Secondary objectives and endpoints (sections synopsis, 3.1, 3.2) • The language is changed to better define what is being evaluated using the objective and endpoints stated. Exclusion criteria (sections synopsis, 4.2): • Criteria 6-12: it is clarified that registration is regarded when the first dose of LOAd703 and atezolizumab is given. • Criteria 18: it is clarified that the contraceptive method must be regarded highly effective, and that abstinence from heterosexual intercourse is a choice of contraceptive method as well depending on the lifestyle of the subject. • Criteria 19: it is clarified that men that has a partner of childbearing potential who refuse highly effective contraceptives are excluded. • Criteria 24: it is added that patients with tested reduced functional respiratory capacity are excluded. Dose limiting toxicity • We added information about the DLT evaluation during dose escalation. • 5.6.1, 5.6.5: we removed the use of Ringer’s acetate infusion solution so that all LOAd703 dilutions will be diluted in formulation buffer or physiological saline. • 5.6.3, 5.6.5: we changed that an unopened vial should be used within 24 hours from thawing. Administrative changes

Administrative changes (EU version 2.1, dated 2020-01-09, was issued to include administrative changes added to the submitted IND version 2.0)

• Exclusion criteria 15 was clarified to relate to monotherapy with a single PD-1/PD-L1 antibody. Administrative changes: • Section 1.4: The dept of Oncology in Uppsala has a new address. • Section 5.6.3: Temporarily storage of LOAd 703 in -20°C for up to 3 months, has been removed. • Section 5.6.5: the preparation instructions for LOAd703 has been clarified, to clearly state that the maximum dose, injected in 1 lesion, will not be diluted. • Section 5.6.6 was clarified in regards to selection of lesion and that subcutaneous lesions, visible to the eye, may be photographed. • Table I: Overview of ongoing clinical trials was updated. • Section 9.4 Immunological AEs and Handling Plan has been updated to refer to the atezolizumab IB. • Table 3 was removed, which affect the numbering of the 2 subsequent tables.

• Exclusion criteria 1 was modified so that patients with acral melanoma will not longer be excluded. Administrative change: • A clarification was made in section 2.6.1 so that it is clear that NSAID or steroid treatment can be used.

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 Synopsis and section 4.2 Exclusion criteria: • Exclusion criteria no 1 was modified so that patients with mucosal melanoma will no longer be excluded. • Exclusion of patients with progressive disease within 8 weeks after checkpoint inhibitor therapy and patients who have had more than 3 lines of treatment; were deemed to be to narrow and was replaced by a criterion excluding patients with rapid progression rate as assessed by the investigator • Exclusion criterion describing number and site of metastases was updated: patients with central nervous system involvement (cerebral metastases) will be excluded, but not patients with bone metastases • Washout period between cytotoxic and radiation therapy and protocol therapy (LOAd703/atezolizumab) was shortened to 14 days • Washout period between immunostimulatory therapy and protocol therapy (LOAd703/atezolizumab) was shortened to 21 days • Patients on warfarin continue to be excluded, but clarification was made that low molecular heparin is permitted Administrative changes

Changes made in EU version only 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

Changes made in EU version only 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.

• 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 that “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”. • Addition for Sweden only. In section 7.3.1 Anti-Adenoviral Antibodies addition of “Valid for Swedish patients: patients enrolled at Uppsala site, Sweden will be asked to provide additional blood samples for research purposes to identify and isolate B-cells producing anti-adenoviral antibodies. Blood samples will be collected at 2-3 occasions (up to 42 ml in total) during the LOAd703 treatment period (starting from week 6 until week 33)” have been made. Administrative 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