A Phase I/II Trial Investigating LOAd703 in Combination With Atezolizumab in Malignant Melanoma
Phase: PHASE1
Conditions: Malignant Melanoma
Sponsor: Lokon Pharma AB

 
Sponsor Study ID: LOKON003 
 
Protocol Version: 6.1, 2023-06-09 
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A Phase I/II Trial Investigating LOAd703 in Combination 
with Atezolizumab in Malignant Melanoma 
 
 
 
EudraCT: 
 
NCT04123470 
IND:
 
 
Sponsor Study ID: LOKON003 
 
Version Nr:  6.1 2023-06-09 
 
 
 
 
 
 
Sponsor: Lokon Pharma AB 
 
 
 
 CEO, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
Sponsor Study ID: LOKON003 
 
Protocol Version:  6.1, 2023-06-09 
2 / 88 
 
Changes to the protocol 
Version 6.1 
Dated 2023-06-09 
Substantial changes 
• 
Definition for the End of study has been modified under section 
Definition and Terms and in the section 3.5 End of Study and 
section 13.4 Study Report 
• 
The expected duration of the study has been updated to reflect 
change of the End of Study definition (synopsis, 3.4 Duration of 
Study, 5.1 Treatment overview) 
• 
Contact details for the new Site Principal Investigator at Baylor 
College of Medicine has been updated.  
Administrative changes 
• 
In sections 2.5 and 9.4.5, an update of adverse events associated 
with atezolizumab was done to align with the latest IB 
atezolizumab  
• 
In section 5.7.5 Administration of Atezolizumab, a reference to 
section 7.2.6 Vital Signs has been added. 
• 
In section 7.5.1 Tumor size; PET assessment has been added. 
• 
Contact details in section 1 General information have been 
updated. 
• 
Minor editorial changes were made throughout the document to 
correct typographical errors and to improve consistency and 
clarity. 
 
Version 6.0 
Dated 2022-04-25 
Substantial changes 
• 
Number of patients needed to be enrolled to achieve at least 25 
evaluable patients at MTD has been changed to up to 50 
throughout the document (synopsis, section 3.3 Summary of 
Trial Design)  
• 
The expected duration of the study has been updated (synopsis, 
section 3.5 End of Study, 5.0 Treatment of Patients).  
• 
An additional site has been added (section 1.0 General 
Information) 
• 
New exclusion criteria no. 32: 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 (synopsis, section 4.2, concomitant 
medication section 5.8). 
• 
In section 5.8 Approved and Non-approved concomitant 
treatment it has been added that palliative surgery and local 
radiotherapy will be allowed. 
• 
The time points for vital signs measurements have been updated 
in section 5.1 Treatment Overview and 7.2.6 Vital signs. 
• 
Addition for US only, as already approved for Sweden. In 
section 5.1 Treatment Overview and 6.2 Screening, 7.2.10 
Blood Chemistry and 7.2.11 Hematology it has been clarified 

  
 
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Protocol Version:  6.1, 2023-06-09 
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• 
Virus units: 10e10 and 10e11 has been consequently changed to 
1010 and 1011 respectively throughout the document.  
• 
The week number for final follow-up visit has been added 
consequently throughout the document.  
• 
Reference to atezolizumab where not relevant, has been 
removed throughout the document.  
• 
Minor editorial changes were made throughout the document to 
correct typographical errors and to improve consistency and 
clarity. 
 
Changes made for 
Sweden only  
Version 5.1_SWE: 
Dated 2021-02-15 
Substantial change, section 7.2.10: Blood Chemistry and 7.2.11: 
Hematology:  
• 
If samples are taken for routine analysis <7 days prior to 
screening, the results can be used for eligibility evaluation at the 
discretion of the investigator, without need of subject the patients 
for new sampling. 
 
Changes made for 
Sweden only 
Version 5.0_SWE: 
Dated 2020-11-11 
Substantial changes:  
 
Synopsis and section 4.1 Inclusion criteria: 
• 
Valid for Swedish patients: Patients not eligible for complete 
resection with locally advanced melanoma or metastatic melanoma 
can be included. 
Valid for US patients: Patients with locally advanced melanoma or 
metastatic melanoma can be included, regardless of patient’s 
eligibility for complete tumor resection.  
• 
Valid for Swedish patients: Patients with B-Raf mutations must 
have received appropriate therapy with tyrosine kinase inhibitors(s) 
or MEK inhibitor (no changes from version 4.0) 
Valid for US patients: Prior treatment with tyrosine kinase 
inhibitor(s) is optional; patients that have not yet received treatment 
with tyrosine kinase inhibitor(s) can be included in the study  
 
Version 5.0:  
Dated 2020-09-21 
Substantial changes:  
 
Synopsis and section 4.1 Inclusion criteria: 
• 
A new criterion was added: A life expectancy of at least 3 months as 
per the investigator: this is a common inclusion criterion for this 
type of patients 
• 
Patients with locally advanced melanoma or metastatic melanoma 
can be included, regardless of patient’s eligibility for complete 
tumor resection.  
• 
Prior treatment with tyrosine kinase inhibitor(s) is optional; patients 
that have not yet received treatment with tyrosine kinase inhibitor(s) 
can be included in the study  
• 
Cut-point for serum albumin levels was changed to ≥ 2.5 mg/dL as 
well as requirement for AST and ALT was changed to ≤ 5 times the 
ULN if liver metastases are present 
• 
Lactate dehydrogenase parameter was removed 
 

  
 
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Protocol Version:  6.1, 2023-06-09 
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TABLE OF CONTENTS 
 
INVESTIGATOR’S STATEMENT ...................................................................................................................... 13 
SYNOPSIS .............................................................................................................................................................. 14 
ABBREVIATIONS ................................................................................................................................................ 18 
DEFINITION OF TERMS .................................................................................................................................... 21 
1.0 GENERAL INFORMATION ......................................................................................................................... 22 
1.1 PROTOCOL NUMBER AND TITLE OF THE STUDY ........................................................................................................ 22 
1.2 SPONSOR ............................................................................................................................................................................ 22 
1.3 CRO .................................................................................................................................................................................... 22 
1.4 INVESTIGATORS AND INSTITUTIONS ............................................................................................................................ 22 
1.5 MANUFACTURERS ............................................................................................................................................................ 23 
1.6 BIOBANK ............................................................................................................................................................................ 23 
1.7 LABORATORIES ................................................................................................................................................................ 24 
2.0 BACKGROUND .............................................................................................................................................. 25 
2.1 TUMOR IMMUNOLOGY AND CANCER IMMUNOTHERAPY .......................................................................................... 25 
2.2 ONCOLYTIC VIRUS (OV) THERAPY .............................................................................................................................. 25 
2.2.1 Oncolytic Viruses ...................................................................................................................................................... 25 
2.2.2 The Investigational Product LOAd703 ........................................................................................................... 25 
2.3 IMMUNE CHECKPOINT BLOCKADE THERAPY ............................................................................................................. 27 
2.3.1 Checkpoint Blockade .............................................................................................................................................. 27 
2.3.2 Atezolizumab ............................................................................................................................................................. 27 
2.4 LOAD703 PREVIOUS CLINICAL STUDIES ................................................................................................................... 27 
2.5 ATEZOLIZUMAB – PREVIOUS CLINICAL STUDIES ....................................................................................................... 29 
2.6 POTENTIAL RISKS AND BENEFITS ................................................................................................................................ 29 
2.6.1 LOAd703 - Potential Risks and Action Plan ................................................................................................. 29 
2.6.2 Atezolizumab - Potential Risks and Action Plan ........................................................................................ 37 
2.6.3 Combination of LOAd703 and Atezolizumab - Potential Risks and Action Plan ......................... 39 
2.6.4 Potential Benefits – Rationale for Combining LOAd703 and Atezolizumab ................................. 40 
2.7 RATIONALE FOR THE PHASE I/II DOSES ..................................................................................................................... 41 
2.8 PATIENT POPULATION .................................................................................................................................................... 41 
3.0 TRIAL DESIGN .............................................................................................................................................. 42 
3.1 OBJECTIVES ....................................................................................................................................................................... 42 
3.2 ENDPOINTS ....................................................................................................................................................................... 42 
3.3 SUMMARY OF TRIAL DESIGN ......................................................................................................................................... 42 
3.4 DURATION OF STUDY ...................................................................................................................................................... 43 
3.5 END OF STUDY .................................................................................................................................................................. 43 
4.0 SELECTION AND WITHDRAWAL OF PATIENTS ................................................................................. 43 
4.1 INCLUSION CRITERIA ...................................................................................................................................................... 43 
4.2 EXCLUSION CRITERIA ...................................................................................................................................................... 44 
4.3 SCREENING, ENROLLMENT AND REGISTRATION LOG, IDENTIFICATION LIST AND NUMBERING OF SUBJECTS
 .................................................................................................................................................................................................... 46 
4.4 WITHDRAWAL OF PATIENTS ......................................................................................................................................... 47 
4.4.1 Off-treatment patient ............................................................................................................................................ 47 
4.4.2 Survival follow-up patient ................................................................................................................................... 48 
4.4.3 Off-study patient ...................................................................................................................................................... 48 
4.5 REPLACEMENT OF PATIENTS ........................................................................................................................................ 48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
  
  
 
  
 
 
 
 
  
 

  
 
Sponsor Study ID: LOKON003 
 
Protocol Version:  6.1, 2023-06-09 
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INVESTIGATOR’S STATEMENT 
1. 
I have carefully read this protocol entitled “A Phase I/II Trial Investigating LOAd703 in 
Combination with Atezolizumab in Malignant Melanoma” 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 the 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: 
 
 
 
 
 
 
 
 

  
 
Sponsor Study ID: LOKON003 
 
Protocol Version:  6.1, 2023-06-09 
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SYNOPSIS 
 
Title:  
A Phase I/II Trial Investigating LOAd703 in Combination with 
Atezolizumab in Malignant Melanoma 
 
Investigational Product: LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus 
serotype 5/35 expressing human trimerized CD40L and full-length 4-
1BBL under a CMV promoter. Atezolizumab is a humanized IgG1 
monoclonal antibody that binds to PD-L1. 
 
Study Design: 
Single arm, open-label, multicenter trial. 
 
Patients will receive up to 12 LOAd703 intratumoral treatments in 
combination with intravenous infusions of atezolizumab. LOAd703 will 
be tested at two dose levels to determine the maximum tolerated dose 
(MTD) of LOAd703 evaluated in the study using a BOIN design. 
 
. Atezolizumab will be tested at a fixed dose.  
At least 25 response evaluable patients will be enrolled at the MTD for 
evaluation of their response 
. The total number 
of patients to be enrolled in the study to achieve at least 25 evaluable 
patients at MTD, should not exceed 50.  
 
 
Objectives: 
The primary objective is to determine the tolerability of LOAd703 
administered by intratumoral injection(s) in combination with 
intravenous atezolizumab. 
 
 
The secondary objectives are to determine the antitumor activity as well 
as the pharmacokinetics and biological mechanisms-of-action of 
LOAd703 in combination with atezolizumab.  
 
Endpoints:  
Primary Endpoints 
1. The primary endpoint is safety, determined by the National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE 
v5.0). 
 
Secondary Endpoints: 
1. Overall response rate evaluated by the Response Evaluation Criteria 
in Solid Tumors (RECIST), v1.1. 
2. Shedding determined as levels of LOAd703 
 
 
3. LOAd703 leakage to blood 
 
4. Anti-adenovirus immunity
 
 
5. 
 
 

  
 
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6. 
 
 
7. Immune profile as 
 
 
8. 
 
 
 
 
Eligibility: 
 
Inclusion Criteria 
1. 
Pathological confirmation of melanoma. 
2. 
A life expectancy of at least 3 months as per the investigator 
3. 
Valid for Swedish patients: Patients has locally advanced melanoma or metastatic 
melanoma, but not eligible for complete resection of melanoma 
Valid for US patients: Patients has locally advanced melanoma or metastatic melanoma. 
4. 
The patient has measurable disease (e.g., measurable tumor lesions must be present that 
can accurately be measured in at least one dimension with a minimum size of 10 mm by CT 
scan and MRI, 10 mm caliper measurement by clinical exam (when superficial), and/or 20 
mm by chest X-ray). 
5. 
Patient has at least one injectable tumor lesion that has not been irradiated or has been 
irradiated but disease progression documented at the site subsequent to radiation therapy. 
6. 
The patient has received appropriate treatment with an anti-PD-1 or anti-PD-L1 antibody 
with or without an anti-CTLA4. 
7. 
Valid for Swedish patients: Patients whose advanced melanoma has a B-Raf mutation 
must have received appropriate therapy with tyrosine kinase inhibitor(s) and/or MEK 
inhibitor 
Valid for US patients: Patients whose advanced melanoma has a B-Raf mutation may have 
received appropriate therapy with tyrosine kinase inhibitor(s) and/or MEK inhibitor as 
assessed by the investigator. 
8. 
Age > 18 years. 
9. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
10. 
Serum albumin ≥ 2.5 g/dL. 
11. 
Absolute neutrophil count (ANC) > 1.0 x 10e9/L. 
12. 
Platelet count ≥ 100 x 10e9/L. 
13. 
Prothrombin (INR) < 1.5 or prothrombin time (PT) < 1.5 times ULN; and either partial 
thromboplastin time or activated partial thromboplastin time (PTT or aPTT) < 1.5 times the 
ULN. 
14. 
Bilirubin < 1.5 times the institutional upper limit of normal (ULN). 
15. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 (< 5 if liver 
metastases are present) times the institutional ULN. 
16. 
The patient must have signed informed consent. 
 
 

  
 
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Protocol Version:  6.1, 2023-06-09 
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Exclusion Criteria 
1. 
Malignant melanoma that is uveal.   
2. 
Subjects considered by the investigator to have rapid clinical progression due to melanoma 
3. 
Subjects must not have greater than 3 cerebral melanoma metastases, and/or clinically 
active cerebral melanoma metastases, and/or a requirement for corticosteroid therapy, 
and/or carcinomatous meningitis regardless of clinical stability.  
4. 
Any concurrent treatment that would interfere with the effect mechanisms of atezolizumab 
and LOAd703, including, but not limited to, continuous high-dose corticosteroids (>10 mg 
per day), lymphodepleting antibodies, or cytotoxic agents. 
5. 
Treatment with inhibitors of immune function, such as lymphotoxic monoclonal antibodies 
(e.g., alemtuzumab), or rapamycin/rapamycin analogs, or cytotoxic agents within 21 days of 
the first dose of LOAd703/atezolizumab.  
6. 
Therapeutic treatment with systemic antibiotics within 14 days of the first dose of 
LOAd703/atezolizumab. 
7. 
Treatment with biologic therapy within 21 days of the first dose of LOAd703/atezolizumab. 
8. 
Treatment with cytotoxic anticancer therapy within 14 days of the first dose of 
LOAd703/atezolizumab. 
9. 
Treatment with wide-field radiation within 14 days of the first dose of 
LOAd703/atezolizumab. 
10. 
Prior treatment with an adenovirus-based gene therapy. 
11. 
Use of any investigational agents within 21 days of the first dose of LOAd703/atezolizumab. 
12. 
The use of systemic immunostimulatory agents (including, but not limited to, interferons 
and IL2) are prohibited within 21 days or 5 half-lives (whichever is longer)  
of the first dose of LOAd703/atezolizumab.  
13. 
Failed resolution/improvement of AEs including those related to anti-PD-1/anti-PD-L1 to 
grade 0-1 and requirement for treatment with >10 mg/day prednisone (or equivalent) for 
at least two weeks prior to registration. 
14. 
History of CTCAE grade 4 immune-related AEs from monotherapy using an anti-PD-1/anti-
PD-L1 antibody. 
15. 
History of CTCAE grade 4 AE that require steroid treatment (>10 mg/day prednisone or 
equivalent) for >12 weeks. 
16. 
Patients requiring warfarin are not eligible (low molecular weight heparin is permitted). 
17. 
Women who are pregnant (as confirmed by pregnancy test during screening in applicable 
patients), breastfeeding, or planning to become pregnant during the study period, or 
women of childbearing potential who are not using acceptable highly effective 
contraceptive methods. A woman is considered of childbearing potential if she is not 
surgically sterile or is less than 1 year since her last menstrual period. The following are 
acceptable as highly effective contraceptive methods: 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 or 
abstinence of heterosexual intercourse during the entire study period (depending on the 
preferred and usual life style of the subject).  
18. 
Men who do not consent to the use of condoms during intercourse during study 
participation or has a partner of childbearing potential, who will not use any of the highly 
effective contraceptive methods exemplified in exclusion criteria no 17.  

  
 
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19. 
Known active hepatitis B or C infection, or HIV infection. 
20. 
Patients with active, severe autoimmune disease or immune deficiency or previous Guillain-
Barré syndrome. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are 
eligible for the study provided all of following conditions are met: 
a. 
Rash must cover <10% of body surface area. 
b. 
Disease is well-controlled at baseline and requires only low-potency topical 
corticosteroids. 
c. 
Occurrence of acute exacerbations of the underlying condition requiring psoralen plus 
ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin 
inhibitors, or high-potency or oral corticosteroids within the previous 12 months. 
21. 
History of leptomeningeal disease. 
22. 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). 
23. 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan or tested reduced 
functional respiration capacity. However, history of radiation pneumonitis in the radiation 
field (fibrosis) is permitted. 
24. 
Unstable angina, uncontrolled cardiac arrhythmia, recent (within 3 months) history of 
myocardial infarction or stroke, or New York Class III/IV congestive heart failure. 
25. 
Major surgical procedure other than for the malignant melanoma diagnosis, within 4 weeks 
prior to initiation of the study treatment, or anticipation of the need for a major surgical 
procedure during the study. 
26. 
Prior allogeneic stem cell or solid organ transplantation. 
27. 
History of severe allergic anaphylactic reactions to chimeric human or humanized 
antibodies, or fusion proteins. 
28. 
Known hypersensitivity to CHO cell products or any component of the atezolizumab 
formulation. 
29. 
Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social 
situations that in the opinion of the Investigator would compromise compliance to study 
requirements or put the patient at unacceptable risk. 
30. 
Other malignancy within the past 2 years (not including basal cell or squamous cell 
carcinoma of the skin, prostate cancer without the need of other treatment than hormones 
or in situ cervix, breast or melanoma). 
31. 
Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation 
of study treatment, during treatment, and for 5 months after the final dose of atezolizumab 
and/or LOAd703. 
32. 
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: Two dose levels of LOAd703 (total viral load: 1x1011 and 5x1011 VP) will 
be tested in combination with a fixed dose of atezolizumab  
(1200 mg). Treatments of LOAd703 (up to 12) will be delivered by 
image-guided intratumoral injection concurrent with intravenous 
atezolizumab treatment (1200 mg), where both treatments will be given 

  
 
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Protocol Version:  6.1, 2023-06-09 
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every 3 weeks. 
 
. Patients will continue atezolizumab treatment up to study 
 
 unless tumor progression or unacceptable toxicity is observed. 
Radiological imaging as well as blood 
 sampling will be 
performed to monitor safety, mechanisms-of-action and disease status. 
 
 
 
Accrual Objective: 
Up to 50 patients 
 
Study Duration: 
The trial encompasses a treatment phase ending with last patient last 
visit (LPLV) (FPI: Q3 2020; LPLV:Q1 2024; study end: Q1 2024). For 
each patient, active participation with study visits is maximum 60 weeks 
where after they are followed for survival as long as the trial remains 
open. Hence, maximum trial duration for a patient is 48 months.  
ABBREVIATIONS 
aCTLA4 
 
Anti-cytotoxic T lymphocyte antigen 4 
ACS 
 
American Cancer Society 
Ad 
 
Adenovirus 
ADA 
 
Anti-drug antibodies 
AE 
 
Adverse event 
AICD 
 
Activation-induced cell death 
ALT 
 
Alanine aminotransferase 
ANC 
 
Absolute neutrophil count 
aPTT 
 
Activated partial thromboplastin time 
ASCO 
 
American Society of Clinical Oncology 
AST 
 
Aspartate aminotransferase 
ATMP 
 
Advanced therapy medicinal product 
AUC 
 
Area under curve 
BOIN 
 
Bayesian Optimal Interval 
 
 
 
CBR 
 
Clinical benefit rate 
CD 
 
Cluster of differentiation 
CDC 
 
Center for Disease Control 
CD40L 
 
CD40 ligand, CD154 
CEA 
 
Carcinoembryonic antigen 
CHO 
 
Chinese hamster ovary cells 
CI 
 
Confidence interval 
CFR 
 
Code of Federal Regulation 
CMV 
 
Cytomegalovirus 
CR 
 
Complete response 
CRO 
 
Contract research organization 
CRP 
 
C reactive protein 
 
CRS 
 
Cytokine release syndrome 
 
 

  
 
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Protocol Version:  6.1, 2023-06-09 
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CT 
 
Computer tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTL 
 
Cytotoxic T lymphocyte 
CV 
 
Curriculum vitae 
DC 
 
Dendritic cell 
DCF 
 
Data clarification form 
DLT 
 
Dose limiting toxicity 
DMP 
 
Data management plan 
DSUR 
 
Development safety update report 
ECG 
 
Electrocardiogram 
ECOG 
 
Eastern cooperative oncology group 
eCRF/CRF 
 
Electronic case report form 
EDC 
 
Electronic data capture 
EGFR 
 
Epidermal growth factor receptor 
ELISA 
 
Enzyme-linked immunosorbent assay 
EMA 
 
European Medicines Agency 
EU 
 
European Union 
FASS 
Swedish online reference of approved drug products  
FDA 
 
Food and Drug Administration 
FPI 
 
First patient in 
FU 
 
Follow-up  
GCP 
 
Good clinical practice 
GDPR 
 
General data protection regulation 
GM-CSF 
 
Granulocyte macrophage-colony stimulating factor 
GMO 
 
Genetically modified organism 
HUVEC 
 
Human umbilical vein endothelial cell 
IA 
 
Immunology assessment 
IB 
 
Investigator’s Brochure 
IEC 
 
International ethics committee 
IFNg 
 
Interferon gamma 
IL 
 
Interleukin 
IND 
 
Investigational new drug 
INR 
 
International normalized ratio 
IRB 
 
Institutional review board 
IRR 
 
Immune-related reaction 
i.t. 
 
Intratumoral 
IU 
 
Infectious units 
IV 
 
Intravenous 
LFF/LÖF 
 
Swedish patient insurance 
LOAd 
 
Lokon oncolytic adenovirus 
LPLV 
 
Last patient last visit 
LOAd703 
 
LOAd virus containing transgenes CD40L and 4-1BBL 
MedDRA 
 
Medical Dictionary for Drug Regulatory Activities 
MDSC 
 
Myeloid-derived suppressor cell 

  
 
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MHC 
 
Major histocompatibility complex 
mLOAd703 
 
LOAd703 virus containing murine transgenes (CD40L and 4-1BBL) 
MPA 
 
Medical products agency 
MR 
 
Mixed response 
MRI 
 
Magnetic resonance imaging 
MSI 
 
Microsatellite instability 
MTD 
 
Maximum tolerated dose 
 
 
 
NCI CTCAE 
 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NK 
 
Natural killer 
NSAID 
 
Nonsteroidal anti-inflammatory drug 
ORR 
 
Overall response rate 
OS 
 
Overall survival 
OV 
 
Oncolytic virus 
 
 
 
PD 
 
Progressive disease 
PDAC 
 
Pancreatic ductal adenocarcinoma 
PD-1 
 
Programmed death receptor 1 
PD-L1 
 
Programmed death receptor ligand 1 
PET 
 
Positron emission tomography 
PFS 
 
Progression-free survival 
PR 
 
Partial response 
PT 
 
Prothrombin time 
PTT 
 
Partial thromboplastin time 
q3w or q4w  
Every third week or every fourth week 
Rb 
 
Retinoblastoma 
RCA 
 
Replication-competent adenovirus 
RECIST 
 
Response evaluation criteria in solid tumors 
RSI 
 
Reference safety information 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
SAR 
 
Suspected adverse reaction 
SD 
 
Stable disease 
SmPC 
 
Summary of Product Characteristics 
SoC 
 
Standard of care 
SOP 
 
Standard operating procedure 
SUSAR 
 
Suspected unexpected serious adverse reactions 
TCR 
 
T cell receptor 
TGFb 
 
Transforming growth factor beta 
Th 
 
T helper 
TLR 
 
Toll-like receptor 
TMZ-CD40L  
Trimerized membrane-bound CD40L 
TNFa 
 
Tumor necrosis factor alpha 
Treg 
 
T regulatory cell 
 

  
 
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TTP 
 
Time-to-tumor progression 
 
 
 
ULN 
 
Upper limit of normal 
VEGF 
 
Vascular endothelial growth factor 
VP 
 
Virus particles 
WBC 
 
White blood cells 
4-1BBL 
 
4-1BB ligand, CD137 ligand 
 
DEFINITION OF TERMS 
 
Baseline 
Assessment/value before the 1st dose of LOAd703/atezolizumab. 
DLT period 
DLT evaluation for each patient is done whe
 
End of treatment  
Last Patient’s Last Visit (LPLV) 
End of study 
Last Patient’s Last Visit (LPLV) 
Enrolled patient 
A patient who has signed informed consent and the screening visit can 
be initiated. 
Evaluable patient 
A patient that has
 
 
A patient that has
 
 
Registered patient 
An enrolled patient who has fulfilled the eligibility criteria after the 
screening visit has been performed and given a treatment slot in the 
study. 
Study month 
One study month = 4 weeks 
Screen failure 
Patient withdrawn before first LOAd703 dose. 
 Off-treatment 
A patient that is discontinued from treatment, but will return for the 
clinical follow-up visits (modified schedule) and survival follow-up. 
Survival follow up 
A patient that is followed for survival. 
Off-study 
A patient that withdraws consent, is lost to follow up or study is 
terminated. No more information is collected for the patient i.e. the 
date for last data capture for the patient.  
 
 
 

  
 
Sponsor Study ID: LOKON003 
 
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1.0 GENERAL INFORMATION 
1.1 Protocol Number and Title of the Study 
Sponsor Protocol Number: LOKON003 
Title: A Phase I/II Trial Investigating LOAd703 in Combination with Atezolizumab in Malignant 
Melanoma 
1.2 Sponsor 
Lokon Pharma AB 
 
 
Chief Executive Officer 
 
  
 
Sponsor Medical Advisor 
 
 
 
 
Clinical Trial Manager 
 
1.3 CRO  
 
 
 
 
1.4 Investigators and Institutions 
 
The dose escalation part of the study is planned to be conducted at 2 sites in US and 1 site in 
Sweden. For the dose expansion part of the study, additional clinics may be added in the US and 
Sweden. An updated contact list will always be available in the Investigator Study File.    
 
Baylor College of Medicine 
 
 
 
Site Principal Investigator: 
 
Email: 
 

  
 
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Cedars-Sinai Medical Center,  
 
 
  
Site Principal Investigator: 
 
Email: 
  
 
Uppsala University Hospital 
 
 
 
Site Principal Investigator: 
  
Email: 
 
Huntsman Cancer Institute  
(Site has been closed, WCG-IRB approval on 03May2023) 
 
 
Site Principal Investigator: 
 
Email: 
 
1.5 Manufacturers 
 
LOAd703 Manufacturer  
 
 
 
Atezolizumab Manufacturer  
F. Hoffmann-La Roche Ltd 
  
1.6 Biobank  
Uppsala Biobank 
 
  
 
 
 
 

  
 
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1.7 Laboratories 
 
Clinical Analyses 
All study sites will use their local laboratory for clinical chemistry and hematology analyses. 
 
Research Analysis Laboratory 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
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2.0 BACKGROUND 
2.1 Tumor Immunology and Cancer Immunotherapy 
The immune system can recognize and kill tumor cells using 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 to CD8+ cytotoxic T 
lymphocytes (CTLs) via major histocompatibility complex I (MHC-I) on the cells. Both virally 
infected cells and tumor cells may prevent CTL recognition by downregulating MHC molecules, 
making the cells targets for natural killer (NK) cells. While viruses initially activate an anti-viral 
immune response by alerting antigen-presenting cells such as dendritic cells (DCs) to activate 
lymphocytes, tumor cells and its stroma tend to produce substances that inhibit immune activation 
and tumor immunity. In order to evade the immune system, tumors inhibit DC maturation and 
promote the differentiation and attraction of immunosuppressive (type 2) cells to the tumor milieu 
such as myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs). These immune 
regulating cells produce suppressive cytokines and growth factors that suppress activated CTLs in 
the tumor mileu and lead to T cell anergy (unresponsiveness) or even death.1,2 
The principal goal 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 that 
includes IFNγ, IL12, IL21 and TNFa.3  
The implementation of checkpoint blockade antibodies targeting CTLA4 and PD-1/PD-L1 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, 
most patients with solid malignancies do not respond to checkpoint blockade therapy or become 
resistant. 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, such as 
immunostimulatory gene therapy utilizing oncolytic viruses as gene delivery vehicles.6 
2.2 Oncolytic Virus (OV) Therapy 
2.2.1 Oncolytic Viruses 
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.6,7,8 For maximum potency, the OVs should infect all tumor cells. However, this is 
challenging if the tumor has metastasized, since systemic spreading of the virus to distal tumor may 
be limited by the immune system. Nevertheless, by arming the OVs with immunostimulatory genes 
(transgenes), it is possible to inject one or a few lesions to induce a systemic anti-tumor response 
whereby activated tumor-specific T cells can circulate and reach all tumor lesions. There are many 
different OVs being evaluated both preclinically and clinically. Most of the clinically advanced OVs 
encode GM-CSF such as the FDA- and EMA-approved OV Imylgic®.9 Other options such as LOAd703 
described herein encodes one or more immune stimulators. Imylgic® and other OVs are currently 
being combined with checkpoint blockade antibodies in clinical trials. 
2.2.2 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 cell binding and infectivity of cells 
expressing human CD46. Virus replication and oncolysis is restricted to cells with a dysfunctional 
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E1A.8 Rb in normal cells is bound to the transcription factor E2F which blocks its intrinsic capacity 
to induce transcription of genes that promote transition from G1 into S phase of the cell cycle. When 
Rb is phosphorylated, E2F is released and stimulates cell proliferation.10 Human tumors have a 
wide spectrum of mutations that alter the Rb protein and/or factors that lead to hyper-
phosphorylation of Rb. Hence, in cancer cells E2F is free to drive transcription of the virus. The 
virus infects and kills tumor cells via oncolysis due to excessive virus replication while healthy non-
malignant cells can be infected but new virus particles are normally not produced. Therefore, 
LOAd703 does not kill, and is therefore not toxic to healthy cells. LOAd703 has a transgene cassette 
with two immunostimulatory genes (TMZ-CD40L and 4-1BBL) driven by a CMV promoter. The CMV 
promoter is not tissue-restricted and the immunostimulatory genes can be expressed in all cells 
that are infected by LOAd703, independent of virus replication. Thus, LOAd703 targets both the 
tumor and its stroma to induce transgene expression but virus-mediated oncolysis will only occur 
in tumor cells. Since the virus is administered by intratumoral (i.t.) injection, the expression of the 
transgenes is localized to the tumor area.  
CD40L is a potent stimulator of myeloid cells and an inducer of Th1 type immune responses.11 The 
TMZ-CD40L transgene is a specially designed human CD40 ligand (CD40L; CD154) that lacks the 
intracellular signaling domain and instead fuses the extracellular and transmembrane domains to 
an isoleucine zipper domain.12 This creates a membrane-bound trimerized CD40L molecule that 
lacks intracellular signaling in the TMZ-CD40L-expressing cell but still binds and transmits signals 
to other cells that express its receptor, CD40. TMZ-CD40L can mature DCs to become potent 
stimulators of T- and NK cells and can enhance the expression of adhesion receptors on endothelial 
cells which promotes lymphocyte attachment and migration into inflamed areas.12,13 On the other 
hand, CD40L can also play a role in tumor cell death due to a dysregulated signaling cascade 
whereby CD40 ligation in CD40+ cancer cells can lead to tumor growth inhibition and apoptosis.11  
The 4-1BB ligand (4-1BBL; CD137L) transgene is the full-length human 4-1BBL gene. It binds to its 
receptor 4-1BB (CD137) expressed on activated T cells and NK cells. 4-1BBL stimulation of T cells 
and NK cells protects the cells from activation-induced cell death (AICD) via upregulation of 
apoptosis inhibitors such as BCL-xL. 4-1BBL stimulation also promotes efficient lymphocyte 
proliferation and memory T cell formation.14,15  
The LOAd703 virus is not functional in animal models since it requires human CD46 for infection 
and cannot replicate even when animal cells are modified to express human CD46. Further, human 
TMZ-CD40L and 4-1BBL do not cross react with their murine receptor counterparts. Hence, toxicity 
studies cannot be performed in in vivo models. Oncolytic effect can be demonstrated in immuno-
deficient xenograft mice implanted with human tumors and treated with LOAd703. This leads to 
tumor growth control and tumor regression, but in this model, the effect of the transgenes cannot 
be evaluated since the mice lack adaptive immunity.13 Effect of the immunostimulatory transgenes 
can be evaluated in immunocompetent mice implanted with a murine tumor expressing human 
CD46 and treated with a LOAd703 virus containing murine TMZ-CD40L and 4-1BBL. This leads to 
the robust stimulation of DCs, T cells and NK cells. Further, LOAd703 can potentiate the effect of 
anti-PD-L1 antibodies in an animal cancer model.  
The major effector mechanisms of LOAd703 are: 1) induction of cell death via either oncolysis or 
CD40-mediated apoptosis, and 2) activation of the immune system via CD40L, 4-1BBL and the 
adenoviral backbone. The major effector arm is likely immune activation, but the induction of cell 
death by oncolysis further strengthens anti-tumor responses due to the release of tumor antigens 
resulting in tumor antigen-specific immune stimulation. 
Detailed preclinical information can be found in the LOAd703 Investigator’s Brochure (IB) Section 
6.0 NONCLINICAL EVALUATION OF LOAd703 which is an integral part of this protocol. 

  
 
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2.3 Immune Checkpoint Blockade Therapy 
2.3.1 Checkpoint Blockade 
Immune checkpoints are inhibitory signals that diminish T cell activation and lead to T cell 
exhaustion. To overcome these inhibitory signals and sustain T cell activation during the anti-tumor 
response, checkpoint blockade antibodies have been developed to block inhibitory immune 
checkpoints such as CTLA4 or PD-L1/PD-1. 
Recently, checkpoint blockade therapy has shown impressive results in cancer patients, in 
particular in malignant melanoma. However, most patients are refractory to treatment or become 
resistant after an initial response. Resistance is likely due to the patient’s immune status, e.g., 
having an immunosuppressive tumor microenvironment with very few activated anti-tumor 
reactive T cells, which may not depend on PD-L1/PD-1 interactions. Studies combining oncolytic 
virus with checkpoint blockade inhibition have demonstrated enhanced effect in preliminary 
reports. The use of Imylgic® with pembrolizumab increased response rates from approximately 
30% to 60%.16  
2.3.2 Atezolizumab 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1, a ligand expressed on a 
variety of cell types as well as malignant cells. Overexpression of PD-L1 on tumor cells may be a 
mechanism of tumor evasion and has been demonstrated to inhibit anti-tumor responses.17 
Atezolizumab inhibits the interaction between PD-L1 and its receptors PD-1 and B7.1 (CD80), 
which would otherwise inhibit T cell proliferation, cytokine production and cytolytic activity.18,19 In 
addition, atezolizumab demonstrates minimal binding to Fc receptors, eliminating detectable 
Fc-effector function and associated antibody-mediated clearance of activated effector T cells. 
Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to improve anti-tumor 
activity by enhancing tumor-specific T cell responses.20,21 Atezolizumab shows anti-tumor activity 
in both nonclinical models and cancer patients and is being investigated as a potential therapy in a 
wide variety of malignancies. Atezolizumab is approved for the treatment of urothelial carcinoma 
and non-small cell lung cancer and is currently being studied as a single agent in advanced cancer 
and adjuvant therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.  
Detailed preclinical information can be found in the atezolizumab Investigator’s Brochure Section 4 
Nonclinical Studies which is an integral part of this protocol. 
2.4 LOAd703 Previous Clinical Studies 
Currently, LOAd703 is being evaluated in combination with standard-of-care (SoC) chemotherapy 
treatment in two ongoing phase I/II clinical trials. In one of the trials, atezolizumab is added to the 
combination treatment in a second study arm. Briefly, the trials are open label studies to evaluate 
dose, safety and efficacy. In both trials, three dose levels are evaluated followed by expansion of the 
maximum tolerated tested dose. An overview of the trials is shown in Table 1.  
 

  
 
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Table 1. Overview of ongoing LOAd703 clinical trials 
 
LOKON001 (NCT02705196) 
LOKON002 (
) 
Site 
US; Baylor College of Medicine; Principal 
Investigator: 
 
Sweden, Uppsala University Hospital; 
Coordinating Principal Investigator: 
 
 
Sweden, Karolinska University Hospital; 
Principal investigator 
 
 
Indication 
Pancreatic ductal adenocarcinoma (PDAC) 
PDAC, ovarian cancer, colorectal cancer, and 
biliary cancer 
Phase 
Phase I/II: LOAd703 dose escalation in 3 
cohorts (5x1010, 1x1011 or 5x1011 
VP/injection) and expansion of cohort at 
MTD 
Phase I (dose escalation in 3 cohorts; 5x10 
10, 1x1011 or 5x1011 VP/injection) and Phase 
II (expansion of MTD cohort) 
No. of 
patients 
Maximum 55 evaluable patients 
Maximum 53 evaluable patients 
Treatment 
Arm 1: LOAd703 + gemcitabine/nab-
paclitaxel 
 
Arm 2: LOAd703 + gemcitabine/nab-
paclitaxel + atezolizumab  
 
• 
LOAd703 i.t. injections given every 
other week (6-12 LOAd703 
treatments total). 
 
• 
Gemcitabine IV infusion 1000 
mg/m2 + nab-paclitaxel 125 
mg/m2 (d1, 8, 15 of a 28-day cycle) 
until progression or toxicity. 
 
• 
Atezolizumab IV infusion 1680 mg 
every fourth week. 
 
LOAd703 + SoC treatment  
 
• 
LOAd703 i.t. injections given every 
other week (8 LOAd703 treatments 
total). 
• 
SoC chemotherapy tailored to the 
indication, or gemcitabine if SoC is 
not an available option (1000 
mg/m2; d1, 8, 15 of a 28-day cycle). 
Study 
duration 
37-47 weeks; then survival follow-up every 
3 months. FPI 2016, LPLV estimated 2023. 
40 weeks; then survival follow-up every 3 
months. FPI 2018, LPLV estimated 2024. 
 
In the LOKON001 study, the safety and efficacy of LOAd703 therapy in combination with 
chemotherapy is being investigated in maximum 55 evaluable patients with PDAC. The patients 
receive 6 injections of LOAd703 combined with gemcitabine plus nab-paclitaxel (28-day cycles with 
treatment on day 1, 8 and 15). Responding patients have the option of 6 additional LOAd703 
treatments.  
In LOKON002, patients with PDAC, ovarian cancer, colorectal cancer or biliary cancer are treated 
with 8 injections of LOAd703 in combination with SoC chemotherapy tailored to the indication, or 
gemcitabine if no SoC option is available (28-day cycle with treatment on day 1, 8 and 15). 
See latest version of Investigator Brochure (IB) for updated information regarding number of 
patients treated with LOAd703. 
 
 
 
 

  
 
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Reference safety information (RSI) is detailed in the LOAd703 IB Section 7 EFFECT IN HUMANS, 
which is an integral part of this protocol.  
2.5 Atezolizumab – Previous Clinical Studies 
Atezolizumab monotherapy is approved in many countries for the treatment of patients with 
advanced urothelial carcinoma and advanced non-small cell lung cancer. Atezolizumab in 
combination with nab-paclitaxel was recently approved for treating patients with advanced triple 
negative breast cancer. It is also currently being studied as a single agent in many other clinical 
settings, including treatment of patients with advanced- and early (adjuvant)-stage disease. 
Atezolizumab is being evaluated as both a monotherapy and in combination with chemotherapy, 
targeted therapy, and cancer immunotherapy. Clinical data are available from more than 20 studies. 
 
 the fixed dose of 1200 mg that will be administered every three weeks 
(q3w) in this study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Detailed clinical information can be found in the atezolizumab IB Section 5 Effects in Humans, 
which is an integral part of this protocol. 
2.6 Potential Risks and Benefits 
2.6.1 LOAd703 - Potential Risks and Action Plan  
LOAd703 is an advanced therapy medicinal product (ATMP) that is classified as a gene therapy, but 
it is also an immunotherapy. The risks that are potentially incurred in this study can be viewed as 
those potential risks associated with LOAd703 as a gene therapy, including the immunostimulatory 
transgenes, as well as the potentially increased risk of combining two immunotherapeutics.  
 

  
 
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Error! Reference source not found. summarizes the risk factors for LOAd703 which is followed 
by a discussion of the known risks of atezolizumab and the potential risks of combination 
treatment. 

 
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Table 2. LOAd703 risks and risk factors 

  
 
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2.7 Rationale for the Phase I/II Doses 
This study will begin at the LOAd703 dose level 1x1011 VP per treatment (cohort 1), and if safe, the 
dose will be escalated to 5x1011 VP per treatment every 3 weeks (q3w) (cohort 2). These dose 
levels have been demonstrated to be safe in the ongoing LOKON001 (NCT02705196) and 
LOKON002 (
) trials where patients were treated i.t. every other week 
(q2w) with 6-12 and 8 LOAd703 treatments, respectively. No intra-patient dose escalation is 
allowed. Dose reductions may be applicable due to toxicity (see 5.5 Dose Limiting Toxicity (DLT), 
and 5.6.8 LOAd703 Dose Modifications). 
Atezolizumab will be given as a fixed dose (1200 mg, q3w) which is the approved dose level and 
schedule for the treatment of urothelial carcinoma and non-small cell lung cancer. Atezolizumab 
may be subject to dose adjustments due to toxicity (see 5.7.7 Atezolizumab Dose Modifications). 
 
 
 
 
 
 
 
 
 
2.8 Patient Population 
Melanoma is a cancer that develops from melanocytes in the epidermal layer of the skin. Melanoma 
is the fifth most common cancer among men and women.32 It is often diagnosed in older patients 
but is also one of the most common cancers in young adults, especially young women.33 Risk factors 
include sun/UV exposure, skin type (white/fair skin, moles, etc.), genetic disposition, and sex; the 
risk is higher for women before the age of 50, and higher for men after 50 years of age.34 More than 
90% of melanoma cancers are due to skin cell damage from ultraviolet radiation exposure.35  
The incidence of melanoma has doubled in the last three decades in the US from an incidence of 
11.2 to 22.7 per 100,000.36 In 2019, it is projected that 96,480 adults in the US (57,220 men and 
39,260 women) will be diagnosed with melanoma.32 Although it accounts for only 1% of all skin 
cancers, melanoma is the deadliest type of skin cancer, accounting for >90% of skin cancer deaths.37 
In 2019, it is estimated that over 7000 people in the US will die from melanoma.32  
While localized melanoma is typically curable with surgery, metastasized melanoma in regional and 
distant areas have a 5-year survival rate of 63% and 20%, respectively.37 Metastatic melanoma is 
known to be refractory to traditional therapies like chemotherapy and radiation, and until 2010, 
there was no evidence-based therapy available that could demonstrate significantly improved 
overall survival (OS) for patients with unresectable advanced melanoma. In patients with stage IV 
metastatic melanoma, less than half survived >1 year and only 20% were alive after 3 years. Since 
2010, new systemic therapies such as checkpoint inhibitors have improved treatment options for 
patients with unresectable advanced melanoma.38 In addition to immunotherapy, targeted 
therapies (BRAF- and MEK-inhibitors) can be utilized in patients with BRAF mutations, which may 
account for over half of all melanomas.34 In 2015, the first oncolytic virotherapy, T-VEC (Imlygic®; 
talimogen lahparepvec), was approved for the treatment of melanoma (FDA and EMA). T-VEC as 
well as several other oncolytic viruses, such as CAVATAK, are being actively developed, as 
monotherapies or as combination therapies together with checkpoint inhibitors. 
 

  
 
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In this study, patients with melanoma that have received at least one prior line of checkpoint 
blockade antibody therapy (mono or combination) can be enrolled in the study. Both men and 
women of all races and ethnic groups are eligible to participate in this trial. However, children are 
not eligible for participation since safety and tolerability have not yet been determined in adults. 
All patients enrolled will receive LOAd703 combined with the checkpoint inhibitor atezolizumab. 
LOAd703 treatment stimulates DCs, NK and T cells while atezolizumab blocks the inhibitory 
signaling via PD-L1/PD-1 which may prolong T cell activation and the anti-tumor response.  
3.0 TRIAL DESIGN 
3.1 Objectives 
The primary objective is to determine the tolerability of LOAd703 given by i.t. injection(s) in 
combination with atezolizumab administered by IV. 
The secondary objectives are to determine the antitumor activity as well as the pharmacokinetics 
and biological mechanisms-of-action of LOAd703 in combination with atezolizumab. 
3.2 Endpoints 
Primary Endpoints 
1) 
The primary endpoint is safety, determined by the National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI CTCAE) v5.0. 
Secondary Endpoints 
• 
Overall response rate evaluated by RECIST v1.1. 
• 
Shedding determined as level of LOAd703 
 
• 
LOAd703 leakage to blood 
 
 
• 
Anti-adenovirus immunity 
 
 
• 
 
• 
 
• 
Immune profile as
 
 
• 
 
 
3.3 Summary of Trial Design 
This trial is a multicenter, open label, single arm, dose-escalation Phase I/II trial. The study will 
have a Bayesian Optimal Interval (BOIN) design (target DLT rate=0.3) to determine the MTD of 
LOAd703 against a fixed dose of atezolizumab. This design has algorithmic escalation/de-escalation 
rules like a traditional 3+3 design, but it also allows for specification of the target DLT rate and 
expanded accrual beyond N=6 with continued and consistent toxicity monitoring. This means that 
the assessment of DLT rate continues throughout the study, giving a well-defined safety evaluation 
of the entire study. Refer also to sections 10.0 STATISTICS, 5.5 Dose Limiting Toxicity (DLT) and 5.6.9 
LOAd703 Maximum Tolerated Dose (MTD). 

  
 
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 The total number of patients to be enrolled in the study to achieve at 
least 25 evaluable patients at MTD, should not exceed 50. 
3.4 Duration of Study 
.  
 
Timeline:  
 First patient in    
Q3 2020 
Last patient’s last visit 
Q1 2024 
Study end  
 
Q12024 
 
After a screening period 
, each patient will receive a maximum of 12 LOAd703 
injections (q3w) in combination with atezolizumab (q3w) after which supportive therapy with 
atezolizumab alone is continued until the final clinical visits (i.e. maximum 7 additional infusions). 
The patients will be scheduled for study visits until final clinical follow-up in study 
 
 If both treatments are prematurely discontinued the final clinical follow-up visit could be 
scheduled earlier,
 
 
In total, patients will visit the clinic regularly for a maximum 60-weeks (
). 
Thereafter only OS will be recorded every 
 whereby information will be collected via e.g. 
telephone calls (US) or medical records (SWE, US) until death or study end.  
  
3.5 End of Study 
The End of the treatment stage is defined as the date of the LPLV and the End of study is defined as 
LPLV.  
4.0 SELECTION AND WITHDRAWAL OF PATIENTS 
Study patients will be recruited among patients taken care of at the study center but may also 
include patients referred from other hospitals. Once a patient is enrolled in the trial, the Site 
Investigator is responsible for the care of the patient.  
Patients must meet all the following inclusion criteria and none of the exclusion criteria to be 
registered in the study: 
4.1 Inclusion Criteria 
1. 
Pathological confirmation of melanoma. 
2. 
A life expectancy of at least 3 months as per the investigator. 
3. 
Valid for Swedish patients: Patients has locally advanced melanoma or metastatic 
melanoma, but not eligible for complete resection of melanoma. 
Valid for US patients: Patients has locally advanced melanoma or metastatic melanoma. 
4. 
The patient has measurable disease (e.g., measurable tumor lesions must be present that can 
accurately be measured in at least one dimension with a minimum size of 10 mm by CT scan 
and MRI, 10 mm caliper measurement by clinical exam (when superficial), and/or 20 mm by 
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5. 
Patient has at least one injectable tumor lesion that has not been irradiated or has been 
irradiated but disease progression documented at the site subsequent to radiation therapy. 
6. 
The patient has received appropriate treatment with an anti-PD-1 or anti-PD-L1 antibody 
with or without an anti-CTLA4. 
7. 
Valid for Swedish patients: Patients whose advanced melanoma has a B-Raf mutation must 
have received appropriate therapy with tyrosine kinase inhibitor(s) and/or MEK inhibitor 
Valid for US patients: Patients whose advanced melanoma has a B-Raf mutation may have 
received appropriate therapy with tyrosine kinase inhibitor(s) and/or MEK inhibitor as 
assessed by the investigator. 
8. 
Age > 18 years. 
9. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
10. 
Serum albumin ≥ 2.5 g/dL. 
11. 
Absolute neutrophil count (ANC) > 1.0 x 10e9/L. 
12. 
Platelet count ≥ 100 x 10e9/L. 
13. 
Prothrombin (INR) < 1.5 or prothrombin time (PT) < 1.5 times ULN; and either partial 
thromboplastin time or activated partial thromboplastin time (PTT or aPTT) < 1.5 times the 
ULN. 
14. 
Bilirubin < 1.5 times the institutional upper limit of normal (ULN). 
15. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 (< 5 if liver 
metastases are present) times the institutional ULN. 
16. 
The patient must have signed informed consent. 
4.2 Exclusion Criteria 
1. Malignant melanoma that is uveal.   
2. Subjects considered by the investigator to have rapid clinical progression due to melanoma. 
3. Subjects must not have greater than 3 cerebral melanoma metastases, and/or clinically active 
cerebral melanoma metastases, and/or a requirement for corticosteroid therapy, and/or 
carcinomatous meningitis regardless of clinical stability. 
4. 
Any concurrent treatment that would interfere with the effect mechanisms of atezolizumab 
and LOAd703, including, but not limited to, continuous high-dose corticosteroids (>10 mg 
per day), lymphodepleting antibodies, or cytotoxic agents. 
5. 
Treatment with inhibitors of immune function, such as lymphotoxic monoclonal antibodies 
(e.g., alemtuzumab), or rapamycin/rapamycin analogs, or cytotoxic agents within 21 days of 
the first dose of LOAd703/atezolizumab.  
6. 
Therapeutic treatment with systemic antibiotics within 14 days of the first dose of 
LOAd703/atezolizumab. 
7. 
Treatment with biologic therapy within 21 days of the first dose of LOAd703/atezolizumab. 
8. 
Treatment with cytotoxic anticancer therapy within 14 days of the first dose of 
LOAd703/atezolizumab. 
9. 
Treatment with wide-field radiation within 14 days of the first dose of 
LOAd703/atezolizumab. 
10. 
Prior treatment with an adenovirus-based gene therapy. 
11. 
Use of any investigational agents within 21 days of the first dose of LOAd703/atezolizumab. 
12. 
The use of systemic immunostimulatory agents (including, but not limited to, interferons 
and IL2) are prohibited within 21 days or 5 half-lives (whichever is longer) of the first dose 
of LOAd703/atezolizumab. 

  
 
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13. 
Failed resolution/improvement of AEs including those related to anti-PD-1/anti-PD-L1 to 
grade 0-1 and requirement for treatment with >10 mg/day prednisone (or equivalent) for 
at least two weeks prior to registration. 
14. 
History of CTCAE grade 4 immune-related AEs from monotherapy using an anti-PD-1/anti-
PD-L1 antibody. 
15. 
History of CTCAE grade 4 AE that require steroid treatment (>10 mg/day prednisone or 
equivalent) for >12 weeks. 
16. 
Patients requiring warfarin are not eligible (low molecular weight heparin is permitted). 
17. 
Women who are pregnant (as confirmed by pregnancy test during screening in applicable 
patients), breastfeeding, or planning to become pregnant during the study period, or 
women of childbearing potential who are not using acceptable highly effective 
contraceptive methods. A woman is considered of childbearing potential if she is not 
surgically sterile or is less than 1 year since her last menstrual period. The following are 
acceptable as highly effective contraceptive methods: 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 or 
abstinence of heterosexual intercourse during the entire study period (depending on the 
preferred and usual life style of the subject).  
18. 
Men who do not consent to the use of condoms during intercourse during study 
participation or has a partner of childbearing potential, who will not use any of the highly 
effective contraceptive methods exemplified in exclusion criteria no 17.  
19. 
Known active hepatitis B or C infection, or HIV infection. 
20. 
Patients with active, severe autoimmune disease or immune deficiency or previous Guillain-
Barré syndrome. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are 
eligible for the study provided all of following conditions are met: 
a. 
Rash must cover <10% of body surface area. 
b. 
Disease is well-controlled at baseline and requires only low-potency topical 
corticosteroids. 
c. 
Occurrence of acute exacerbations of the underlying condition requiring psoralen plus 
ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin 
inhibitors, or high-potency or oral corticosteroids within the previous 12 months. 
21. 
History of leptomeningeal disease. 
22. 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). 
23. 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan or tested reduced 
functional respiration capacity. However, history of radiation pneumonitis in the radiation 
field (fibrosis) is permitted. 
24. 
Unstable angina, uncontrolled cardiac arrhythmia, recent (within 3 months) history of 
myocardial infarction or stroke, or New York Class III/IV congestive heart failure. 
25. 
Major surgical procedure other than for the malignant melanoma diagnosis, within 4 weeks 
prior to initiation of the study treatment, or anticipation of the need for a major surgical 
procedure during the study. 
26. 
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27. 
History of severe allergic anaphylactic reactions to chimeric human or humanized 
antibodies, or fusion proteins. 
28. 
Known hypersensitivity to CHO cell products or any component of the atezolizumab 
formulation. 
29. 
Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social 
situations that in the opinion of the Investigator would compromise compliance to study 
requirements or put the patient at unacceptable risk. 
30. 
Other malignancy within the past 2 years (not including basal cell or squamous cell 
carcinoma of the skin, prostate cancer without the need of other treatment than hormones 
or in situ cervix, breast or melanoma). 
31. 
Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation 
of study treatment, during treatment, and for 5 months after the final dose of atezolizumab 
and/or LOAd703. 
32. 
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, Enrollment and Registration Log, Identification List and Numbering of 
Subjects 
It is the responsibility of the Investigator that all patients considered candidates for the study be 
listed in the “Screening, Enrollment and Registration log”. The reason for rejecting a patient before 
informed consent is obtained should be specified in the comments field of the log. Patients will 
receive a consecutive patient number when signing the informed consent and are thereafter 
considered enrolled as study patients so they can initiate the screening visit. The patient number 
will have the following format: 
. The trial site will keep an “Identification list” of all 
enrolled patients that connects the subject’s identity to their study number. 
Study patients who have been screened and excluded before the week 0 visit are considered 
screening failures and will be noted as such in the “Screening, Enrollment and Registration log”. The 
reason for excluding the patient from the study should be specified in the comments field of the 
“Screening, Enrollment and Registration log”. 
When the inclusion criteria and none of the exclusion criteria have been fulfilled, the site can 
request a study slot by the CRO. When the study slot is confirmed by the CRO, the patient is 
considered registered in the study and the registration date is documented in the “Screening, 
Enrollment and Registration log. The study investigators participate in regular phone conferences 
with the CRO and Sponsor to follow the recruitment process and study development. 
NOTE: During dose escalation, the slots are limited to 3 per cohort, of which the first patient must 
receive 
 
before patient 2 and 3 can start. During dose escalation it is 
therefore important to have close communication with the CRO before screening, in order to 
confirm the timing and avoid having eligible patients ready for treatment when there is no slot 
available.  During dose escalation, the first dose will not be given to two or more patients on the 
same day (within 24 hours of dosing).  
Instructions on communication and the registration procedures are found in the Investigator Site 
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4.4 Withdrawal of Patients 
A patient has the right to withdraw his or her consent for participating in the study, at any time, and 
without giving any specific reason.  
The study treatment can be discontinued (i.e. from either LOAd703 or atezolizumab or from both 
treatments) at any time if it is medically necessary, as judged by the Investigator or the Sponsor, 
based on the development of toxicity as specified in sections 5.5 Dose Limiting Toxicity (DLT), 5.6.8 
LOAd703 Dose Modifications, 5.6.9 LOAd703 Maximum Tolerated Dose (MTD) and 5.7.7 Atezolizumab 
Dose Modifications. 
If only one of the study treatments is discontinued, the patient still continues with the other study 
treatment and follows the study schedule according to the protocol.  
4.4.1 Off-treatment patient 
The patient is discontinued from both LOAd703 and atezolizumab (
) or from Atezolizumab 
(
) if the following criteria are met: 
1. The development of toxicity, which precludes further treatment with both study treatments, 
in the Investigator’s judgment, and as specified in sections 5.5 Dose Limiting Toxicity (DLT), 
5.6.8 LOAd703 Dose Modifications, 5.6.9 LOAd703 Maximum Tolerated Dose (MTD) and 5.7.7 
Atezolizumab Dose Modifications. 
2. A response that is 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 has confirmed progressive disease 
4. Patient requests to discontinue treatment. 
5. Female patient becomes pregnant. 
Off-treatment patients: should continue to be followed according to a modified clinical follow-up 
schedule (see section 6.4 Evaluation, Modified Follow-Up and Final Follow-Up Visit and 14.3 
Appendix III: Modified Follow-Up Schedule). This means that patients will continue his/her 
participation in the study and return to visits for AE assessment, sampling, and radiology 
(according to protocol) but not receive treatment.  
The visits should continue at least 
 
 meaning that the final clinical follow-up visit 
(
 
) may be scheduled earlier.
 
  
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
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5.3 Study Sites 
5.3.1 General Description 
The patients recruited in this trial will participate in the trial activities at the study sites under the 
guidance of the site Principal Investigator. As soon as a patient is enrolled in the trial, the 
Investigator is responsible for the patient. 
LOAd703 is administered by i.t. injection. The selection of injectable lesions is decided by the 
Investigator after consultation with the interventional radiologist. The injections are performed by 
the radiologist or Investigator following the same procedures as when a biopsy is taken, see 
“Instructions for tumor lesion selection for LOAd703 injections and effect evaluation” in the 
Investigator Site File. 
The hospital personnel involved in this trial have experience and/or training using 
immunostimulatory adenovirus-based treatments. Study patients are treated in a hospital with a 
fully equipped emergency care unit. The study nurse/coordinator brings the patient and the 
LOAd703 virus to the injection suite and stays during the injection, whereupon the patient is 
transferred to the appropriate hospital unit for monitoring and atezolizumab administration. Trial 
visits such as sampling and meetings with the study team will also take place at the hospital unit. 
5.3.2 GMO Regulation at Trial Site 
The LOAd703 virus will be handled only by genetically modified microorganism (GMO)-trained 
staff. The Sponsor is responsible for GMO training. Trained staff are receiving a GMO certificate, and 
a copy is archived in the Investigator Site File as proof that they have received appropriate training. 
Beside information in section 5.6 LOAd703 Drug Product, a GMO booklet with training material, 
instructions for GMO handling and accidents (see instruction: LOKON003 Handling, preparation and 
treatment with LOAd703), and a list of certified staff will be available at each trial site. 
5.4 Referrals from Other Hospitals 
If a patient is referred to a study site by another hospital to participate in this trial, all study 
activities will be carried out only at the study site including treatments, sampling and assessments. 
The site Principal Investigator is responsible for all trial patients during their participation in the 
trial. 
5.5 Dose Limiting Toxicity (DLT) 
As LOAd703 will be dose escalated, the patients will be monitored for dose limiting toxicity (DLT). 
DLT is defined as any grade 3 or higher toxicity (CTCAE Version 5.0) that is attributed (definitely, 
possibly or probably) to LOAd703. A DLT attributed to LOAd703 will lead to dose reduction (see 
5.6.8 LOAd703 Dose Modifications).  
Phase I: The first patient on each dose level must have been evaluated for DLT 
 
before patient 2 and 3 in the same cohort can start 
treatment. Patient 2 and 3 should start treatment at least 24 hours apart.  
All 3 patients in the cohort must have been evaluated for DLT before decision on dose escalation is 
taken for the next cohort.  
Phase II: Patient enrollment continues and evaluation for DLTs 
 
 (see 10.2 Sample Size).   
Toxicity attributed to atezolizumab will not be assessed as DLTs in the study but can still lead to 
dose modifications (see 5.7.7 Atezolizumab Dose Modifications). 

 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 

  
 
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5.7.2 Atezolizumab Packaging and Labeling 
 
 
 
5.7.3 Atezolizumab Storage and Handling 
 
 
 
 
5.7.4 Preparation of Atezolizumab Prior to Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
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5.7.5 Administration of Atezolizumab 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
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5.7.6 Atezolizumab Unused Clinical Trial Supplies 
All unused trial supplies of atezolizumab will be returned to the Sponsor, unless the Sponsor 
decides otherwise.
 
 
5.7.7 Atezolizumab Dose Modifications 
Atezolizumab dose, dose modifications, and omissions will be instituted per standard practice (US: 
TECENTRIQ® Full Prescribing Information, 
, Sweden: SmPC/FASS for 
atezolizumab/TECENTRIQ®) and according to the continuation criteria (see 7.2.5 Continuation 
Criteria). Missed doses will not be made up in order to maintain adherence to the protocol 
schedule.  
5.7.8 Continuation of Atezolizumab Treatment Post Study 
The study drugs are not available for patients post study from Sponsor without approval from the 
Sponsor, the ethics committee (IEC/IRB), and by the relevant regulatory authorities. The patients 
will discuss with the physician the next steps for their cancer treatment.  
5.8 Approved and Non-Approved Concomitant Treatment 
Patients can receive full supportive care while on this study. 
 
 
 
 
 
 
 
 
 
 
 
Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation of study 
treatment, during treatment, and for 5 months after the final dose of atezolizumab and/or 
LOAd703. 
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. 
Need for palliative surgery as well as palliative local radiotherapy, e.g., for brain or bone metastasis, 
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5.9 Monitoring Subject Compliance 
Since LOAd703 and/or atezolizumab will be administered by the study personnel, compliance with 
study drug administration will be ensured and documented in the eCRF. Patient compliance with 
concomitant medications and protocol-specified assessments will be recorded in the eCRF. 
6.0 STUDY EVALUATIONS 
 
 
Imaging will be used at several time points to determine tumor size. Patients 
will undergo their final follow-up evaluation visit 
  
6.1 Schedule of Events  
All study evaluations are summarized in 14.1 Appendix I: Schedule of Events. 
6.2 Screening 
Before beginning the screening visit, the patient will be informed about the trial and sign informed 
consent whereupon the patient is enrolled in the trial. The patient will be evaluated for health 
status, pregnancy (if applicable) and tumor load (by appropriate radiological imaging). If the 
patient has been subjected to radiology examination within three weeks prior to registration, this 
imaging can be reused for evaluation at the discretion of the Investigator.  
Also, if samples have been taken for routine analysis <7 days prior to screening, the results can be 
used for eligibility evaluation at the discretion of the Investigator.  
If all of the inclusion criteria and none of the exclusion criteria are met, the patient is registered to 
participate in the trial. 
6.3 Treatment Study Visits 
Figure 1 and Appendix 1 (Schedule of Events) shows the treatment schedule and timing of the 
study visits. Patients will undergo 12 LOAd703 treatments (q3w) administered by i.t. injection until 
study 
. Atezolizumab infusions (q3w) will continue during the study until progression or 
toxicity requires treatment discontinuation. On the day of the treatment
 
 
.  
The treatments are scheduled on any of the designated study week working days. If the treatments 
are delayed to the next week, then they must be omitted in order to adhere to the protocol 
schedule. 
 
If both treatments are discontinued, a modified follow-up schedule will apply (see section 6.4 
Evaluation, Modified Follow-Up and Final Follow-Up Visit). 
6.4 Evaluation, Modified Follow-Up and Final Follow-Up Visit 
During evaluation visits, the patient will be evaluated for health status, toxicity, and treatment 
effect on tumor size (radiology exam). 
 
The final follow-up visit is scheduled at study 
(see Figure 
1).  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

  
 
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7.5 Efficacy Assessments 
Response and tumor progression will be determined for all patients receiving 
 
. However, patients receiving
 
 
7.5.1 Tumor Size 
Tumor size will be determined using a suitable imaging technique, depending on the localization of 
the tumor. Computer tomography (CT) will preferably be selected. Radiology exams will be 
performed every 9th week (±1 week) post-treatment initiation (i.e., 
 
). However, at screening, if the patient has been subjected to radiology 
examination within 3 weeks prior to registration, this imaging can be used as baseline at the 
discretion of the Investigator. Definitions of measurable disease and response to treatment will 
follow RECIST 1.1 criteria. For research purposes, other methods such as immune-related (ir) 
RECIST may be compared to the RECIST v1.1 outcome. Further, a study-specific tumor evaluation 
will also be performed (see “Instructions for lesion selection and effect evaluation” provided by the 
Sponsor in the Investigator Site File). 
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 10 mm by CT scan (irrespective of 
scanner type), 10 mm caliper measurement by clinical exam (when superficial), or 20 mm by chest 
X-ray (if clearly defined and surrounded by aerated lung). 
 
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In addition to CT/MRI imaging, position emission tomography (PET) may be performed as a 
part of tumor assessment, at the discretion of the Investigator. If PET is used, the measures are 
documented according to the EORTC assessment. The PET evaluation will be exploratory. 
7.5.2 Tumor Markers 
Tumor-specific genetic markers such as BRAF mutation or mutations in DNA repair (i.e., mismatch 
repair-deficient cancers) will be listed if available during 
. Otherwise, the tumor biopsy 
(
 can be used for analysis. Genetic analysis of the biopsy within the study is done via the 
Research Laboratory, if applicable or send for analysis within Sweden and EU or third country (US, 
UK). After the analysis, sample will be destroyed or returned to the biobank. 
7.5.3 Survival Follow-Up 
After the final clinical follow-up visit at the clinic, overall survival (OS) will be recorded 
 
. OS will be collected until the trial is closed, i.e until LPLV. OS may be 
collected via medical records (Sweden, US) or by telephone/email (US) from the Investigator or 
research nurse/research coordinator to the patient and will consist only of questions regarding the 
patient’s health. If the patient is initiating another anti-cancer treatment, the treatment will be 
documented if the information is available, since it may affect the OS. The day of death will be 
documented.  
8.0 Response Criteria  
8.1 RECIST 
The tumor response will be evaluated using an appropriate imaging technique, depending on the 
localization of the tumor. Tumor regression or progression will be evaluated according to RECIST 
v1.1 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 PR 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). 
Confirmation of Progression: Due to the potential immunostimulatory capacity of the study 
treatments, it is possible that the induced immune stimulation may induce an inflammatory 
swelling of the tumor that initially may be mistaken for progression. Therefore, PD during study 
participation leading to discontinuation of repeated treatment needs to be confirmed by 
radiological imaging at a later time point (within 4-12 weeks) and/or by a biopsy and/or tumor 
serum marker to confirm tumor progression. 
 
Mixed Response (MR) 
One or more lesions fulfilling the criteria for PR and other(s) for PD. 
Clinical Benefit Rate (CBR) 
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Overall Response Rate (ORR) 
ORR is defined as PR plus CR.  
 
 
 
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) 
OS is defined as the time from the start of treatment to death due to any cause. 
9.0 Adverse Events (AE) 
Reference safety information (RSI) for LOAd703 and atezolizumab is listed in the Investigator’s 
Brochure for each study drug. Note that both LOAd703 and atezolizumab are regarded as 
experimental drugs within this protocol and safety evaluation including attribution needs to 
carefully be considered for both agents. 
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 requires clinical intervention or further investigation (beyond ordering 
a repeat/confirmatory test). Injury or accidents, medical conditions for operations that are not pre-
planned, or deterioration of the concurrent illness are also considered as AEs. 
9.1.2 Serious Adverse Event (SAE) 
A serious adverse event 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 dying at the time of the event. It does not refer 
to an event that hypothetically may have caused death if it was more severe). 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization excluding that for 
pain management, disease staging/re-staging procedures, prolonged monitoring for possible 
AE, 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 

  
 
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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, even if 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 the patient’s life. 
Planned or elective hospitalizations (e.g., for administration of protocol therapy) and the 
hospitalization per se should not be considered SAEs. However, should an adverse event occur 
during this planned or elective hospitalization due to the administration of protocol therapy, it will 
be regarded as an AE, unless the severity of the event would justify hospitalization, if the patient 
was not already hospitalized. 
 
9.1.3 Suspected Unexpected Serious Adverse Reactions (SUSAR)  
An unexpected adverse event 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 
Reference Safety Information (RSI) in the current LOAd703 and/or atezolizumab IBs. 
Unexpected, as used in this definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the IB) as opposed to the adverse drug experience not being 
anticipated from the pharmacological properties of the pharmaceutical product. 
9.1.4 Serious Adverse Reactions (SAR) 
A serious adverse reaction (SAR) is any AE for which there is evidence to suggest a causal 
relationship (reasonable possibility) between the study drug and the AE. By definition, all SARs are 
AEs, nevertheless, not all AEs are SARs. Both LOAd703 and atezolizumab are regarded as study 
drugs in this study. 
9.1.5 Non-Serious Adverse Event 
All 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 5.0 (refer to http://ctep.cancer.gov). All AEs (except for grade 1 and 2 laboratory 
abnormalities that do not require an intervention) are to be recorded on the AE page in the eCRF 
and source documentation.  
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 the investigational products 
LOAd703 and/or atezolizumab. 
The general AE reporting period for this trial begins upon receiving the first LOAd703 and/or 
atezolizumab treatment and continues until final clinical follow-up visit at 
  
If both study treatments are prematurely discontinued, AEs should be recorded 
 
 
see 4.4.1 Off-treatment patient). 
If patients are prematurely withdrawn from the study and enter survival follow-up (i.e., survival 
follow-up patients),they will be followed for a minimum 
 

  
 
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 (see 
4.4.2  Survival follow up patient). 
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 and/or atezolizumab have been administrated when an AE occurs, its relationship to the 
study drugs will be judged by the Investigator.  
9.2.1 Severity Grading 
The Investigator must determine the intensity of any AEs according to the NCI CTCAE Version 5.0 
(see http://ctep.cancer.gov) and the 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 the symptom but may be given because of the patient’s 
personality/character. 
 
2. 
Moderate: Discomfort sufficient enough to reduce or affect normal daily activity. Patient is 
able to continue in the study; treatment for the 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: Symptom(s) place the patient at immediate risk of death from the reaction 
as it occurred; does not include a reaction that, had it occurred in a more serious form, 
might have caused death. 
 
5.  
Fatal: Event caused the death of the patient.  
9.2.2 Attribution Definitions 
The Investigator will attempt to assess the relationship of the event to the study drugs separately. 
An AE is considered to be associated with the use of any or both of the investigational products if 
the attribution is determined as possible, probable or definite. Attribution of AEs will be recorded 
in the CRF as: 
- Unrelated:  The AE is clearly NOT related to LOAd703 (or atezolizumab). 
- Unlikely:  
The AE is doubtfully related to LOAd703 (or atezolizumab). 
- Possible:  
The AE may be related to LOAd703 (or atezolizumab). 
- Probable:  
The AE is likely related to LOAd703 (or atezolizumab). 
- Definite:  
The AE is clearly related to LOAd703 (or atezolizumab). 
Attribution will be specified for LOAd703, atezolizumab, treatment procedure (i.e., intratumoral 
injection and/or intravenous infusion), disease or other. 
9.2.3 Duration of Event 
The date of onset (and time if relevant), change of severity and the duration of the AE (i.e., date of 
resolution) will be recorded. Events that are ongoing at the time the patient completes follow-up 
will be documented as ongoing.  

  
 
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9.2.4 Action(s) Taken Regarding the Study Drugs 
The method used to treat the AE, specifically any action taken with the study drugs, should be 
recorded. This includes, but is not limited to e.g., “dose reduced” or “discontinued”. 
9.3 Reporting Serious Adverse Events (SAE), Deaths, Unexpected AEs and DLTs 
9.3.1 Reporting to Sponsor 
AEs classified as serious require expeditious handling and reporting to the CRO as the Sponsor’s 
representative, to comply with regulatory requirements. The Sponsor and its designees must be 
notified immediately (within 24 hours of becoming aware of the event) by email or telephone. 
Notification by email is preferred. The email and telephone numbers listed below may be used. 
Initial notification via telephone or email does not obviate the need for the Investigator to provide a 
completed SAE form/eCRF entry within the designated reporting time frames.  
 
 
  
The completed Serious Adverse Event Report Forms are submitted by email to 
 
 within 24 hours of becoming aware of the event.  
The SAE form and detailed instructions describing the procedure for reporting SAEs are found in 
the Investigator’s Site File. 
  
Email: 
 
Phone: please see the Investigator Site File 
9.3.2 Safety Report – Reporting by Sponsor 
The Sponsor is responsible for submitting safety reports to the relevant regulatory authorities and 
ethics committees of any Suspected, Unexpected Serious Adverse Reactions (SUSARs). A SUSAR that 
is fatal or life-threatening should be reported as soon as possible, not later than 7 calendar days 
after the Sponsor becomes aware of the SUSAR, and with a follow-up report within another 8 days. 
Any other SUSARs should be reported within 15 days.  
9.3.2.1 MPA/EMA Safety Report (EU) 
The Sponsor is responsible for submitting safety reports to the MPA/EMA and IEC and this will be 
delegated to the CRO. A SUSAR that is fatal or life-threatening should be reported as soon as 
possible, not later than 7 calendar days after the Sponsor becomes aware of the SUSAR, and with a 
follow-up report within another 8 days. Any other SUSARs should be reported within 15 days.  
SAEs that do not require expedited reporting should be listed together with SUSARs in the annual 
drug safety update report (DSUR), written by the Sponsor and submitted to the relevant regulatory 
authorities and ethics committees according to current legislation.  
9.3.2.2 IND Safety Report (US)  
Under Title 21 Code of Federal Regulation (CFR) Part 312.32, the Sponsor (or designee) is required 
to notify the FDA (
) and all participating Investigators (i.e., all Investigators to 
whom the Sponsor is providing drug under its IND or under any Investigator’s IND) of any of the 
following: 

  
 
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Any SAR, that is both serious and unexpected, and if there is evidence to suggest a causal 
relationship between the study drug and the event, such as: 
- 
A single occurrence of an event that is uncommon and known to be drug related. 
- 
One or more occurrences of an event that is not commonly associated with the drug but is 
otherwise uncommon in the population exposed to the drug. 
- 
An aggregate analysis of specific events observed in a clinical trial that indicates those 
events occur more frequently in the drug-treatment group than in a concurrent or historical 
control group. 
In addition, the Sponsor must report the following: 
- 
Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND and whether or not conducted by the 
Sponsor, that suggest a significant risk in humans exposed to the drug.  
- 
Any findings from laboratory animals or in vitro testing, whether or not conducted by the 
Sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or 
near the expected human exposure dose. 
- 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
that listed in the protocol or IB. 
SAEs that do not require expedited reporting should be listed together with SUSARs in the annual 
DSUR, written by the Sponsor and submitted to the relevant regulatory authorities and ethics 
committees according to current legislation.  
9.3.3 Reporting to IEC/IRB 
Investigators must report SAEs and AEs to his/her IRB or IEC per institutional guidelines and/or 
other applicable guidelines. 
9.3.4 Procedures in Case of Medical Emergency 
The Investigator should ensure that the necessary procedures and expertise are available to cope 
with any emergencies during the study.  
If an emergency occurs, please notify 
  
Email: 
  
Phone: please see the Investigator Site File 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 

  
 
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9.5 Handling of Pregnancy 
Any pregnancy diagnosed during the study participation must be reported immediately to the 
Sponsor. Women of childbearing potential and male with a partner of child bearing potential, will 
be thoroughly informed about contraceptive medication (see section 7.2.12 Concomitant 
Medications ) before 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 participating in the study, the 
study drugs should be immediately discontinued. Pregnancy information about a female patient or 
a female partner of a male patient should be reported immediately from the time the Investigator 
first becomes aware of a pregnancy or its outcome. This will be performed by the Investigator by 
completing a Pregnancy Form. 
Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for medical 
reasons, outcome of stillbirth, congenital anomaly/birth defect, or SAE in the mother will be 
recorded as an SAE and reported. 
10.0 STATISTICS 
10.1 Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be prepared as a separate document and will include a more 
technical and detailed description (including templates for Tables, Listings, and Figures) of the 
planned statistical summaries regarding safety and effect evaluation. The SAP will be finalized 
before initiating any statistical analysis. Unless otherwise stated, tabulation of summary statistics 
and data analysis will be performed using SAS® Version 9 or later. 
Statistical Methods 
Statistics will be displayed for response evaluation for the patients treated at MTD.  
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
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11.0 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) and will provide access to source data/hospital records. The Sponsor 
verifies that each patient has consented in writing to grant access to the original source 
data/hospital records by means of the written patient information and signed informed consent. 
During monitoring, the data recorded in the CRFs by the Investigator or designee will be checked 
for consistency with the source data/hospital records by the Monitor (i.e., source data verification). 
Any data discrepancies will be documented and explained in the monitoring reports.  
11.2 Source Data 
The requirements for the information contained in the patient’s medical records corresponds to the 
requirements of the “Patientdatalagen” (SFS 2008:355), “The Medical Product Agency’s regulations 
on clinical trials of medicinal products for human use” (LVFS 2011:19), and Department of Health 
and Human Services Standards for Privacy of Individually Identifiable Health Information, 45 CFR 
164.508 which means that in addition to information that is pertinent to the care and well-being 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, EudraCT /IND/NCT number and short study description 
• 
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) 
• 
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For information that is study specific and of no interest to the medical care of the patient, other 
documents may be considered as source data. Prior to study start, the site Principal 
Investigator/study nurse/coordinator and the Monitor must identify and document the expected 
location of the source data (e.g., medical record notes, laboratory reports, etc.). 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 Monitor.  
11.3 Monitoring  
In accordance with the principles of Good Clinical Practice (GCP), the Sponsor is responsible that 
the trial is adequately monitored. In this study, the CRO 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 monitoring 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 to verify consistency with the data recorded in the CRFs. All patients that 
have performed any study-specific assessments will be monitored for signed informed consent and 
all patients that have received study drug will be monitored for date of study visits, 
inclusion/exclusion criteria and AE/SAE.  
The Monitor will also check the Investigator Site File and provide information and support to the 
Investigator(s). The extent of monitoring will be described in a monitoring plan, which will be 
approved by the Sponsor.  
The study site may be subject to quality assurance audit(s) by the Sponsor as well as inspection by 
regulatory authorities. The Investigator and other responsible personnel must be available during 
the monitoring visits, audits and inspections and should devote sufficient time to these processes.  
For investigational sites in the EU: All site Principal Investigators should provide a curriculum vitae 
(CV) to the CRO to be responsible for the study. All Sub-Investigators and other responsible 
personnel should be listed on the delegation list, together with their study responsibilities, and 
provide their CVs to the CRO. GCP certificates for the Principal Investigator and all study team 
members on the delegation log must be provided. 
For investigational sites in the US: All site Principal Investigators will be required to provide a 
current signed and dated CV, medical license, proof of human subject research protections training, 
a completed FDA Form 1572 (required in the US) and a financial disclosure statement (required in 
the US) to the CRO. All Sub-Investigators will be required to provide a current NIH biosketch or CV, 
medical license, proof of human subject research protections training and a financial disclosure 
statement (required in the US) to the CRO. GCP certificates for the Principal Investigator and all 
study team members on the delegation log must be provided. 
12.0 ETHICS 
12.1 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 
relevant regulatory authorities/ethics committees 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 or 
telephone number). Other administrative revisions, which may impact the clinical portion of the 
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the site Principal Investigator, or designee, under the guidance of the CRO and with the approval of 
the Sponsor. 
12.2 Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
It is the responsibility of the site Principal Investigator to obtain approval of the study protocol, 
protocol amendments, patient information and informed consent from the relevant IEC/IRB before 
enrollment of any subject into the study.  
The Sponsor or designees shall report all SUSARs to the IEC/MPA. 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/site 
Principal Investigator should notify the IEC.  
The Sponsor/site Principal Investigator should file all correspondence with the relevant IEC/IRB 
and provide the other party with copies.  
12.3 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, applicable regulatory requirements, 
GCP, and the ethical principles of the latest version of the Declaration of Helsinki. 
12.4 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 enrollment in the 
study.  
Upon signing informed consent, the subject consents to: 
- 
Participating in the study. 
- 
Allowing personnel connected with the Sponsor or regulatory authorities to gain full access to 
hospital records to check study data.  
- 
Recording, collection, processing and storing of data in a database. 
- 
Possible transfer of study information to countries outside of the European Union (EU)/United 
States (US).  
- 
Storing of study samples in a biobank when required (i.e., European sites require a biobank). 
It should be clearly stated that the data will not identify any subject taking part in the study, in 
accordance with the national guidelines for handling personal data. 
The Investigator who gave the verbal and written information to the subject shall sign and date the 
informed consent form. A copy of the patient information and the informed consent form should be 
given to the subject. The Investigator should file the signed informed consent forms in the 
Investigator Site File for possible future audits and inspections. The Investigator Site File shall be 
archived according to the applicable regulations. 

  
 
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13.0 DATA MANAGEMENT  
13.1 Data Management 
The CRO is responsible for 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 CRFs (eCRFs). 
The Investigator is responsible for ensuring the accuracy, completeness and legibility of the data 
reported in the eCRFs, and this will be checked by the Monitor. 
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. All 
inconsistencies detected during these procedures will be resolved through electronic Data 
Clarification Forms (DCFs) in the eCRF, 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 is done and approved, and all queries are solved, the Database Closure procedures will 
begin. Decisions will be made on 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. 
13.2 Electronic Case Report Forms (eCRFs) 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness of 
the data recorded in the eCRFs. 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) within 6 months from the last visit of the 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 other languages.  
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 relevant regulatory authorities) 
without written permission from the Sponsor. All eCRF electronic files should be kept in the 
Sponsor’s Trial Master File and a copy of all eCRFs electronic files should be kept in the Investigator 
Site File. 
In this study, clinical data including AEs and concomitant medications will be entered into a 21 CFR 
Part 11-compliant eCRF 
. The eCRF includes password 
protection, audit trails 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 the 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 guarantees the minimum data loss in the events of a disastrous failure.  
13.3 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 at least 10 years after final 
report. This includes any original source data related to the study, the subject identification list 
(with subject identification numbers, full names and addresses), original signed informed consent 
forms, copies of all eCRF-generated files and detailed records of the investigational product’s 
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13.4 Study Report 
The survival follow-up will continue until LPLV and the study is thereafter completed. 
A full study report should be submitted to the regulatory authorities by the Sponsor within 12 
months from the completion of the study. The site Principal Investigator and study site personnel 
must provide the necessary information by completing the eCRF for every patient no later than 3 
weeks from the LPLV to allow for close-out activities such as monitoring and correction of the 
eCRFs if necessary.  
13.5 Publication Policy 
The investigation is considered as a collaboration between the clinical sites, Hoffmann LaRoche Ltd 
and the Sponsor. Publication ideas for manuscripts, abstracts or presentations will be jointly 
discussed and prepared. 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. Investigators as well as employees or representatives of the 
Sponsor and Hoffmann LaRoche Ltd should be listed as co-authors in the event that they have 
provided scientific input into the study design, data interpretation, etc. 
13.6 Insurance 
Study patients enrolled in Sweden are covered by the Swedish Patient Insurance (LÖF) and the 
Swedish Pharmaceutical Insurance, 
 
. Study patients enrolled in the US are insured by 
, held by Sponsor.  
 
14.0 APPENDICES 
 

 
 
 
 
 
 
 
 
  
 

  
 
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