Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C Melanoma Patients

The present study is an open-label, randomized, controlled, two-arm multi-center study of the
efficacy of Daromun neoadjuvant intratumoral treatment followed by surgery versus surgery
alone in clinical stage III B/C melanoma patients. 248 patients will be randomized in a 1:1
ratio to receive Daromun treatment followed by surgery (Arm 1) or surgery alone (Arm 2).

In both arms, follow-up for assessing RFS will be performed up to five years after
randomization. Survival information will also be collected in the following year (up to six
years in total after randomization).

This is an open-label study and there is no blinding.

Patients who successfully complete the screening evaluations and are eligible for
participation in the study will be enrolled and randomly assigned (1:1) to two parallel
treatment arms: Daromun and surgery (Arm 1) or surgery alone (Arm 2).

To ensure a balance across treatment groups, stratified randomisation with permuted block
will be used and separate randomization list for each subgroup (stratum) will be produced.
Patients will be stratified on the basis of the following prognostic factors:

- Stage of disease (2 levels): Stage IIIB vs. Stage IIIC

- Planned post-surgical adjuvant therapy (4 levels): high-dose interferon-α2b, Ipilimumab,
anti-PD-1and other adjuvant therapies.

The primary objective of the study is to demonstrate that a neoadjuvant Daromun treatment
followed by surgery improves in a statistically significant manner the recurrence-free
survival (RFS) of Stage IIIB/C melanoma patients with respect to the standard of care
(surgery alone).

Primary endpoint of the study is RFS in a time-to-event analysis in the Daromun plus surgery
treatment group (Arm 1) versus the surgery alone control group (Arm 2). Analysis will be
based on the "Intention To Treat" population.

The key secondary objective of the study is to demonstrate that a neoadjuvant Daromun
treatment followed by surgery improves in a statistically significant manner the overall
survival (OS) of patients with resectable Stage IIIB/ or C melanoma patients with respect to
the standard of care (surgery alone).

Inclusion Criteria:

1. Diagnosis of clinical stage IIIB and IIIC metastatic melanoma, eligible for complete
surgical resection of all metastases (surgically resectable).

2. Eligible subjects must have measurable disease and must be candidate for intralesional
therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion
(≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate
have a longest diameter of ≥ 10 mm.

3. Males or females, age ≥ 18 years

4. ECOG Performance Status/WHO Performance Status ≤ 1

5. Life expectancy of > 24 months

6. Absolute neutrophil count > 1.5 x 109/L

7. Hemoglobin > 9.0 g/dL

8. Platelets > 100 x 109/L

9. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl)

10. ALT and AST ≤ 2.5 x the upper limit of normal (ULN)

11. Serum creatinine < 1.5 x ULN and 24 h creatinine clearance > 60 mL/min

12. LDH serum level ≤ 1.5 x ULN

13. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of
HBsAg, anti-HBsAg Ab and anti-HBcAg Ab is required. In patients with serology
documenting previous exposure to HBV (e.g. anti-HBs Ab with no history of vaccination
and/or anti-HBc Ab) negative serum HBV-DNA is also required.

14. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved
to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above

15. All women of childbearing potential (WOCBP) must have negative pregnancy test results
at the screening. WOCBP must be using, from the screening to three months following
the last study drug administration, highly effective contraception methods. WOCBP and
effective contraception methods are defined by the "Recommendations for contraception
and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies'
Clinical Trial Facilitation Group and which include, for instance, progesterone-only
or combined (estrogen- and progesterone-containing) hormonal contraception associated
with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing
systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.
Pregnancy test will be repeated at the safety visit (only WOCBP and only for patients
in Arm 1).

16. Male patients with WOCBP partners must agree to use simultaneously two acceptable
methods of contraception (i.e. spermicidal gel plus condom) from the screening to
three months following the last study drug administration.

17. Evidence of a personally signed and dated informed consent document indicating that
the subject has been informed of all pertinent aspects of the study.

18. Willingness and ability to comply with the scheduled visits, treatment plan,
laboratory tests and other study procedures.

Exclusion Criteria:

1. Uveal melanoma or mucosal melanoma

2. Evidence of distant metastases at screening

3. Previous or concurrent cancer that is distinct in primary site or histology from the
cancer being evaluated in this study except cervical carcinoma in situ, treated basal
cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in
situ or any cancer curatively treated ≥ 5 years prior to study entry

4. Concurrent disease, which, in the opinion of the investigator, would place the patient
at undue risk or interfere with the study.

5. History within the last year of acute or subacute coronary syndromes including
myocardial infarction, unstable or severe stable angina pectoris.

6. Inadequately controlled cardiac arrhythmias including atrial fibrillation

7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)

8. LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram
investigations that are considered as clinically significant by the investigator.

9. Uncontrolled hypertension

10. Ischemic peripheral vascular disease (Grade IIb-IV)

11. Severe diabetic retinopathy

12. Active autoimmune disease

13. History of organ allograft or stem cell transplantation

14. Recovery from major trauma including surgery within 4 weeks prior to enrollment.

15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or
any other constituent of the product.

16. Breast feeding female

17. Anti-tumor therapy (except small surgery) within 4 weeks before enrollment

18. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6
weeks before enrollment

19. Planned administration of growth factors or immunomodulatory agents within 7 days
before enrollment

20. Patient requires or is taking corticosteroids or other immunosuppressant drugs on a
long-term basis. Limited use of corticosteroids to treat or prevent acute
hypersensitivity reactions is not considered an exclusion criterion.

21. Any conditions that in the opinion of the investigator could hamper compliance with
the study protocol