First in Human Study of NG-350A (an Oncolytic Adenoviral Vector Which Expresses an Anti-CD40 Antibody)

The aim of the study is to characterise the safety and tolerability of NG-350A in patients
with metastatic or advanced epithelial tumours.

Phase Ia of the study is a dose escalation and safety expansion phase investigating NG 350A
administration by intratumoural injection and intravenous infusion. Phase Ib of the study is
to investigate efficacy in separate efficacy cohorts of patients with specific epithelial
tumour types.

Inclusion Criteria:

1. Provide written informed consent to participate

2. Males or females aged 18 years or over

3. Histologically or cytologically documented metastatic or advanced epithelial cancer
(carcinoma or adenocarcinoma) that has relapsed from, or is refractory to, standard
treatment, or for which no standard treatment is available

4. a) For patients undergoing surgical excision/resection:

- Excisable tumour/tumour lesion accessible for baseline biopsies and biopsies
deemed safe by the Investigator

- Willing to consent for baseline biopsies and surgical procedure

- Patient able to undergo surgical procedure and appropriate anaesthesia b) For
patients not undergoing surgical excision/resection:

- Tumour accessible for biopsy and biopsies deemed safe by the Investigator

- Willing to consent to tumour biopsies at baseline and during the study

5. Safety expansion and efficacy cohorts only: at least one measurable site of disease
according to RECIST criteria; this lesion must be either (i) outside a previously
irradiated area or (ii) progressive if it is in a previously irradiated area (not
applicable in patients undergoing surgical excision/resection if the lesion to be
resected is the target lesion)

6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

7. Predicted life expectancy of 3 months or more

8. Ability to comply with study procedures in the Investigator's opinion

9. Recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for
their malignancies

10. Non-impaired renal function

- Creatinine ≤1.5 mg/dL and estimated glomerular filtration rate (eGFR) using the
Cockroft Gault formula ≥60 mL/min/1.73m2 (or measured creatinine clearance ≥60
mL/min)

- Urine dipstick for proteinuria at screening and baseline negative or trace.
Patients may be included with results of 1+ if they have a spot urinary albumin:
creatinine ratio (ACR) of either (i) ≤3 mg/mmol or (ii) >3 mg to <70 mg/mmol with
a 24 hour urinary protein <0.2 g/24hours

- Serum complement components C3 and C4 above the lower limit of normal range

11. Adequate hepatic function:

- Serum bilirubin <1.5 mg/dL (except patients with Gilbert's syndrome who may have
total bilirubin <3.0 mg/mL)

- Aspartate aminotransferase and alanine aminotransferase ≤3 x upper limit of
normal

- Albumin ≥3 g/dL

12. Adequate bone marrow function:

- Absolute neutrophil count ≥1.5 x 109/L

- Platelets ≥100 x 109/L

- Haemoglobin ≥90 g/L (9 g/dL)

13. Prothrombin time and activated partial thromboplastin time within normal range or
international normalised ratio ≤1.5, as appropriate

14. Meeting reproductive status requirements:

- Females must not be pregnant or breastfeeding

- Females of childbearing potential must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic
gonadotrophin [hCG]) within 24 hours before the first dose of study treatment

- Females of childbearing potential must agree to use a highly effective method of
contraception, for the duration of study treatment with NG-350A and 6 months
following the last dose of study treatment. Females of childbearing potential who
are continuously not heterosexually active are exempt from contraceptive
requirements, but must still undergo pregnancy testing

- Fertile males who are sexually active with females of childbearing potential must
agree to follow instructions for method(s) of contraception, for the duration of
study treatment with NG-350A and 6 months following the last dose of study
treatment. In addition, males must be willing to refrain from sperm donation
during this time. Azoospermic males are exempt from contraceptive requirements

Exclusion Criteria:

1. Known history or evidence of significant immunodeficiency due to underlying illness
(e.g. human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS])
and/or medication (e.g. systemic corticosteroids or other immunosuppressive
medications, including cyclosporine, azathioprine, interferons in the 4 weeks before
the first dose of study treatment). Patients with a condition requiring systemic
treatment with either corticosteroids (>10 mg daily prednisolone equivalent) or other
immunosuppressive medications within 14 days of the first dose of study treatment.
Inhaled or topical steroids and adrenal replacement steroid doses are permitted in the
absence of autoimmune disease

2. Splenectomy

3. Prior allogeneic or autologous bone marrow or organ transplantation

4. Active infections requiring antibiotics, physician monitoring or recurrent fevers
(>38.0˚C) associated with a clinical diagnosis of active infection

5. Active viral disease or positive test for hepatitis B virus using hepatitis B surface
antigen test or positive test for hepatitis C virus (HCV) using HCV RNA or HCV
antibody test indicating acute or chronic infection. Positive test for HIV or AIDS;
testing is not required in the absence of history

6. Use of the following antiviral agents: ribavirin, adefovir, lamivudine or cidofovir
within 7 days prior to the first dose of study treatment; or pegylated interferon in
the 14 days before the first dose of study treatment

7. Administration of an investigational drug in the 28 days, or six half-lives (whichever
is longer) before the first dose of study treatment

8. Major surgery or treatment with any chemotherapy, radiation therapy, biologics for
cancer or investigational therapy in the 28 days before the first dose of study
treatment. All toxicities attributed to prior anti-cancer therapy other than alopecia
must have resolved to Grade 1 or baseline before the first dose of study treatment.
Patients with toxicities (other than renal toxicities) attributed to prior anti-cancer
therapy which are not expected to resolve and result in long lasting sequelae, such as
neuropathy after platinum based therapy, are permitted to enrol

9. Other prior malignancy active within the previous 3 years except for local or organ
confined early stage cancer that has been definitively treated with curative intent,
does not require ongoing treatment, has no evidence of residual disease and has a
negligible risk of recurrence and is therefore unlikely to interfere with the primary
and secondary endpoints of the study, including response rate and safety

10. Symptomatic brain metastases or any leptomeningeal metastasis that is symptomatic
and/or requires treatment. Patients with brain metastases are eligible if these have
been locally treated (surgery, radiotherapy). There must also be no requirement for
immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalent)
for at least 2 weeks before the first dose of study treatment

11. Any history of renal disease or renal injury or autoimmune disease. Patients with
active, known or suspected auto-immune disease or a syndrome that requires systemic or
immunosuppressive agents; patients with vitiligo, type I diabetes mellitus, residual
hypothyroidism due to autoimmune disease only requiring hormone replacement, psoriasis
not requiring systemic treatment or conditions not expected to recur in the absence of
an external trigger are permitted to enrol providing they comply with the other
eligibility criteria relating to renal function

12. Any serious or uncontrolled medical disorder that, in the opinion of the Investigator
or the Medical Monitor, may increase the risk associated with study participation or
study treatment administration, impair the ability of the patient to receive protocol
therapy or interfere with the interpretation of study results

13. History of coagulopathy, transient ischaemic attacks, cerebrovascular accidents or
venous thromboembolism

14. Previous treatment with enadenotucirev or an anti-CD40 antibody

15. Known allergy to NG-350A transgene products or formulation

16. Any other medical or psychological condition that would preclude participation in the
study or compromise ability to give informed consent