Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer
Phase: PHASE1
Conditions: Pancreatic Adenocarcinoma, Ovarian Cancer, Biliary Carcinoma, Colorectal Cancer
Sponsor: Lokon Pharma AB



  
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................ 72 
11.1. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................................................. 72 
11.2. 
SOURCE DATA .......................................................................................................................................................... 72 
11.3. 
MONITORING ........................................................................................................................................................... 72 
11.4. 
PROTOCOL MODIFICATIONS .................................................................................................................................. 73 
12. 
ETHICS ..................................................................................................................................................... 73 
12.1. 
INDEPENDENT ETHICS COMMITTEE .................................................................................................................... 73 
12.2. 
ETHICAL CONDUCT OF THE STUDY ...................................................................................................................... 73 
12.3. 
PATIENT INFORMATION AND INFORMED CONSENT ......................................................................................... 74 
13. 
DATA MANAGEMENT .......................................................................................................................... 74 
13.1. 
DATA MANAGEMENT ............................................................................................................................................. 74 
13.1.1. 
Data Entry and Data Validation ............................................................................................................ 75 
13.1.2. 
Database Closure .......................................................................................................................................... 75 
14. 
DATA HANDLING AND RECORD KEEPING ................................................................................... 75 
14.1. 
ELECTRONIC CASE REPORT FORMS (ECRF) ..................................................................................................... 75 
14.2. 
RECORD KEEPING ................................................................................................................................................... 76 
14.3. 
STUDY REPORT ........................................................................................................................................................ 76 
14.4. 
INSURANCE ............................................................................................................................................................... 76 
14.5. 
PUBLICATION POLICY ............................................................................................................................................. 76 
15.0 REFERENCES .............................................................................................................................................. 77 
16.0 APPENDICES ............................................................................................................................................... 82 
 
 
 
 
 
 
 

  
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INVESTIGATOR’S STATEMENT 
 
1. 
I have carefully read this amended protocol entitled “Phase I/II Trial Investigating an 
Immunostimulatory Oncolytic Adenovirus for Cancer” and agree that it contains all the 
necessary information required to conduct the study.  I agree to conduct this study as 
outlined in the protocol. 
 
2. 
I understand that this study will not be initiated without approval of the appropriate 
Institutional Review Committee/Independent Ethics Committee (IRB/IEC), and that all 
administrative requirements of the governing body of the Institution will be complied with 
fully. 
 
3. 
Informed written consent will be obtained from all participating patients in accordance with 
institutional guidelines, FDA requirements as specified in Title 21 CFR, Part 50, the European 
Union Directive 2001/20/EC and its associated Detailed Guidance’s, European Union GAP 
Directive 2005/28/EC, the ICH Guideline for Good Clinical Practice, Section 4.8, and the terms 
of the Declaration of Helsinki (2013) depending on country of patient enrollment. 
 
4. 
I will enroll patients who meet the protocol criteria for entry. 
 
5. 
I understand that my signature on each completed Case Report Form indicates that I have 
carefully reviewed each page and accept full responsibility for the contents thereof. 
 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released without 
prior consent from the Sponsor unless this requirement is superseded by the Food and Drug 
Administration, a Competent Authority of the European Union or another Regulatory 
Authority. 
 
 
 
Investigator: 
 
Name: 
 
 
 
Telephone:
 
 
 
 
Institution: 
 
 
 
 
Signature: 
 
 
Date: 
 
 
 
 
 
 
 

  
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 SYNOPSIS 
 
Title:  
Phase I/II Trial Investigating an Immunostimulatory Oncolytic 
Adenovirus for Cancer 
 
Investigational Product: LOAd703, an oncolytic adenovirus serotype 5/35 expressing human 
trimerized CD40L and 4-1BBL under a CMV promoter. 
 
Study Design: 
Single arm, open-label, multi-center trial.  
 
Phase I: 3+3 patients receive 8x LOAd703 injections at three dose levels 
(5x1010 VP, 1x1011 VP, 5x1011 VP) during standard of care (SoC) or 
gemcitabine conditioning, 9 DLT evaluable patients.  
 
Phase II 
: Phase II  includes a total 
of 18 evaluable patients (colorectal, pancreatic, biliary and ovarian 
cancer) treated at the highest virus dose 5x1011 VP (MTD). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Up to 35 efficacy evaluable patients 
will be recruited 
. 
 
  
Objectives: 
The primary objective is to determine the tolerability of increasing doses 
of LOAd703 intratumoral injections during SoC or added conditioning 
chemotherapy. 
 
 
The secondary objective is to determine the effects of LOAd703 
intratumoral injections during SoC or added conditioning chemotherapy. 
 
Endpoints:  
Primary Endpoints 
 
Phase I 
1. Tolerability is determined by physical examination, hematological 
and clinical chemistry analysis using CTCAE v 4.03. 
 
 
 

  
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Phase II 
1. Tolerability is determined by physical examination, hematological 
and clinical chemistry analysis using CTCAE v 4.03. 
 
 
 
 
Secondary Endpoints 
 
Phase I 
 
 
3. Local and distant anti-tumoral effects assessed by appropriate 
imaging dependent on tumor localization and by monitoring tumor 
marker/s when available. Responses are judged accordingly to 
RECIST 1.1. 
4. Effects evaluated as time to tumor progression (TTP), progression 
free survival (PFS) and overall survival (OS). 
 
Phase II 
1. 
Local and distant anti-tumoral effects on tumor assessed by 
appropriate imaging dependent on tumor localization and by 
monitoring tumor marker/s when available. Objective responses are 
measured using RECIST 1.1. 
2. 
Effect evaluated as TTP, PFS and OS. 
 
 
 
  
 
Eligibility:       
Inclusion criteria 
1. 
Have histologic or cytologic evidence of colorectal carcinoma (CRC), 
pancreatic carcinoma (PC), biliary cancer, or epithelial ovarian 
carcinoma (EOC which may encompass epithelial ovarian, fallopian 
tube or primary peritoneal carcinoma). 
2. 
Have advanced disease, defined as cancer that is either metastatic or 
locally advanced, unresectable, and for which radiotherapy or other 
locoregional therapies are not considered treatment of choice but 
systemic chemotherapy or no therapy is planned. 
3. 
Have one of the following treatment situations apply: 
 
a) Colorectal carcinoma (CRC) , 
 
 
I. 
A patient with refractory or recurrent metastatic CRC who has 
either received all conventional therapy; or is entering a 
“resting” phase between reasonable conventional treatments. 
 
II. 
A patient who is amenable to treatment with LOAd703 plus 
gemcitabine as a single agent conditioning regimen.  
 

  
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b) Pancreatic cancer 
 
I. 
A patient with either locally advanced, unresectable or 
metastatic disease who is eligible to receive first or second line 
of conventional treatment consisting of gemcitabine and/or 
nab-paclitaxel. 
II. 
A patient who is amenable to treatment with LOAd703 as an 
“add-on” to standard-of-care gemcitabine-based or nab-
paclitaxel-based regimens or gemcitabine or nab-paclitaxel as 
single agents.  
 
c.   Biliary cancer, 
 
 
I. 
A patient with either locally advanced unresectable or 
metastatic biliary cancer who is either treatment-naïve or has 
received any number of lines of treatment. 
II. 
Patient who is amenable to treatment with LOAd703 as an 
“add-on” 
to 
standard-of-care 
treatment 
consisting 
of 
gemcitabine 
combined 
with 
other 
agents 
(e.g. 
gemcitabine/low-dose cisplatin, gemcitabine/oxaliplatin, etc) 
in the first line setting or gemcitabine in a combination 
regimen or as a single agent in latter lines of treatment. 
 
d. Ovarian Cancer 
 
I. 
A patient with either epithelial ovarian, fallopian tube or 
primary peritoneal carcinoma.      
II. 
The patient has either:  
 
i) 
Residual disease following first line standard of care 
combination chemotherapy.  
ii) Platinum-sensitive 
relapse 
(platinum 
free 
interval 
≥6 months) and have previously received at least one line of 
chemotherapy 
and 
not 
eligible 
for 
PARP-inhibitor 
maintenance after chemotherapy. 
iii) Platinum-resistant 
relapse 
(platinum 
free 
interval 
< 6  months), who have not received more than two lines of 
appropriate standard of care and not eligible for 
bevacizumab. Maintenance treatment does not count as a 
line of therapy. 
iv) The patient has received appropriate therapy with PARP 
inhibitors if eligible.  
III. 
Amenable to treatment with LOAd703 as an “add-on” to 
standard-of-care (excluding bevacizumab) as described in  
5.10.4  
 
4. Have a disease burden that is considered low (i.e. low tumor burden), 
which is defined on a patient-by-patient basis as per Principal 
Investigator’s discretion. A rough guideline for defining low tumor 

  
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burden is that the sum of the product of the bidimensional 
measurements for all lesions is < 70 cm2. 
5. Have a measurable disease by standard imaging techniques per 
RECIST criteria. Measurable lesions must be outside of any prior 
radiation field(s), unless disease progression has been documented at 
that disease site subsequent to radiation.  
6. At least one non-irradiated (or irradiated but disease progression 
documented at the site subsequent to radiation) lesion must be 
suitable for image-guided intratumoral injection and needle biopsy. 
7. Be medically suited to sedation if required during intratumoral 
injections.  
8. Be at least 18 years-old. 
9. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 
or 2. 
10. Have no remaining acute toxic effects from previous anticancer 
therapy > grade 1, except for any grade of alopecia. 
11. Have 
adequate 
baseline 
organ/hematological 
function, 
as 
demonstrated by the following: 
a) Absolute neutrophil count (ANC) ≥1.0 x 109/l 
b) Hemoglobin ≥90 g/l 
c) Platelet count ≥ 100 x 109/l 
d) Bilirubin < 1.5 times the institutional upper limit of normal (ULN) 
e)  Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) <2.5 (3, if liver metastases are present) times the institutional 
ULN. 
f) Serum creatinine <2 times the institutional ULN or calculated 
creatinine clearance >35 mL/min 
g) Prothrombin (INR)<1.5 or prothrombin time (PT) <1.5 ULN; and 
either partial thromboplastin time or activated partial thromboplastin 
time (PTT or aPTT) ≤ 1.5 times the ULN.  
12. The patient must understand and be willing to provide written 
informed consent. 
 
 
 
Exclusion criteria 
1. Any concurrent treatment that would compromise the study including 
but not limited to continuous high dose corticosteroids (>0.5mg/kg), 
lymphodepleting antibodies or cytotoxic agents. 
2. Treatment with high dose immune inhibitors including lymphotoxic 
monoclonal antibodies such as alemtuzumab (CampathR), or sirolimus 
(RapamuneR) and its analogs, biological therapy, cytotoxic agents or 
any investigational agents within 21 days of registration.  
3. Ovarian carcinoma patients should not be eligible to PARP inhibitor 
treatment. 
4. Patients on warfarin are not eligible. 
5. Women who are pregnant, lactating, or planning to become pregnant 
during the study period, or women of childbearing potential who are 
not using acceptable contraceptive methods. A woman is considered 
of childbearing potential if she is not surgically sterile or is less than 
1 year since last menstrual period. Acceptable contraceptive methods 
are: combined (estrogen and progesterone containing) hormonal 
contraception associated with inhibition of ovulation (oral, 

  
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intravaginal, 
transdermal), 
progesterone-only 
hormonal 
contraception associated with inhibition of ovulation (oral, injectable, 
implantable), intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion and vasectomized partner. 
6. Men who do not consent to the use of condom during intercourse 
during study participation. 
7. Known active hepatitis B or C infection, or HIV infection. 
8. Patients with active, severe, autoimmune disease. 
9. Uncontrolled intercurrent illness including but not limited to 
psychiatric illness/social situations that in the opinion of the 
Investigator would compromise compliance of study requirements or 
put the patient at unacceptable risk. 
10. Other malignancies within the past 2 years (not including basal and 
squamous cell carcinoma of the skin, localized prostate cancer or in 
situ cervix carcinoma). 
11. Patients must agree to not to vaccinate with living vaccines during 
participation in the trial. 
12. Prior treatment with an adenovirus-based gene therapy 
13. Adenovirus-based vaccines (e.g Vaxzevria, known as COVID-19 
vaccine Astra Zeneca, J&J Covid-19 vaccine) are prohibited 3 months 
prior to initiation of study treatment, during treatment and 6 months 
after the final dose of LOAd703. 
 
Treatment Description: In Phase I, three doses (total viral load - 5x1010, 1x1011, 5x1011 VP) of 
LOAd703 are tested as “add-on” to SoC or conditioning gemcitabine 
chemotherapy. 
 
 
 
 
 
  
 
 
  
 
 
 
 
Phase II 
 with recruitment of 18 patients at 
5x1011VP (MTD) and 
 with recruitment of PC and EOC patients 
at two dose levels: 1x1011 VP and 5x1011VP (MTD).
 
 
 
 
  
Accrual Objective: 
Up to 53 efficacy evaluable patients in Phase II (
 
.  
The total number of patients to be enrolled in the study to achieve up to 
53 evaluable patients shall not exceed 80.  
  
Study Duration: 
72 months 
 

  
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ABBREVIATIONS 
 
 
 
 
Ad 
 
Adenovirus 
AE 
 
Adverse event 
 
 
 
ALT 
 
Alanine aminotransferase 
ANC  
 
Absolute Neutrophil count 
aPPT 
 
Activated partial thromboplastin time 
AST 
 
Aspartate aminotransferase 
AUC 
 
Area under curve 
CBR 
 
Clinical benefit rate 
 
 
 
 
 
 
 
 
 
CR 
 
Complete response 
CRC 
 
Colorectal cancer 
CRF 
 
Case report form 
 
 
 
 
CRS 
 
Cytokine release syndrome 
CT 
 
Computerized tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
 
 
 
CV 
 
Curriculum vitae 
 
 
 
DCF 
 
Data clarification form 
DLT 
 
Dose Limiting Toxicity 
DMP 
 
Data management plan 
DSUR 
 
Drug safety update report 
ECOG 
 
Eastern cooperative oncology group 
EOC  
 
Epithelial ovarian cancer 
GCP 
 
Good clinical practice 
 
 
 
GMM 
 
Genetically modified microorganism 
GMO 
 
Genetically modified organism 
 
 
 
IL 
 
Interleukin 
 
 
 
JEC 
 
International ethics committee 
LOAd 
 
Lokon oncolytic adenovirus 
 
 
 
MPA 
 
Medial product agency 
 
 
 
 
 
 
 
 
MTD 
 
Maximum tolerated dose 
 
 
 
 
  
ORR 
 
Overall response rate 
OS 
 
Overall survival 

  
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PC 
 
Pancreatic carcinoma 
 
 
 
PD 
 
Progressive disease 
PDAC 
 
Pancreatic ductal adenocarcinoma 
 
 
 
 
PFS 
 
progression free survival 
PI 
 
Principal investigator 
PR 
 
Partial response 
PT 
 
Prothrombin time 
 
 
 
PTT 
 
Partial thromboplastin time 
 
 
 
 
 
RECIST 
 
Response evaluation criteria in solid tumors 
RSI 
 
Reference safety information 
SAE 
 
Serious adverse event 
SD 
 
Stable disease 
SoC 
 
Standards of care 
SUSAR 
 
Suspected unexpected serious adverse reactions 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
TTP 
 
Time to tumor progression 
ULN 
 
Upper limit of normal 
VP 
 
Virus particles 
 
 
 
 
 

  
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1. GENERAL INFORMATION 
 
1.1. Protocol Number and Title of the Study 
 
Sponsor Protocol Number: LOKON002 
 
Title: Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer 
 
1.2. Sponsor 
 
Lokon Pharma AB 
 
 
 
 
1.2.1. 
Chief Executive Officer 
 
 
 
 
1.2.2. 
Sponsor Medical Advisor 
 
 
 
 
1.3. CROs 
1.3.1. 
Study conduct 
 
 
 
 
 
 
 
 
  
 
 
 
  

  
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1.3.2. 
SUSAR reporting to MPA/EMA 
 
 
 
  
 
 
1.1. Investigators and Institutions 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
1.2. Research Nurse 
 
 
 
 
 
  
 
 
 
 
  
 
 
 

  
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1.3. Radiology (ultrasound-guided therapy) 
 
 
 
 
 
 
 
1.4. Manufacturer 
 
 
 
 
  
 
 
 
 
 
 
 
1.5. Importer & Pharmacy 
 
 
 
 
 
 
 
 
1.6. Biobank 
 
 
 
 
1.7. Laboratories 
 
1.7.1. 
Research Analysis Laboratory 
 
 

  
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1.7.2. 
Clinical Analyses 
 
 
 
 
 
  
 
 
 
 
 
 

  
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2. BACKGROUND 
 
2.1. Cancer Immunotherapy 
 
2.1.1. 
Tumor Immunology and Cancer Immunotherapy 
The immune system can recognize and kill tumor cells by the same mechanisms as it recognizes and 
kills virally-infected cells to save the host against lethal infections. Like virally-infected cells, tumor 
cells are self-cells, and viral- or tumor-associated epitopes are presented on major histocompatibility 
complex I (MHC-I) on the cells to CD8+ cytotoxic T lymphocytes (CTLs). Both virally-infected cells 
and tumor cells may prevent CTL recognition by down-regulating MHC molecules making the cells 
targets for natural killer (NK) cells. However, viruses initially activate an innate immune defense 
response, alerting antigen-presenting cells such as dendritic cells (DCs) to activate anti-viral 
immunity, while tumor cells do not induce the same degree of stimulation. Indeed, during cancer 
progression the tumor and its stroma produce substances that inhibit immune cells. Tumor immunity 
is restrained by blocking DC maturation and instead promoting differentiation and attraction of 
immunosuppressive cells to the tumor milieu. These suppressive cells are usually M2 macrophages, 
a variety of immature myeloid cells collectively called myeloid-derived suppressor cells (MDSCs) and 
T regulatory cells (Tregs). Such cells produce suppressive cytokines and growth factors such as IL10, 
TGFβ, Prostaglandin E2, Arginase I and myeloid peroxidase (1, 2). In the tumor milieu, activated CTLs 
are rapidly suppressed by these factors and become anergic, a state of reversible unresponsiveness, 
or die. 
 
The essence of cancer immunotherapy is to break tumor tolerance (e.g. break anergy) and revert the 
ongoing type 2 immune responses to type 1. Type 1 is characterized by activation of T helper 1 (Th1) 
lymphocytes, CTLs, NK cells and M1 macrophages as well as by a cytokine pool such as IFNγ, IL12, 
IL21 and TNF (3).  
 
The implementation of checkpoint blockade antibodies targeting CTLA4 and PD1/PDL1 for various 
solid malignancies as well as chimeric antigen receptor (CAR) T cells for B cell malignancies has made 
immunotherapy a cornerstone in cancer management (4, 5). Nevertheless, despite the success the 
majority of patients with solid malignancies are not responding to checkpoint blockade therapy. 
Novel concepts to treat cancer by stimulating the immune system are currently being investigated 
that may be used alone or in combination with checkpoint antibodies. One of these concepts is 
immunostimulatory gene therapy utilizing oncolytic viruses as gene delivery vehicles (6). 
 
2.1.2. 
Immunostimulatory Gene Therapy 
Immunostimulatory gene therapy aims to transfer genes coding for immunostimulatory proteins 
into the tumor area. The first studies using immunostimulatory gene therapy in experimental models 
were published in the late 1990s with promising results (7, 8). Different approaches were used in 
clinical trials as well but many failed to show sufficient efficacy. However, these studies were 
performed before the increased knowledge of suppressive immune cells infiltrating the tumor and 
the possibility to aid the immune responses using preconditioning or supportive chemotherapy that 
reduce the levels of these immunosuppressive cells (9). Further, the responses to immunotherapy 
follow a different course compared to traditional chemotherapy or irradiation. Initial swelling of the 
tumor due to inflammation may have been misinterpreted as progression leading to premature 
interruption of treatment (10). The combination of preconditioning or supportive chemotherapy 
together with awareness of how to interpret data will likely pave the way for immunostimulatory 
gene therapy as it has for other immunotherapies. Compared to the systemic delivery of soluble 
immunostimulatory cytokines, growth factors and antibodies, gene therapy can be delivered to a 

  
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distinct site with days to weeks of expressing the immunostimulatory transgenes depending on the 
vector used. This leads to a high concentration of the immunostimulatory proteins in the tumor 
reducing toxicity due to unnecessary withdrawal of tolerance to self-cells that can be seen upon 
systemic immune activation.  
 
Therapeutic immunostimulatory genes are delivered to the tumor by many types of vehicles. 
Replication deficient adenoviruses have been commonly used since they can carry large transgene 
cassettes. Transgene expression is of limited duration because adenoviruses do not integrate into the 
host cell genome. The lack of integration renders this approach generally safety since the risk for 
mutagenesis of the host cell is unlikely. Moreover, humans are fully equipped to handle adenoviral 
infections. For example, most individuals have had upper respiratory tract infections due to 
adenoviruses and have pre-formed antibodies against several serotypes, and T cells cross-reactive to 
all (11). For immunostimulatory gene therapy, the immunostimulatory effects of the virus may 
enhance formation of anti-tumor responses by activating TLRs on tumor antigen-loaded DCs. 
Nevertheless, upon intratumoral delivery, the virus infects cells in the needle tract and there is a need 
to increase virus infection to prolong transgene expression. This may be achieved by using oncolytic 
viruses as gene delivery vehicles.  
 
2.1.3. 
 Oncolytic Virus (OV) Therapy 
The ability of certain viruses to infect cells, propagate and kill them by lysis during the release of new 
virions means that they can be utilized as cancer therapeutics. To limit oncolysis to tumor cells, the 
expression of viral replication genes is restricted by adding promoters that are preferentially active 
in the tumor (6, 12,  13). For full benefit, the OVs should infect all tumor cells, which can be a challenge 
if the tumor has metastasized. Since systemic viral spreading to distal tumor may be limited by the 
immune system, attempts are being made to develop less immunogenic OVs. 
 
Instead of decreasing the immunogenicity of OVs, another approach is to utilize and boost their 
intrinsic immunostimulating capacity of the virus by adding immunostimulatory genes into the OV 
genome. Oncolytic adenoviruses armed with immunostimulatory transgenes successfully deliver 
them to the tumor and initiate an anti-tumor immune response active against both local and 
metastatic disease. The full efficacy of the combined oncolysis and immune stimulation is difficult to 
determine in murine models since the oncolysis is non-existing or rather limited in murine cells and 
the immunostimulatory effect cannot be evaluated in xenograft models in immunodeficient mice. 
There has been at least one published study using an oncolytic adenovirus carrying the full-length 
human CD40L gene to patients with end-stage cancer demonstrating feasibility and safety (14). 
There are other studies ongoing using GM-CSF armed oncolytic viruses and a herpes simplex virus 
armed with GM-CSF (talimogene laherparepvec) is approved for the treatment of patients with 
melanoma (15, 16). 
 
2.1.4. 
 Preconditioning or Conditioning Chemotherapy 
Preconditioning prior to cancer immunotherapy, or conditioning chemotherapy during cancer 
immunotherapy is often given to patients receiving immunotherapy to decrease immune inhibitory 
cells such as Tregs and MDSCs that may otherwise hinder the intended immune activation (9). 
Further, chemotherapy-induced lymphocyte or myeloid cell depletion may induce bone marrow 
cytokine production that restores the immune cell populations (i.e. by homeostatic replication), 
thereby favoring the activation of anti-tumor responses. Dependent on diagnosis and type of 
chemotherapy, tumor growth may also be decreased. Metronomic cyclophosphamide has been given 
to patients undergoing immunotherapy attempting to control suppressive immune cells (17). Such 
conditioning chemotherapy protocols may be of great value if they do not hamper the desired anti-
tumor responses. Conditioning chemotherapies of interest that restrain immunosuppression but 

  
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leave the capacity of lymphocytes in a responsive mode are gemcitabine, paclitaxel/nab-paclitaxel 
and platinum-based chemotherapies. 
  
Gemcitabine is a nucleoside analog that replaces cytidine during DNA replication, and leads to growth 
arrest and apoptosis. Gemcitabine also targets ribonucleotide reductase thereby blocking the 
function of this enzyme. It is currently a component of standard of care (SoC) for pancreatic cancer 
both as adjuvant treatment to surgery and as treatment for advanced tumors +/- nab-paclitaxel. 
Although gemcitabine treatment of advanced metastasized tumors is only palliative, several studies, 
including our own, have shown that patients treated with gemcitabine have significantly lower levels 
of the immunosuppressive molecule TGFb, Tregs and MDSCs but a sustained level of activated T cells 
(18, 19). Recently it was shown that gemcitabine reduced MDSC recruitment to the tumor and 
accelerated the development of anti-tumor T cell responses, which aided combination therapy with 
an oncolytic retrovirus (20). In mice, gemcitabine reduced MDSCs and enhanced the efficacy of 
immunotherapy (21). Paclitaxel targets tubulin by binding to the beta-tubulin subunits. By its 
binding to tubulin, paclitaxel stabilizes tubulin polymers and prevents tubulin disassembly, thereby 
perturbing mitotic spindle assembly dynamics and cell division. It is also manufactured in an 
albumin-binding form (nab-paclitaxel), which appears to be associated with increased therapeutic 
indices in some tumor types. Platinum-based chemotherapies such as cisplatin and carboplatin 
crosslinks DNA. The crosslinking prevents DNA repair and/or DNA synthesis in cancer cells. Also 
taxanes and platinium compounds have shown to reduce immunosuppressive cells while favoring 
cytotoxic T cell responses both in animal models and in the clinic (22). 
 
Hence, continuous conditioning of a patients with gemcitabine, paclitaxel/nab-paclitaxel and/or 
platinum-based chemotherapy during immunotherapy with LOAd703 may be beneficial. 
 
2.2. The Investigational Product LOAd703 
 
LOAd703 is a novel immunotherapy for cancer. It is an oncolytic adenovirus serotype 5 with a fiber 
(shaft and knob) from serotype 35 (Ad5/35) to increase binding to cells and thereby its infectivity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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2.3. Preclinical Studies 
 
2.3.1. 
Summary of Preclinical Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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2.3.2. 
 Summary of In Vivo Toxicity Data 
 
 
 
 
 
 

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2.5.2. 
Potential Benefits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.6. Rationale for the Phase I/II  Doses 
 
 
 
 
 
. 
 

  
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2.7. Patient Populations 
 
Below is a description of the targeted indications. Note that all patients enrolled will receiving 
palliative SoC treatment or gemcitabine conditioning.  
 
2.7.1. 
Colorectal Cancer (
) 
 
Colorectal cancer (CRC) is one of the most common cancers (http://res.cloudinary.com 
/cancerfonden/image/upload/v1491294472/documents/cancerfondsrapporten-2017.pdf).  
If possible, treatment is initiated with surgery to remove all or as much as possible of the tumor mass. 
Surgery is followed by chemotherapy. Chemotherapy with 5-flourouracil (5-Fu) is standard 
treatment in the advanced setting (http://www.cancercentrum.se/globalassets/cancerdiagnoser 
/tjock--och-andtarmanal/ vardprogram/ nvpkolorektalcancer_2016-03-15.pdf). Capecitabine is an 
oral equivalent to 5-Fu and is as effective but hand-foot syndrome is a common adverse reaction (55). 
Irinotecan and oxaliplatin are the other two established chemotherapeutics (56, 57). Chemotherapy 
is sometimes combined with antibodies i.e. bevacizumab which binds to VEGF-A (58) or the anti-
EGFR antibodies cetuximab (ErbituxR) and panitumumab (VectibixR) (59). The infiltration of immune 
cells was found to be more important to predict prognosis than the TNM staging, indicating that the 
immune system may play a key role in CRC (60). The microsatellite instability (MSI) high CRC subtype 
is particularly immunogenic and FDA just approved the checkpoint blockade antibody 
pembrolizumab for the use in MSI-high tumors independently of tumor origin (www.fda.gov). 
According to common practice, a treatment break is introduced after at least four months of 
chemotherapy (61). In this situation, all forthcoming treatments are regarded as palliative since cure 
cannot be expected. The same treatment is usually re-introduced when the disease progresses and 
the patients has a suitable health condition. The break constitutes a window of opportunity to 
evaluate new promising drugs such as immunotherapy. However, for active immunotherapy (e.g. 
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antibodies) it is crucial to reduce immunosuppressive cells for effect. Conditioning chemotherapy is 
therefore needed. Several studies have demonstrated that the rather mild chemotherapeutic agent 
gemcitabine can enhance immune responses in many ways including the active suppression of 
myeloid-derived suppressor cells (MDSCs) (62-64). Hence, gemcitabine is a suitable conditioning to 
LOAd703 despites that it has no effect on its own in CRC.  
 
This study will enroll subjects with refractory or recurrent CRC who have low tumor burden and 
either: 
 
• 
Have received all reasonable conventional therapy.  
• 
 Are entering a “resting” phase during reasonable conventional palliative treatments (as 
indicated above)  
 
LOAd703 will be administered only with gemcitabine as a single agent conditioning regimen in both 
CRC settings. 
 
2.7.2. 
 Pancreatic Cancer (
) 
 
With a 5-year survival rate of only 5%, pancreatic ductal adenocarcinoma (PDAC) is currently the 
fourth most common cause of cancer-related death in the US (65, 66) and is expected to raise to 
second place within a couple of decades. Due to the inherently aggressive biology of PDAC and the 
relatively late onset of cancer-related symptoms, most cases are not diagnosed until the tumor is 
unresectable due to involvement of adjacent vasculature and/or since it has already metastasized 
to distant sites. In fact, only 10-20% of PDAC patients are diagnosed with localized, resectable 
disease, and only 29% of these patients, after being treated with aggressive surgical resection and 
adjuvant chemotherapy, are alive 5 years after diagnosis (Comparison of adjuvant gemcitabine and 
capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer, ESPAC-4) 
(67). All treatments of unresectable tumors are considered palliative. Combination regimens, such 
as gemcitabine/nab-paclitaxel and FOLFIRINOX (5-FU/irinotecan/oxaliplatin) have been shown to 
be more effective than single-agent regimens at shrinking or stabilizing advanced disease, but 
tumor control is relatively short-lived, and most patients with advanced PDAC still die of their 
disease within one year of diagnosis 
(https://www.cancercentrum.se/globalassets/cancerdiagnoser/bukspottkortel/vardprogram/natvp_ 
pankreascancer_20121030_final.pd). Novel treatment approaches are therefore greatly needed. 
 
This study will enroll subjects with unresectable pancreatic cancer whom have low tumor burden 
and, 
 
• 
Are eligible to receive first or second line of conventional palliative treatment consisting of 
gemcitabine with or without nab-paclitaxel 
 
LOAd703 will be administered as an “add-on” to standard-of-care gemcitabine-based or nab-
paclitaxel-based regimens or gemcitabine or nab-paclitaxel as single agents (section 5.10.2). Both 
gemcitabine and taxol-based therapy reduces immunosuppressive cells and are suitable 
conditioning treatments to immunotherapy. 
 
2.7.3. 
Biliary Cancer  (
) 
 

  
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Biliary cancer includes cholangiocarcinoma and gallbladder cancer which both have a poor 
prognosis (www.cancercentrum.se/globalassets/cancerdiagnoser/lever-och-galla/vardprogram/nat 
vp_ gallvagscancer _version1.0_170202_final.pdf). Patients with intrahepatic bile duct cancer have 
less than a 15% 5-year survival. while localized extrahepatic bile duct cancer has a better prognosis 
(30% 5-year survival). Patients who are diagnosed with metastatic disease have a median 5-year 
survival of only 2% (www.cancer.org). Unfortunately, tumors are often diagnosed at later stages. 
Similarly, patients with gallbladder cancer are commonly not detected at an early stage and 
advanced gallbladder cancer has a 2-8% 5-year survival (www.cancer.org). First line treatment 
after resection (if possible) is gemcitabine combined with low dose cisplatin based on the ABC 
study which demonstrated prolonged survival without additional side effects in patients treated 
with gemcitabine + low dose cisplatin compared to patients treated with gemcitabine alone (68).   
Other conventional first-line regimens include gemcitabine plus oxaliplatin.  Treatment after 
resection or treatment of unresectable patients is considered palliative. 
 
This study will enroll subjects with either locally advanced, unresectable or metastatic biliary cancer 
whom have low tumor burden and,  
 
• 
Are eligible to receive any line of conventional palliative treatment consisting of gemcitabine 
combined with other agents (e.g. gemcitabine/low-dose cisplatin, gemcitabine/oxaliplatin, 
etc) in the first line or gemcitabine in a combination regimen or as a single agent (latter lines).  
 
LOAd703 will be administered as an “add-on” to standard-of-care gemcitabine-based regimens or 
gemcitabine as a single agent in any line.  
2.7.4. 
Ovarian Cancer (
) 
 
Epithelial ovarian carcinoma (EOC) is the deadliest gynecological malignancy and the 6th leading 
cancer-related cause of death in developed countries (77). Patients commonly respond well to first 
line chemotherapy given after surgery, but disease recurs in most patients, at which point it is not 
usually amenable to long remissions. Hence, treatments after surgery plus first line chemotherapy 
is considered palliative. Five-year survival for patients with late stage disease is less than 30%. 
Standard of care for both chemotherapy naive patients and after relapse with a platinum-free 
interval more than 6 months consists of carboplatin combined with paclitaxel, or gemcitabine, or 
liposomal doxorubicin administered every three weeks (69,70). For platinum-resistant patients 
(relapse within 6 months after platinum therapy) weekly paclitaxel in combination with 
bevacizumab is recommended (71,72). Patients with high-grade ovarian cancer may be eligible for 
PARP inhibitors after response to platinum treatment regardless of BRCA mutations. Studies 
indicate that paclitaxel also might be an effective conditioning drug similarly to gemcitabine 
(73,74).  
 
This study will enroll patients with unresectable, palliative epithelial ovarian carcinoma (EOC) 
including epithelial ovarian, fallopian tube or primary peritoneal carcinoma whom have low tumor 
burden and either, 
 
• 
Platinum-sensitive relapse (platinum free interval ≥ 6 months) received at least one line of 
standard-of-care combination chemotherapy and not eligible for PARP-inhibitor 
maintenance after chemotherapy. 
 Platinum-resistant relapse (platinum free interval < 6 months) who have not received more 
than two lines of appropriate standard of care and not eligible for bevacizumab. Maintenance 
treatment does not count as a line of therapy. 

  
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• 
The patient has received appropriate therapy with PARP inhibitors if eligible.  
 
LOAd703 will be administered as an “add-on” to standard-of-care regimens as described in section 
5.10.4.  
 
 
2.8. Study Rationale 
 
Patients diagnosed with solid tumors are commonly treated with surgery followed by cancer 
therapeutics such as chemotherapy. Cancer cells promote expansion of immature myeloid cells that 
act as immunosuppressive cells in the tumor microenvironment. Immunoactivating therapies, such 
as LOAd703, require conditioning of the patients to release the brakes of the immune system. 
Checkpoint blockade antibodies will likely be an interesting combination therapeutic for immune 
activating agents but for Phase I/II development, it is informative to perform studies with 
chemotherapy-conditioning during immunoactivating therapy since they have well-known 
therapeutic outcomes. Gemcitabine, nab-paclitaxel and platinum-based chemotherapy seem all to 
have the desired outcome on immunosuppressive cells while leaving expanding cytotoxic T cells 
unaffected (22). Hence, LOAd703 will be tested in this study in patients receiving such drugs.    
 
 
 
  
 
Up to 8 doses of LOAd703 will be given with SoC tailored for the indication. .  
 
In this study, LOAd703 is given to patients with rapidly progressing cancers such as pancreatic cancer 
and biliary cancer, as an “add-on” therapy to any line of SoC treatment including first line since there 
are no curative treatments and short expected survival in these patients.  For patients with CRC and 
ovarian cancer, LOAd703 is given only if the patients have not experienced complete responses to 
their respective first line SoC regimens, or experience a fast relapse post treatment, thus, have a high 
risk of rapid progression. Treatment of these patients with remaining approved options is considered 
palliative since cure is not any longer expected. Hence, patients with low tumor burden, with 
refractory or recurrent lesions will be enrolled. Since high tumor burden, end stage patients, do not 
have a satisfactory operating immune system, defining MTD in such patients may give misleading 
information on tolerability. Due to the well-known safety profile of oncolytic adenoviruses, this 
design with “add-on” virus therapy was chosen to utilize their standard chemotherapy as immune 
conditioning treatment. For patients with no current chemotherapy schedule, gemcitabine will be 
given as conditioning. 
 
The study will demonstrate if LOAd703 administration is safe, if the immune system can be activated 
by LOAd703, if LOAd703 can be successfully delivered as “add-on” to different chemotherapy 
regimens, and if LOAd703 therapy will have clinical benefit that warrants further investigation.  
 
3. TRIAL DESIGN 
 
3.1. Objectives 
 

  
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The primary objective is to determine the tolerability of increasing doses of LOAd703 intratumoral 
injections during SoC or added conditioning gemcitabine chemotherapy. 
 
The secondary objective is to determine the effects of LOAd703 intratumoral injections during SoC 
or added conditioning gemcitabine chemotherapy. 
 
 
3.2.  Endpoints 
 
Primary Endpoints 
 
Phase I 
1. Tolerability is determined by physical examination, hematological and clinical chemistry 
analysis using CTCAE  v 4.03. 
 
 
 
Phase II 
1. Tolerability is determined by physical examination, hematological and clinical chemistry 
analysis using CTCAE v 4.03. 
 
. 
 
 
Secondary Endpoints 
 
Phase I 
 
 
3. Local and distant anti-tumoral effects assessed by appropriate imaging dependent on tumor 
localization and by monitoring tumor marker/s when available. Responses are judged 
accordingly to RECIST 1.1. 
4. Effects are evaluated as time to tumor progression (TTP), progression free survival (PFS) and 
overall survival (OS). 
 
Phase II 
1. Local and distant anti-tumoral effects on tumor assessed by appropriate imaging dependent 
on tumor localization and by monitoring tumor marker/s when available. Objective 
responses are measured using RECIST 1.1. 
2. Effect evaluated as TTP, PFS and OS. 
  
 

  
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4.1. Inclusion Criteria 
 
Patients must meet all of the following criteria for inclusion into the study: 
 
1. Have histologic or cytological evidence of colorectal carcinoma (CRC), pancreatic carcinoma 
(PC), biliary cancer, or epithelial ovarian carcinoma (EOC which may encompass epithelial 
ovarian, fallopian tube or primary peritoneal carcinoma). 
2. Have advanced disease, defined as cancer that is either metastatic or locally advanced, 
unresectable, and for which radiotherapy or other locoregional therapies are not considered 
treatment of choice but systemic chemotherapy or no therapy is planned. 
3. Have one of the following treatment situations apply: 
 
a) Colorectal carcinoma (CRC), 
   
 
i. 
A patient with refractory or recurrent metastatic CRC who has either received all 
conventional therapy; or is entering a “resting” phase between reasonable conventional 
treatments. 
 
ii. A patient who is amenable to treatment with LOAd703 plus gemcitabine as a single agent 
conditioning regimen.  
 
b) Pancreatic cancer 
 
i. 
 A patient with either locally advanced, unresectable or metastatic disease who is eligible 
to receive first or second line of conventional treatment consisting of gemcitabine and/or 
nab-paclitaxel. 
 
ii. 
A patient who is amenable to treatment with LOAd703 as an “add-on” to standard-of-
care gemcitabine-based or nab-paclitaxel-based regimens or gemcitabine or nab-
paclitaxel as single agents (section 5.10.2).  
 
 
c) Biliary cancer, 
 
 
I. 
 A patient with either locally advanced unresectable or metastatic biliary cancer who is 
either treatment-naïve or has received any number of lines of treatment. 
  
II. 
Patient who is amenable to treatment with LOAd703 as an “add-on” to standard-of-care 
treatment consisting of gemcitabine combined with other agents (e.g. gemcitabine/low-
dose cisplatin, gemcitabine/oxaliplatin, etc) in the first line setting or gemcitabine in a 
combination regimen or as a single agent in latter lines of treatment. 
 
d) Ovarian Cancer 
 
I. 
A patient with either epithelial ovarian, fallopian tube or primary peritoneal carcinoma.     
The patient has either:  
 
i) Residual 
disease 
following 
first-line 
standard-of-care 
combination 
chemotherapy.  

  
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ii) Platinum-sensitive relapse (platinum free interval ≥ 6 months) and have 
previously received at least one line of chemotherapy and not eligible for PARP-
inhibitor maintenance after chemotherapy. 
iii) Platinum-resistant relapse (platinum free interval < 6 months) who have not 
received more than two lines of appropriate standard of care and not eligible for 
bevacizumab. Maintenance treatment does not count as a line of therapy. 
iv)  The patient has received appropriate therapy with PARP inhibitors if eligible.  
 
II. 
Amenable to treatment with LOAd703 as an “add-on” to standard-of-care (excluding 
bevacizumab) as described in 5.10.4.  
4. Have a disease burden that is considered low (i.e. low tumor burden), which is defined on a 
patient-by-patient basis as per Principal Investigator’s discretion. A rough guideline for 
defining low tumor burden is that the sum of the product of the bidimensional measurements 
for all lesions is < 70 cm2. 
5. Have a measurable disease by standard imaging techniques per RECIST criteria. Measurable 
lesions must be outside of any prior radiation field(s), unless disease progression has been 
documented at that disease site subsequent to radiation.  
6. At least one non-irradiated (or irradiated but disease progression documented at the site 
subsequent to radiation) lesion must be suitable for image-guided intratumoral injection and 
needle biopsy. 
7. Be medically suited to sedation if required during intratumoral injections.  
8. Be at least 18 years-old. 
9. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2. 
10. Have no remaining acute toxic effects from previous anticancer therapy > grade 1, except for 
any grade of alopecia. 
11. Have adequate baseline organ/hematological function, as demonstrated by the following: 
a) Absolute neutrophil count (ANC) ≥1.0 x 109/l 
b) Hemoglobin ≥90 g/l 
c) 
Platelet count ≥ 100 x 109/l 
d) Bilirubin < 1.5 times the institutional upper limit of normal (ULN) 
e)  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 (3 if liver 
metastases are present) times the institutional ULN 
f) 
Serum creatinine <2 times the institutional ULN or calculated creatinine clearance 
>35 mL/min 
g) Prothrombin (INR) <1.5 or prothrombin time (PT) <1.5 ULN; and either partial 
thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 times 
the ULN.  
12. The patient must understand and be willing to provide written informed consent. 
 
 

  
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4.2.  Exclusion Criteria 
 
1. 
Any concurrent treatment that would compromise the study including but not limited to 
continuous high dose corticosteroids (>0.5mg/kg), lymphodepleting antibodies or cytotoxic 
agents. 
2. 
Treatment with high dose immune inhibitors including lymphotoxic monoclonal antibodies 
such as alemtuzumab (CampathR), or sirolimus (RapamuneR) and its analogs, biological 
therapy, cytotoxic agents or any investigational agents within 21 days of registration.  
3. 
Ovarian carcinoma patients should not be eligible to PARP inhibitor treatment. 
4. 
Patients on warfarin are not eligible. 
5. 
Women who are pregnant, lactating, or planning to become pregnant during the study period, 
or women of childbearing potential who are not using acceptable contraceptive methods. A 
woman is considered of childbearing potential if she is not surgically sterile or is less than 
1 year since last menstrual period. Acceptable contraceptive methods are: combined 
(estrogen and progesterone containing) hormonal contraception associated with inhibition 
of ovulation (oral, intravaginal, transdermal), progesterone-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion and vasectomized partner. 
6. Men who do not consent to the use of condom during intercourse. 
7. 
Known active hepatitis B or C infection, or HIV infection. 
8. 
Patients with active severe autoimmune disease. 
9. 
Uncontrolled intercurrent illness including but not limited to psychiatric illness/social 
situations that in the opinion of the Investigator would compromise compliance of study 
requirements or put the patient at unacceptable risk. 
10. Other malignancies within the past 2 years (not including basal and squamous cell carcinoma 
of the skin, localized prostate cancer or in situ cervix carcinoma). 
11. Patients must agree to not to vaccinate with living vaccines during participation in the trial. 
12. Prior treatment with an adenovirus-based gene therapy. 
13. Adenovirus-based vaccines (e.g Vaxzevria, known as COVID-19 vaccine Astra Zeneca, J&J 
Covid-19 vaccine) are prohibited 3 months prior to initiation of study treatment, during 
treatment and 6 months after the final dose of LOAd703. 
 
 
4.3. Screening Log, Registration and Identification Log and Numbering of Subjects 
 
It is the responsibility of the Principal Investigator that all patients, considered as candidates for the 
study, are listed in the “Screening and enrolment log”. The reason for rejecting a patient before 
informed consent is obtained should be specified in the comment field of the log. Patients will 
receive a consecutive study number when signing the informed consent and are thereafter 
considered enrolled as study patients. The trial site will keep a Registration and Identification log 
for all enrolled patients connecting a subject to the study number. 
 
Study patients who have been screened and are excluded before week 1-visit are considered screen 
failures and noted in the “Screening and enrolment log”. The reason for excluding the patient from 
entering the study should be specified in the comment field of the “Screening and enrolment log”. 
 

  
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When the inclusion and exclusion criteria have been fulfilled and confirmed in the eCRF, the patient 
is registered in the study. 
4.4. Off-treatment and off-study patients 
 
A patient can discontinue the study treatment at any time if it is medically necessary, as judged by 
the Investigator or the Sponsor. 
 
Modified Follow-Up Criteria: The patient would not continue to receive treatment but would 
continue to be followed as otherwise specified in this trial if the following criteria are met: 
 
1. The development of toxicity, which, in the Investigator’s judgment, precludes further 
treatment. 
2. A response sufficient to downstage the patient to resectable or borderline resectable disease, 
in which case the Investigator may decide to pursue chemoradiation and/or surgical 
resection. 
3. Patient request to discontinue treatment. 
4. Female patient becomes pregnant. 
5. If a DLT has been observed, that will not warrant dose reduction (or addition of 
corticosteroids pre-injection), or if a DLT occurs also after a dose reduction and/or addition 
of corticosteroids, the patient will be withdrawn from treatment, but will continue follow up 
according to the study schedule. 
6. Confirmed progressive disease without any other treatment options available. 
 
 
Hence, if the patient discontinue treatment, analysis of late toxicity, virus persistence, immunological 
reactions and effect can still be continued within the study accordingly to timelines in the protocol.      
 
 
Off-Study Criteria: A patient has the right to withdraw consent for the study at any time without 
giving any specific reason. The patient will be withdrawn from participation in this trial at any time 
if any of the following criteria is met: 
 
1. Progressive disease that will require another treatment regimen. 
2. Patient request to be removed from the trial (withdrawn consent).  
3. Lost to follow-up/noncompliance to protocol. 
4. Study termination. 
 
4.5. Withdrawn Patients 
 
After treatment discontinuation or premature withdrawal a patient from the trial, the Investigator 
will clearly document the reason in the case report form.  
 
Off treatment patients should continue to be followed and assessed as specified in the trial, i.e. all 
LOAd703 visits (despite no virus is injected) and evaluation visits up to the final follow-up visit, if 
possible.  
 

  
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If the patient is withdrawn from this protocol (off-study), the final follow-up visit should be 
scheduled as soon as possible to collect end-point data prior the patient’s discontinuation, if possible. 
Nevertheless, these patients will be followed for a minimum of 
 
treatment for ongoing or occurrence of new AEs if possible.  
If the patient withdraw consent, this follow up should be done outside the study, i.e. no data will be 
collected in the study.  
 
4.6. Noncompliance 
 
All instances of noncompliance and all resulting protocol deviations will be recorded and explained. 
5. TREATMENT OF PATIENTS 
5.1. Phase I 
 
The patients will be informed about the study and sign informed consent whereby they are enrolled 
in the screening phase of the protocol to determine eligibility, including assessment of health status 
and radiological evaluation. Imaging obtained 
 prior of first LOAd703 injection and 
blood tests done 
 of screening may be used for baseline evaluations at the discretion of 
the Investigator. Patient registration will occur following successful screening and confirmation of 
all eligibility criteria via eCRF.  
 
 post registration the patients will initiate their biweekly LOAd703 injections 
) given in combination with SoC chemotherapy, or gemcitabine 
conditioning if there are no current chemotherapy schedule available (Figure 1, Section 5.3). The 
patients will be given a total of 8 LOAd703 injections. Three cohorts consisting of at least three 
patients per cohort will be evaluated in Phase I. The dose will be escalated, one dose per cohort, 
evaluating the doses 5x1010 VP/injection (cohort 1), 1x1011 VP/injection (cohort 2) and 5x1011 VP 
(cohort 3). The treatment will be administered by image-guided intratumoral injection either 
percutaneously (preferred) or endoscopically, depending on the tumor location. Patients who will 
receive their injections of LOAd703 by endoscopic route may require sedation as determined by the 
endoscopist and performed as per standard practice at the Hospital.  
 
 
 
 
 
 
 
 
Prior each LOAd703 injection (
) the Investigator must make a complete AE evaluation 
and assess the toxicity screening to assure that the patient is able to receive further LOAd703 
injections.  
 
  

  
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 Radiological assessment will be performed at enrollment 
and thereafter every other month as per routine at the hospital. 
 post the final LOAd703 
administration, patients will undergo a final follow-up analysis and come off-study.
 
 
Date of death will be captured and will be reported as descriptive addendum to the 
study report when all subjects can be concluded.  
 
The informed consent form includes a specific question if the patients are willing or not for the study 
team to follow up on their condition regularly after final follow-up visit. Patients will participate for 
survival monitoring even if they disagree to the extended follow up post study.  
 
 
 
 
When the first patient has received at least three doses of virus without DLT (as evaluated at the next 
AE evaluation 
 after third dose), the next two patients in the first cohort can begin 
LOAd703 treatment. No patients are dosed the same day in Phase I. Note that enrollment plus 
screening is allowed if slots are available in a cohort at any time. If a patient does not complete the 
three doses for a reason other than virus- or administration route-related DLT, this patient will be 
replaced by another subject and not regarded as a DLT. For details regarding DLT, see section 5.7. 
 
Treatment with an escalated virus dose, can be initiated when at least three patients at the previous 
dose have received at least three doses of LOAd703 virus without DLT prior the AE assessment 
before 
 The decision for the next cohort to escalate dose, or stay at current 
dose, is taken by the Sponsor after a safety meeting including the Sponsor, the Clinical Project 
Manager (for taking notes only), the Medical Advisor and the Principal Investigator. 
 
Note: at least 1 of 3, or 2 of 6, patients per dose cohort should be represented by a patient within one 
of the orphan indications pancreatic, biliary or ovarian cancer. 
 
The justification of cohort sizes is outlined in chapter 10 (Statistics). 
 
5.2.  Phase II  
 
 
The Phase II  is initiated when maximum tolerated dose (MTD) is determined in Phase I by a safety 
meeting in which the Sponsor, the Clinical Project Manager (for taking notes only), the Clinical 
Advisor and the Principal Investigator participate.  
Phase II  is initiated after approval of Amendment no.5.  
 
The same procedures are followed for Phase II  
:  

  
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The patients will be informed about the study and sign informed consent whereby they are enrolled 
in the screening phase of the protocol to determine eligibility, including assessment of health status 
and radiological evaluation. Imaging obtained 
 prior to screening and blood tests 
done 
 of screening may be used for baseline evaluations at the discretion of the 
Investigator. Patient registration will occur following successful screening and confirmation of all 
eligibility criteria via eCRF.  
 
 LOAd703 injections 
 
) (Figure 1, Section 5.3) given in combination to SoC or gemcitabine conditioning 
if there are no current chemotherapy options available. The patients will be given a total of 8 
LOAd703 injections. The treatments will be administered by image-guided intratumoral injection 
either percutaneously (preferred) or endoscopically, depending on the tumor location. Patients who 
will receive their injections of LOAd703 by endoscopic injection may require sedation as determined 
by the endoscopist and performed as per standard practice at the Hospital.    
 
 
 
 
 
 
 
  
 
 
 
 
Prior each LOAd703 injection (
) the Investigator must make a complete AE evaluation 
and assess the toxicity screening to assure that the patient is able to receive further LOAd703 
injections.  
 
  
 
 
 
 
 
 
 
 
   
 
 
 Radiological assessment will be performed at enrollment 
and thereafter every other month as per routine at the hospital. 
 post the final LOAd703 
administration, patients will undergo final follow-up analysis and come off-study.
 
 
Date of death will be captured and will be reported as descriptive addendum to the 
study report when all subjects can be concluded. The informed consent form includes a specific 
question if the patients are willing or not for the study team to follow up on their condition regularly 
after final follow-up visit. Patients will participate for survival monitoring even if they disagree to the 
extended follow up post study.  
 

  
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5.5.7. 
 Unused Clinical Trial Supplies 
 
 
 
 
 
5.6. LOAd703 Dose Modifications 
 
  
  
 
  
 
 
 
 
 
 
 
 
  

  
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5.7. Dose Limiting Toxicity 
 
DLT is defined as a CTC adverse event (CTCAE) Version 4.03, grade 3 or higher that can be attributed 
(definitely, possibly or probably) to LOAd703. A DLT will be reported to Sponsor in an expedite 
manor, following the procedures for SAE reporting, regardless if the event fulfil the serious criteria 
or not, see section 9.3.1. 
 
 
 
 
 
 
 
 
 
5.8. Maximum Tolerated Dose 
 
Maximum tolerated dose (MTD) is defined as the highest safe dose tested in Phase I, in which DLT 
does not occur in >1 of 3, or >2 of 6 treated patients. 
5.9.  Continuation of Treatment 
 
If subjects are judged by the Investigator to be deriving significant clinical benefit (at least partial 
response) from LOAd703 once all scheduled injections (maximum 8) have been administered, 

  
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additional treatments need to be approved by the Sponsor, the ethical review board and by the 
Medical Products Agency. 
 
5.10. 
Chemotherapy Standard of Care/Gemcitabine Conditioning Schedules 
LOAd703 is given as an “add-on” to standard of care (SoC). If no regimen is available, gemcitabine 
conditioning can be used instead. Below are options that can be combined with LOAd703 in this 
protocol. The dose can be omitted or reduced as per standard guidelines at the Hospital. 
 
5.10.1. 
Colorectal Cancer (
) 
Patients with colorectal cancer will receive LOAd703 treatments “add-on” to gemcitabine 
conditioning if there are no standard options or the patients is in a scheduled treatment break (e.g. 
resting between standard options). 
 
 
 
Gemcitabine 1000mg/m2 is given intravenously in repeated 28-day cycles with treatments day 1, 8 
and 15. 
 
5.10.2. 
Pancreatic Cancer 
Patients with pancreatic cancer will receive LOAd703 treatments “add-on” to SoC gemcitabine with 
or without nab-paclitaxel.  
 
Gemcitabine (1000mg/m2) with or without nab-paclitaxel (125mg/m2) are given intravenously in 
repeated 28-day cycles with treatments day 1, 8 and 15. 
 
5.10.3. 
Biliary Cancer (
) 
Patients with biliary cancer will receive LOAd703 treatments as an “add-on” to SoC gemcitabine 
combined with other agents (e.g gemcitabine/low dose cisplatin, gemcitabine/oxaliplatin etc) in 
the first line setting or gemcitabine in a combination regimen or as a single agent in latter lines of 
treatment. 
Gemcitabine (1000mg/m2) with or without cisplatin (25 mg/m2) are given intravenously in 
repeated 21-day cycles with treatments day 1 and 8. 
 
5.10.4. 
Ovarian Cancer 
Patients with ovarian cancer with platinum-sensitive relapse will receive LOAd703 treatments 
“add-on” to SoC treatments at the discretion of their physician: 1) liposomal doxorubicin 
(40mg/m2) and carboplatin (AUC5) at a 28-day cycle with treatments on day 1 or, 2) gemcitabine 
(800mg/m2) and carboplatin (AUC5) at a 21-day cycle with treatments on day 1.  
 
Patients with platinum-sensitive relapse who are felt not to be appropriate candidates for the 
platinum-based regimens, as per the discretion of their treating physician, may be treated with 
LOAd703 added on to either paclitaxel or gemcitabine according to the schedules below. 
 
Patients with ovarian cancer with platinum-resistant relapse will receive LOAd703 treatment 
added on to the following standard-of-care treatments at the discretion of their treating physician: 
1)  paclitaxel (80mg/m2) on a 28-day cycle with treatments on day 1, 8, 15 and 21; or 2) 
Gemcitabine (1000mg/m2) conditioning on a day 1, 8 and 15 schedule. 

  
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5.11. 
Concomitant Treatment 
 
Patients can receive full supportive care while on this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
5.12. 
Monitoring Subject Compliance 
 
As LOAd703 will be administered by the clinical study medical personnel, compliance with study 
drug administration will be ensured. Patient compliance with concomitant medications and protocol-
specified assessments will be recorded at the study visits. 
 
 
6. STUDY EVALUATIONS 
 
 
 
 
 
 
 
6.1. Schedule of Events  
 
All study evaluations are summarized in Table II (Appendix I). 
 
6.2.  Screening 
 
During the screening phase, the patient will be informed about the trial and sign informed consent. 
The patient will be evaluated for health status, pregnancy (if applicable) and tumor load (appropriate 
radiological imaging). If the patient has been subjected to radiology examination within the past 
, the previous imaging can be reused for evaluation at the discretion of the Investigator. 
However, the imaging should not be older than 
 at the time for first LOAD703 injection. If all 
of the inclusion criteria and none of the exclusion criteria are met, the patient is enrolled to 
participate in the trial. 
 

  
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6.3.  LOAd703 Visits 
 
The patients will undergo maximum 8 biweekly (
) repeated treatments with 
LOAd703. LOAd703 is administered by image-guided intratumoral injection. 
 
 
  
Prior each administration (
) the Investigator must see the patient to make a complete 
AE evaluation and assess the toxicity screening to assure that the patient is able to receive further 
LOAd703 injections. For continuation criteria, see section 5.1 for Phase I and section 5.2 for Phase II. 
 
 
 
 
 
 
 
Chemotherapy should be given 
 
 
 
 
 
 
 
6.4.  Evaluation Visits 
 
During evaluation visits, the patient will be evaluated for health status, toxicity, and treatment effect 
on tumor size (radiology exam and tumor marker when available every other month). 
 
 
 
 
 
6.5.  Collection of Information After 
/Study End  
 
If the patient consented to collection of information on his/her condition after study end, information 
on tumor evaluations and further treatment will be collected from the medical record.  
All patients will be followed for survival after study end.  
7.  STUDY ASSESSMENTS 
 
 
 
 
 
 

  
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7.2.  Safety Parameters  
7.2.1. 
  Demographics 
 
- Age (
) 
- Gender (
) 
- Race 
 
7.2.2. 
 Medical History/Patient History  
 
- Prior and ongoing medical illness and conditions (
) 
- Date of diagnosis (
) 

  
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- Diagnosis stage and extent of the disease (
) 
- Previous anti-tumor therapy and response to the respective treatment (
) 
- Previous or ongoing smoker 
 
 
7.2.3. 
 Physical Exam  
 
-  Full physical examination (
) 
- Physical assessment 
). For details, see section 5.1 for Phase I 
and section 5.2 for Phase II. 
- Baseline symptoms (
) 
 
7.2.4. 
 Vital Signs, height and weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Height (
) 
- Weight (
) 
 
After injection 
.  
 
7.2.5. 
 ECOG Performance Status 
 
To be assessed according to the ECOG score (Appendix II). 
 
7.2.6. 
Pregnancy Test 
 
Urine or serum pregnancy test for females of child-bearing potential is to be completed at 
 
 
 
7.2.7. 
 12-Lead ECG 
 
A 12-led ECG will be performed after 5 min rest 
, and will be judged 
clinically normal/abnormal by the Investigator. Any clinical abnormalities should be described. 
 

  
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7.2.8. 
 Blood Chemistry  
 
 
 
 
 
 
 
 
 
 
Blood sampling for safety should be taken 
 before each injection. However, if 
 
 virus injection no 1, these results are considered as baseline and 
no new sampling is needed. Further, if samples have been taken for routine analysis 
 
enrollment, the results can be used for screening evaluation at the discretion of the Investigator 
without need of subject the patients for new samples. 
 
.  
 
7.2.9. 
 Hematology  
 
Hemoglobin, WBC with differential count, platelet count at screening, LOAd703 visits, evaluation 
visits and at final follow-up. 
Blood sampling for safety should be taken 
 before each injection. However, if screening 
samples are taken 
 virus injection no 1, these results are considered as baseline and 
no new sampling is needed. Further, if samples have been taken for routine analysis 
 
enrollment, the results can be used for screening evaluation at the discretion of the Investigator 
without need of subject the patients for new samples. 
 
7.2.10. 
 Concomitant Medications 
 
All on-going medications should be listed at screening with start and stop time, excluding LOAd703 
and chemotherapy, and those already registered as concomitant medications at a prior visit. The 
list is updated at every study visit if applicable. Since patients usually are prescribed numerous 
concomitant medications, of which many are to be used per needed, the actual medication list in the 
medical records should be confirmed with the patient by the study nurse/Investigator at each visit.  
 
7.2.11. 
 Adverse Events Monitoring 
 
Adverse events will be monitored continuously during the trial and data on all AEs will be collected 
regardless of severity and causality. See section 9 about AE reporting. 
 
 
 
 
 
 
 

  
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7.5.  Efficacy Assessments 
 
Response and progression will be determined for all patients
 
 
 
7.5.1. 
 Tumor Size 
 
Tumor size will be determined with suitable imaging depending on the localization of the tumor. 
Computer tomography (CT) will preferably be selected. Radiology exams will be performed every 
other month post treatment initiation: 
). However, at screening: 
if the patient has been subjected to radiology examination within the 
, the previous 
imaging can be reused for evaluation at the discretion of the Investigator. Note that the baseline CT 
should not be older than 
 at the time of first LOAd703 injection. Definitions of measurable 
disease and response to treatment will follow RECIST 1.1 criteria.  
 
 
 
 
 
 
 
 
 
 
Definition of Measurable Disease 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of 10mm by CT scan (irrespectively of 
scanner type) 
 
 
7.5.2. 
 Tumor Markers 
 

  
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Serum markers, if available, will be evaluated simultaneously to tumor size imaging (
 
 These samples are 
sent together with the clinical chemistry samples in section 7.2.8. The level of a serum marker will 
not be considered in the response criteria.
 
 
 
 
 After the analysis, sample will be destroyed or returned to the biobank. 
 
 
8.  Response Criteria  
8.1.  RECIST 
 
The tumor response will be evaluated using appropriate imaging technique depending on the 
localization of the tumor. Tumor regression or progression will be evaluated accordingly with 
RECIST 1.1 criteria. 
 
Complete Response (CR) 
Complete macroscopic disappearance of all tumors. 
 
Partial Response (PR) 
A reduction of at least 30% in the sum of all tumor diameters from baseline. 
 
Stable Disease (SD) 
Neither partial response nor progressive disease. 
 
Progressive Disease (PD) 
At least a 20% increase in the sum of all tumor diameters from the smallest tumor size and/or the 
appearance of new tumor lesion/s. 
 
 
 
 
 
 
 
 
 
 
Clinical Benefit Rate (CBR) 
CBR is defined as MR or better. 
 
Overall Response Rate (ORR) 
ORR is defined as PR or better. The below Table is used for guiding overall response. 
 

  
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8.2.  OS, TTP and PFS 
 
Time to Tumor Progression (TTP) 
TTP is the time from start of treatment to disease progression. 
 
Progression free survival (PFS) 
PFS is the time from start of the treatment to progression or death. 
 
Overall Survival (OS) 
Overall survival is defined as the time from the start of treatment to death due to any cause. 
 
9. Adverse Events (AE) 
 
9.1.  Definitions 
 
9.1.1. 
  Adverse Event (AE) 
 
An AE is any untoward medical occurrence that does not necessarily have to have a causal 
relationship with the treatment. An AE can therefore be any unfavorable, unintended clinical sign, 
symptom, disease or clinically relevant change in laboratory variables or clinical tests temporally 
associated with the use of an investigational product, whether or not considered related to the 
investigation product, that require clinical intervention or further investigation (beyond ordering a 
repeat/confirmatory test). Injury or accidents, the medical condition for operations not pre-planned, 
or deterioration in concurrent illness are also considered as AEs. 
 
9.1.2. 
  Serious Adverse Event (SAE) 
 
A serious AE is defined as any untoward medical occurrence that at any dose: 
 
- 
Results in death. 
- 
Is life-threatening (i.e. the patient was at risk of death at the time of the event. It does not 
refer to an event that hypothetically may have caused death if it was more severe). 

  
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- 
Requires in-patient hospitalization or prolongation of existing hospitalization excluding that 
for pain management, disease staging/re-staging procedures, or catheter placement unless 
associated with other serious events. 
- 
Results in persistent or significant disability or incapacity. 
- 
Is a congenital anomaly or birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious adverse drug events when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
 
The term “severe” is often used to describe the intensity (severity) of an event; the event itself may 
be of relatively minor medical significance (e.g., a severe headache).  This is not the same as “serious” 
which is based on patient/event outcome or action criteria usually associated with events that pose 
a threat to a patient’s life. 
 
Planned or elective hospitalizations (e.g., for administration of protocol therapy) should not be 
considered SAEs. 
 
9.1.3. 
  Suspected Unexpected Serious Adverse Reactions (SUSAR) 
 
An unexpected AE is defined as any adverse drug experience where there is evidence to suggest a 
causal relationship, the specificity or severity of which is not consistent with the current 
Investigator’s Brochure with Reference Safety Information (RSI); or, if an Investigator’s Brochure is 
not required or available, the specificity or severity of which is not consistent with the risk 
information described in this protocol or in the regulatory agency study authorization application.   
Unexpected, as used in this definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the Reference Safety Information in the Investigator Brochure) 
rather than from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product. 
 
9.1.4. 
   Non-Serious Adverse Event 
 
All other AEs not fulfilling the previous definitions are classified as non-serious. 
 
9.2.  Evaluating and Documenting Adverse Events (AE) 
 
AEs are graded in the study according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (see: http://ctep.info.nih.gov). All AEs (except grade 1 and 2 laboratory 
abnormalities that do not require an intervention) are to be recorded on the AE page in the case 
report form (eCRF) and source documentation.   
 
All AEs fulfilling the criteria for Serious (section 9.1.2) should also be reported as a serious adverse 
event (SAE) with the following exception: bone marrow toxicities induced by chemotherapy will only 
be reported as an SAE if the event leads to hospitalization or death, or in any other way deviates from 
what the Investigator considers to be expected. 
 

  
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During 
 the Investigator will note the occurrence and nature of each patient’s existing 
medical condition/s. Occurrence and nature of AEs (including lab events) directly observed by the 
study personnel or spontaneously reported by the patient during the study will be reported. Each 
patient will be asked about AEs at each visit after the first dose of investigational product LOAd703. 
 
The AE reporting period for this trial begins upon receiving the first cycle of LOAd703/chemotherapy 
and ends at study termination (e.g. at final follow-up). If a patient experiences an AE after signing the 
Informed Consent, but before treatment is started, the event will be recorded as an existing medical 
condition unless the Investigator believes that the event may have causal relationship to a study-
specific procedure described in the protocol. If LOAd703 has been administrated when an AE occurs, 
its relationship to LOAd703 will be judged by the Principal Investigator. 
 
9.2.1. 
  Severity Grading 
 
The Investigator must determine the intensity of any AEs according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03 (see http://ctep.info.nih.gov) and their causal 
relationship. Those AEs not covered by these criteria will be graded as follows:  
 
1. 
Mild: Discomfort noticed, but no disruption of normal daily activity. Prescription drug not 
ordinarily needed for relief of symptom but may be given because of personality of patient. 
2. 
Moderate: Discomfort sufficient to reduce or affect normal daily activity. Patient is able to 
continue in study; treatment for symptom may be needed. 
3. 
Severe: Incapacitating, severe discomfort with inability to work or to perform normal daily 
activity. Severity may cause cessation of treatment with test drug; treatment for symptom may 
be given and/or patient hospitalized. 
4. 
Life-Threatening: Life-threatening consequences, urgent intervention may be required;  
5.  
Fatal: Event caused the death of the patient.  
 
For AEs of grade 3 or higher related to the LOAd703 virus, DLT should be considered. See section 5.7. 
 
9.2.2. 
  Attribution Definitions 
 
The Investigator will attempt to assess the relationship of the event to LOAd703, the injection 
procedure, chemotherapy, underlying cancer disease or other reason.  An AE is considered to be 
associated with any of these reasons if the attribution is determined as possible, probable or definite.  
Attribution of AEs for each of the reasons will be recorded in the CRF as: 
 
- Unrelated:  
The AE is clearly NOT related  
- Unlikely:  
The AE is doubtfully related  
- Possible:  
The AE may be related  
- Probable:  
The AE is likely related  
- Definite:  
The AE is clearly related  
 
 
 

  
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9.3.2. 
  Safety Report – Reporting by Sponsor 
 
The Sponsor is responsible for informing MPA/EMA and IEC of any Suspected, Unexpected Serious 
Adverse Reactions (SUSARs). SUSARs that is fatal or life-threatening, should be reported as soon as 
possible and not later than 7 calendar days after first knowledge by the Sponsor, and with a follow-
up report within another 8 days. Any other SUSARs should be reported within 15 days.   
 
The third party vendor will be delegated the task to report SUSAR to the MPA/EMA and IEC as per 
regulations. 
 
SAEs that are not objects for expedited reporting, should be listed together with SUSARs in the annual 
drug safety update report (DSUR), written in cooperation between Principal Investigator, Sponsor 
and UCR, and submitted to MPA and IEC according to current legislation.  
 
9.3.3. 
  Reporting to IRBs 
 
Investigators must report SAEs and unexpected AEs to his/her IRB or ethics committee according to 
national legislation and per the institutional guidelines. 
 
9.3.4. 
  Procedures in case of Medical Emergency 
 
The Investigator should ensure that there are procedures and expertise available to cope with 
emergencies during the study.  
 
If an emergency occurs, please notify the Sponsor and 
: 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 

  
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9.5.  Handling of Pregnancy 
 
Any pregnancy diagnosed during the study, or that occurs within the AE reporting period after 
stopping study medication, must be reported immediately to the Sponsor. Women of childbearing 
potential will be informed about contraceptive medication during trial participation and to 
immediately inform the Investigator if pregnancy should occur during study participation. 
Pregnancy, in and of itself, is not regarded as an AE, unless there is suspicion that study medication 
may have interfered with the effectiveness of a contraceptive medication. If the patient becomes 
pregnant while on-study, the study drug should be immediately discontinued. Pregnancy information 
about a female patient or a female partner of a male patient should be reported immediately from 

  
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10.3. 
Safety Reporting 
 
Safety data will be tabulated for the safety population. AEs will be tabulated by body system, 
preferred term, severity, seriousness, and relationship to treatment. Each value will be classified as 
falling above, below, or within the normal range.  Laboratory parameters will also be tabulated by 
the maximum NCI-CTCAE severity grade. AE terms will be coded using the Medical Dictionary for 
Drug Regulatory Activities (MedDRA).  
 
10.4. 
 Efficacy Reporting 
 
Efficacy will be tabulated by response category per the RECIST1.1 criteria for the efficacy evaluable 
population. The clinical benefit rate and overall response rate (ORR) will be determined. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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11. QUALITY CONTROL AND QUALITY ASSURANCE 
 
11.1. 
 Direct Access to Source Data/Documents 
The Investigator(s)/institution(s) will permit study-related monitoring, audits, review and 
regulatory inspection(s), providing access to source data/hospital records. Sponsor verifies that each 
patient has consented in writing to direct access to the original source data/hospital records by the 
use of written patient information and signed Informed Consent. 
  
During the monitoring, the data recorded in the CRFs by the Investigator will be controlled for 
consistency with the source data/hospital records by the study monitor (source data verification). 
Any discrepancies of data will be documented and explained in the monitoring reports.  
 
11.2. 
 Source Data 
The requirements regarding information in the medical records follows the “Patientdatalagen” (SFS 
2008:355), the General Data Protection Regulation (GDPR: EU2016-679) and “The Medical Product 
Agency’s regulations on clinical trials of medicinal products for human use” (LVFS 2011:19:), which 
means that except information that are of importance for the wellbeing and care of the patient, the 
following minimum study specific information must be recorded: 
 
• 
Date when patient information was given and when signed Informed Consent was obtained. 
• 
Patient study number 
• 
The name of the study and the EudraCT number 
• 
Fulfilment of inclusion criteria. 
• 
Diagnosis 
• 
Dates of all visits during the study period 
• 
Any information relating to AEs 
• 
All treatments and medications prescribed/administered (including dosage) 
• 
Date of study termination 
 
For details and information that is study specific and of no interest for the medical care of the patient, 
CRF and other documents may be considered as source data. Prior to study start, the Principal 
Investigator/study nurse and the Monitor must identify and document the expected source location 
of source data (e.g. medical record notes, laboratory reports and the CRF itself). This will be done by 
completing a site-specific source data verification log (Origin of Source Data). The site must clearly 
communicate any deviation from the expected source data location to the study monitor. Note that 
the patient journal shall include a short description of the study. 
11.3. 
 Monitoring  
In accordance with the principles of Good Clinical Practice (GCP), monitoring of the study will be 
performed by Sponsor. In this study, 
 will be responsible for monitoring activities on behalf of 
the Sponsor. During the study, the Monitor will have regular contacts with the study site, including 
visits to ensure that the study is conducted and documented properly in compliance with the 
protocol, GCP and applicable regulatory requirements.  
The Monitor will ensure that accountability of investigational products is performed and will review 
source documents for verification of consistency with the data recorded in the CRFs. All patients that 
have performed any study specific assessment will be monitored for Signed Informed Consent and 
all patients that have received study drug will be monitored for date of visits, inclusion and exclusion 
criteria and AE/SAE.  

  
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Since patients usually are prescribed numerous concomitant medications, of which many are to be 
used per needed, the actual medication list in the medical records should be confirmed with the 
patient by the study nurse/Investigator at each visit.  
The monitor will compare the eCRF only with the notes in the medical records, except for periods of 
hospitalization (SAE) when concomitant medication will be checked against the medicinal 
dispensing lists. When start/stop dates, doses or indications are missing in the medical records, the 
CRF will be considered source data.  
 
The extent of monitoring is described in the monitoring plan, which will be approved by the Sponsor. 
The Monitor will also check theInvestigator Site File and provide information and support to the 
Investigator(s).  
 
The study site may be subject to quality assurance audit by the Sponsor as well as inspection by the 
Medical Products Agency (MPA). The Investigator and other responsible personnel must be available 
during the monitoring visits, audits and inspections and should devote sufficient time to these 
processes.  
 
The Investigator should provide a curriculum vitae (CV) or equivalent documentation of suitability 
to be responsible for the study. All Sub-investigators and other responsible personnel should be 
listed together with their function in the study on the delegation list and provide their CVs. 
11.4. 
 Protocol Modifications 
 
No modification of the protocol should be implemented without the prior written approval of the 
Sponsor. Any such changes, which may affect a patient’s treatment or informed consent, especially 
those increasing potential risks or scientific quality of the study, must receive prior approval by the 
MPA and the International ethics committee (IEC) before implementation. The exception to this is 
where modifications are necessary to eliminate an immediate hazard to trial subjects, or when the 
change involves only logistical or administrative aspects of the trial (e.g., change in monitor, change 
in telephone number). Other administrative revisions, which may impact the clinical portion of a 
study, will be duly reported to the MPA by the Sponsor and/or IEC by the Principal Investigator, or 
designee, under guidance of 
 and with approval of the Sponsor. 
 
12.  ETHICS 
12.1. 
Independent Ethics Committee 
It is the responsibility of the Principal Investigator to obtain approval of the study protocol/protocol 
amendments, the patient information and the Informed Consent from the IEC before enrolment of 
any subject into the study.  
 
The Sponsor shall report all SUSARs to the IEC. If a study stops prematurely at a study center for any 
reason, the IEC must be informed. At the end of the study, the Sponsor should notify the IEC.  
The Sponsor/Principal Investigator should file all correspondence with the IEC and provide the other 
party with copies.  
 
12.2. 
  Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, applicable regulatory requirements, 
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This Phase I/II-study is conducted at 2 clinics in Sweden:
 
 
 Medical staff with appropriate level of training is available at both sites. The sites have 
procedures for handling emergency situations.  
 
12.3. 
 Patient Information and Informed Consent 
It is the responsibility of the Investigator to provide each subject with full and adequate verbal and 
written information about the objectives, procedures and possible risks and benefits of the study. All 
subjects should be given the opportunity to ask questions about the study and should be given 
sufficient time to decide whether or not to participate in the study. The written patient information 
must not be changed without prior discussion with the Sponsor. 
The subjects will be notified of their voluntary participation and of their freedom to withdraw from 
the study at any time and without giving any particular reason. Subjects must also be informed that 
withdrawing from the study will not affect their future medical care, treatment or benefits to which 
the subject is otherwise entitled.  
The Investigator is responsible for obtaining written Informed Consent from all subjects (or their 
legally acceptable representatives and/or witnesses, where applicable) prior to enrolment in the 
study.  
The subjects will consent to: 
- 
Participating in the study. 
- 
Personnel concerned at the Sponsor and regulatory authorities to gain full access to hospital 
records, to control the data collected in the study.  
- 
Recording, collection and processing of data and storing of data in a database. 
- 
Possible transfer of information from the study to countries outside the European Union (EU).  
- 
Storing of study samples in a biobank. 
- 
Allow for samples to be analysed in within EU or outside EU (third country).  
- 
Further follow-up of their condition via the medical records after final follow-up visit (Yes/No) 
 
It should be clearly stated that the data will not identify any subject taking part in the study, in 
accordance with the EU General Data Protection Regulation (2016/679). 
A copy of the patient information and the Informed Consent form should be given to the subject. The 
Investigator who gave the verbal and written information to the subject shall sign the Informed 
Consent form. The Investigator should file the signed Informed Consent forms in the Investigator’s 
File for possible future audits and inspections.  
It is suitable to notify the subject’s family doctor of the subject’s consent to participate in the study.  
13.   DATA MANAGEMENT 
 
13.1. 
 Data Management 
 

  
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 will be responsible for the Data Management and will write a study specific Data Management 
Plan (DMP) where further details will be specified. All data will be recorded in electronic (e)CRFs. 
The Investigator is responsible for ensuring the accuracy, completeness and legibility of the data 
reported in the eCRFs. The monitor will check the accuracy, completeness and legibility of the data 
reported in the eCRFs. 
 
13.1.1. 
Data Entry and Data Validation  
 
Data will be entered into the study eCRF and will be subject to both logical computerized checks and 
manual validation checks against listings in accordance with the study specific DMP. In addition, 
selected key variables will be proofread. All inconsistencies detected during these procedures will be 
resolved through electronic Data Clarification Forms (DCF’s) in the eCRF, being issued to the monitor 
or investigational site personnel.  
 
13.1.2. 
Database Closure   
 
When all patients have been completed, all data have been entered into the eCRF database, all coding 
done and approved, and all queries solved, the Database Closure procedures will start. Decisions will 
be made how to classify patients into analysis populations, and how to handle protocol violations and 
deviating or missing data. All decisions will be dated and documented in a Database Closure 
document. After finalization of the Database Closure document, the database will be locked. Any 
changes in the database thereafter will be documented. 
14.   DATA HANDLING AND RECORD KEEPING 
 
14.1. 
 Electronic Case Report Forms (eCRF) 
 
An eCRF is required and should be completed for each included subject on a visit-by-visit basis. The 
eCRF should be completed, monitored and corrected if needed 
 to the last visit of a 
study patient. The subject’s identity must always remain confidential. All information in the eCRFs 
should be in English. If necessary, the Monitor should translate any information or comments 
recorded in Swedish.  
 
The completed eCRFs are the sole property of the Sponsor and should not be made available in any 
form to third parties (except for authorized representatives of appropriate regulatory authorities) 
without written permission from the Sponsor. A paper copy of the electronic CRFs should be kept in 
the Sponsor’s Study File and and in the Investigator Site File. 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness of 
the data recorded in the eCRFs.  
 
In this study, clinical data including AEs and concomitant medication swill be entered into a 21 CFR 
Part 11-compliant eCRF (
) provided by 
. The eCRF includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. Backups of data are automatically performed on a regular basis. Backups are stored and 
encrypted on both magnetic and optical media in a separate physical location. This process 

  
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guarantees the minimum data loss in the events of a disastrous failure. This loss will be limited to all 
data recorded during the last 8 hours prior to the failure in the worst case. 
14.2. 
 Record Keeping 
 
To enable audits and evaluations by the Sponsor and inspections by regulatory authorities, the 
Investigator shall keep records (essential documents) of the study for 10 years. This includes any 
original source data related to the study, the subject identification list (with subject numbers, full 
names and addresses), the original signed Informed Consent forms, copies of all eCRFs and detailed 
records of investigational products disposition.  
 
14.3. 
Study Report 
 
A full study report should be submitted to EudraCT by Sponsor within 12 months from last patient’s 
last visit. The PI and study site must provide necessary information by completing the eCRF for every 
patient no later than 6 months from last patient’s visit to allow close out activities including 
monitoring and correction of eCRFs if necessary. 
 
14.4. 
 Insurance 
 
Patients in the study are covered by the 
 
  
 
14.5. 
 Publication Policy 
 
The investigation is considered as collaboration between Uppsala University, Uppsala University 
Hospital, Karolinska University Hospital and the Sponsor. The Investigator agrees to inform the 
Sponsor of any publication or presentations on the study.  All manuscripts, abstracts or presentations 
(in outline form with copies of slides if available) will be submitted to the Sponsor at least 30 days 
prior to the submission of the data for publication in order for the Sponsor to protect proprietary 
information.  The Sponsor will review the submitted material within a reasonable period of time and 
will not unreasonably withhold publication permission. Employees at the Sponsor or representatives 
of the Sponsor should be coauthors should they have provided scientific input to the study design, 
data interpretation etc. 

Sponsor Study ID: LOKON002 
Protocol Version:  5.1, 2022-12-21 
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16.0 APPENDICES 
 
 
 
 
 
 

                                                                                                                                                   Table II. Schedule of Event 
Sponsor Study ID: LOKON002 Protocol Version: 6.0 date 2022-12-xx 
.   
 
 
 

Sponsor Study ID: LOKON002 
Protocol Version:  60, 2022-12-xx 
Sponsor Study ID: LOKON002 Protocol Version: 6.0 date 2022-12-xx