will review all tables, listings, and figures prior to final database lock. Final 
SAS datasets, programs and outputs will be transferred to the sponsor at project 
completion. 


  
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12 
Tables and Listings Conventions 
Data collected in this study will be documented using summary tables and patient data 
listings. Continuous variables will be summarized using descriptive statistics (number of 
patients, mean, median, standard deviation, minimum, and maximum). Categorical 
variables will be summarized using frequencies and proportions. Time-to-event data will 
be summarized via Kaplan-Meier (KM) methodology using the 25th, 50th (median), and 
75th percentiles with associated 2-sided 95% confidence intervals.  
Mock-ups for statistical tables and listings will be provided. Final formats for the 
statistical tables and listings may deviate from these mock-ups upon agreement with the 
sponsor. Footnotes will be used as needed to clarify the information that is presented in 
the tables and listings. Unless otherwise requested by the sponsor, the term ‘subject’ will 
be used in all tables and listings, in accordance with CDISC standards. Basic 
demographic information (age/gender) will be presented along with subject id for each 
listing. Similar endpoints (e.g., all lab tests, all time to events endpoints etc.) should 
present in one listing or table for completeness or comparisons. 
The general layout of tables and listings will be as follows: 
 
 
 
All tables and listings will use landscape orientation. Margins will be at least 2.0 cm at 
the top and bottom and at least 0.8 cm on the left and right, excluding headers and 
footnotes, in accordance with electronic Common Technical Document (eCTD) 
guidelines. Font will be Courier, unless otherwise specified, with an 8-point font size in 
Ludwig Institute for Cancer Research 
 
Page x of y
Protocol: LUD2015-008
 
Run Date: DDMMMYY -HH:MM  
Clinical Study Report
 
Listing 16.2_x (or Table 14.x_x)  
<Title>  
<Population>  
___________________________________________________________________________________________________
Col 1  
Col 2  
Col 3  
etc.  
 
 
 
 
__________________________________________________________________________________________________ 
___________________________________________________________________________________________________ 
 
<Any footnotes>  
File Name:   <pathname for SAS program>  


  
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most cases. Page numbering will be sequential within each table, listing, and figure. 
Column headers should be in initial capital letters. Units for numeric data will be 
included when appropriate. 
Tables and data listings will be created from different SAS programs. A single program 
may produce multiple tables or multiple data listings from the same dataset (e.g. all 
clinical chemistry data listings may be generated by a single program). 
12.1 Statistical Table Conventions 
Mock-ups for statistical tables will include headers, title numbers, titles, column headers 
and footers, and a proposed layout for the display of data. The final decision on the 
precision (i.e. number of decimal places) for presentation of descriptive statistics will be 
made by the sponsor after review of draft statistical tables and before database freeze. 
12.2 Data Listing Conventions 
Mock-ups for data listings will include headers, title numbers, titles, column headers, and 
footnotes as appropriate. Data listings will provide all data collected on the corresponding 
eCRF page or provided by external vendors, unless otherwise indicated. 
In general, data listings should include all subjects with data. However, if only subjects 
who meet a certain condition are listed (e.g., subjects with AEs) and no subjects meet the 
condition, the data listing will so indicate. 
The sort order for data presented in data listings will be subject ID, unless otherwise 
requested by the sponsor. Within a subject, data will be listed in chronological order. 
Whenever possible, formatted values will be displayed (i.e., decoded). Where applicable, 
calendar date and study day of evaluations/events will be provided in the data listings. 
13 
References 
None. 
14 
List of Statistical Tables, Listings and Figures to Be 
Programmed  
The tables, figures, and listings displayed below represent the initial outputs planned.  
There may be minor variations to this output in the final summary package without 
updates to the lists displayed in this section. 
14.1     Statistical Tables 
Table 14.1.1 
Subject Disposition, All Subjects 
Table 14.1.2 
Demographic and Baseline Characteristics, Safety Population 
Table 14.1.3.1 
Demographic and Baseline Characteristics, ITT Clinical Efficacy (CE) 
Population 
Table 14.1.3.2 
Demographic and Baseline Characteristics, Per Protocol Clinical Efficacy 
Population 


  
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Table 14.1.4 
Non-Oncological Medical History, Safety Population 
Table 14.1.5 
Prior Anti-Cancer Therapies,  Safety Population 
Table 14.1.6 
Treatment Exposure, Safety Population 
Table 14.2.1.1 
Progression Free Survival Based on RECIST v1.1 Criteria ITT CE 
Population 
Table 14.2.1.2 
Progression Free Survival Based on irRECIST Criteria ITT CE Population 
Table 14.2.1.3 
Progression Free Survival Based on RECIST v1.1 Criteria PP CE 
Population 
Table 14.2.1.4 
Progression Free Survival Based on irRECIST Criteria PP CE Population 
Table 14.2.1.5 
Progression Free Survival at Week 24 Based on RECIST v1.1 Criteria ITT 
CE Population 
Table 14.2.1.6 
Progression Free Survival at Week 24 Based on irRECIST Criteria ITT CE 
Population 
Table 14.2.1.7 
Progression Free Survival at Week 24 Based on RECIST v1.1 Criteria PP 
CE Population 
Table 14.2.1.8 
Progression Free Survival at Week 24 Based on irRECIST Criteria PP CE 
Population 
Table 14.2.2.1 
Summary of Response Rates and Durable Clinical Benefit Based on 
RECIST v1.1 Criteria ITT CE Population 
Table 14.2.2.2 
Summary of Response Rates and Durable Clinical Benefit Based on 
irRECIST Criteria ITT CE Population 
Table 14.2.2.3 
Summary of Response Rates and Durable Clinical Benefit Based on 
RECIST v1.1 Criteria PP CE Population 
Table 14.2.2.4 
Summary of Response Rates and Durable Clinical Benefit Based on 
irRECIST Criteria PP CE Population 
Table 14.2.3.1 
Summary of Duration of Response Based on RECIST v1.1 Criteria ITT CE 
Population 
Table 14.2.3.2 
Summary of Duration of Response Based on irRECIST Criteria ITT CE 
Population 
Table 14.2.3.3 
Summary of Duration of Response Based on RECIST v1.1 Criteria PP CE 
Population 
Table 14.2.3.4 
Summary of Duration of Response Based on irRECIST Criteria PP CE 
Population 
Table 14.2.4.1 
Overall Survival, ITT Clinical Efficacy Population 
Table 14.2.4.2 
Overall Survival, Per Protocol Clinical Efficacy Population 
Table 14.3.1.1  
Summary of Treatment-Emergent Adverse Events, Safety Population 
Table 14.3.1.2  
Summary of Treatment Related Adverse Events, Safety Population 


  
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Table 14.3.2 
Incidence of Treatment Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term, Safety Population 
Table 14.3.3 
Incidence of Treatment Emergent Adverse Events by MedDRA Preferred 
Term, Safety Population 
Table 14.3.4 
Incidence of Treatment Emergent Adverse Events by Maximum CTCAE 
Grade, MedDRA System Organ Class and Preferred Term, Safety 
Population 
Table 14.3.5.1 
Incidence of ONCOS-102 Related Adverse Events by MedDRA System 
Organ Class and Preferred Term, Safety Population 
Table 14.3.5.2 
Incidence of Cyclophosphamide Related Adverse Events by MedDRA 
System Organ Class and Preferred Term, Safety Population 
Table 14.3.5.3 
Incidence of Durvalumab Related Adverse Events by MedDRA System 
Organ Class and Preferred Term, Safety Population 
Table 14.3.5.4 
Incidence of Adverse Events related to any component of study therapy by 
MedDRA System Organ Class and Preferred Term, Safety Population 
Table 14.3.6.1 
Incidence of Treatment Related Adverse Events Leading to ONCOS-102 
Withdrawal by MedDRA System Organ Class and Preferred Term, Safety 
Population 
Table 14.3.6.2 
Incidence of Treatment Related Adverse Events Leading to Durvalumab 
Withdrawal by MedDRA System Organ Class and Preferred Term, Safety 
Population 
Table 14.3.7 
Incidence of Serious Adverse Events by MedDRA System Organ Class and 
Preferred Term, Safety Population 
Table 14.3.8 
Incidence of Adverse Events related to any component of study therapy by 
Maximum CTCAE Grade, MedDRA System Organ Class and Preferred 
Term, Safety Population 
Table 14.4.1 
Hematology Parameters – Change from Baseline by Visit, Safety 
Population 
Table 14.4.2 
Hematology Parameters – Shift from Baseline by Visit, Safety Population 
Table 14.4.3 
Chemistry Parameters – Change from Baseline by Visit, Safety Population 
Table 14.4.4 
Chemistry Parameters – Shift from Baseline by Visit, Safety Population 
Table 14.4.5.1 
Vital Signs – Change from Baseline by Visit, Safety Population 
Table 14.4.6     
Concomitant Medications, Safety Population 
 
14.2     Figures 
Figure 1 
KM Estimate of Progression-free Survival based on RECIST v1.1, ITT 


  
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Clinical Efficacy Population 
Figure 2 
KM Estimate of Progression-free Survival based on irRECIST, ITT Clinical 
Efficacy Population 
Figure 3 
KM Estimate of Progression-free Survival based on RECIST v1.1 by Cohort, 
Per Protocol Clinical Efficacy Population 
Figure 4 
KM Estimate of Progression-free Survival based on irRECIST by Cohort, Per 
Protocol Clinical Efficacy Population 
Figure 5 
KM Estimate of Overall Survival by Cohort, ITT Clinical Efficacy Population 
Figure 6 
KM Estimate of Overall Survival by Cohort, Per Protocol Clinical Efficacy 
Population 
14.3     Data Listings 
Listing 16.2.1 
Inclusion and Exclusion Criteria Not Met  
Listing 16.2.2 
Study Disposition 
Listing 16.2.3 
Demographic Characteristics 
Listing 16.2.4 
Baseline Disease Characteristics 
Listing 16.2.5 
Non-Oncological Medical History and Procedures 
Listing 16.2.6 
Other Prior Cancer History 
Listing 16.2.7 
Prior Oncological Treatment History 
Listing 16.2.8 
Prior Oncological Radiation History 
Listing 16.2.9 
Prior Oncological Surgical History 
Listing 16.2.10 
Study Drug Exposure 
Listing 16.2.11 
Target Lesions 
Listing 16.2.12 
Non-Target Lesions 
Listing 16.2.13 
RECIST 1.1 Tumor Response by Visit 
Listing 16.2.14 
irRECIST Tumor Response by Visit 
Listing 16.2.15 
CA-125 and CEA Tumor Markers 
Listing 16.2.16 
RECIST 1.1 Progression-free Survival and Overall Survival 
Listing 16.2.17 
irRECIST Progression-free Survival 
Listing 16.2.18 
Prior and Concomitant Medications 
Listing 16.2.19 
Concomitant Procedures/Surgeries 
Listing 16.2.20 
Treatment Emergent Adverse Events 
Listing 16.2.21 
Serious Adverse Events 
Listing 16.2.22 
Adverse Events Leading to Study Drug Interruption or Discontinuation 
Listing 16.2.23 
Adverse Events Leading to Treatment Withdrawal 
Listing 16.2.24 
Dose-Limiting Toxicities 
Listing 16.2.25 
Deaths 
Listing 16.2.26 
Hematology Laboratory Results 
Listing 16.2.27 
Chemistry Laboratory Results 
Listing 16.2.28 
Urinalysis Laboratory Results 
Listing 16.2.29 
Coagulation Laboratory Results 


  
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Listing 16.2.30 
Endocrine, Amylase, Lipase Laboratory Results 
Listing 16.2.31 
Vital Signs 
Listing 16.2.32 
ECOG Performance Status 
Listing 16.2.33 
Physical Examination, ECG, and Weight 
 
 


  
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15 
Change history 
Version 
Date 
Description of Changes  
1 
04APR2019 
Original Approved Document  
2.0 
15MAY2020 
Revised to enhance clarity of the efficacy sections including the 
corresponding TFL mock shells. The following sections were 
updated: 
I. 
Section 8.2.3: Section rephrased to emphasize the criteria 
for censoring in the analysis.  
II. 
Section 8.2.3: PFS at the End of Week 24 added since 
subjects without progression at week 24 is a primary end 
point 
III. 
Section 8.2.4  (Overall Survival (OS)) rephrased to define 
censoring more clearly. The analysis populations to be 
analyzed for OR were inserted 
IV. 
Section 8.2.5 (Duration of Response (DoR) added including 
how it will be analyzed 
V. 
Section 8.2.6  (Analysis of Time to Event (TTE) Variables 
added to indicate how these variables will be analyzed  
VI. 
Table 14.2.2.1 split into 2 tables: Table 14.2.2.1 Summary 
of Response Rates and Durable Clinical Benefit Based on 
RECIST v1.1 Criteria and Table 14.2.3.1 Summary of 
Duration of Response Based on RECIST v1.1 Criteria 
VII. 
List of Tables in SAP updated to align with current table 
shells  
3.0 
10SEP2020 
Section 10.3 (Clinical Laboratory Data) revised to reflect intended 
analysis 
4.0 
19FEB2021 
Section 8.2.5 (Duration of Response) revised. Clinical Progression 
(CP) removed from documented response options to assess DoR. 
The updated text reads as follows: ‘The DoR analysis will be 
performed on only those subjects with a documented response 
(CR, PR)’. First paragraph in the section rephrased to reflect this 
change 
4.0 
23FEB2021 
Section 8.2.5: ‘The DoR analysis will be performed on only those 
subjects with a documented response (CR, PR)’. The Word 
documented in this sentence was replaced with ‘confirmed’