A Study of Combination Treatment With HF10 and Ipilimumab in Patients With Unresectable or Metastatic Melanoma

The study is designed to assess efficacy and safety with repeated administration of
intratumoral injections of HF10 at 1x10^7 TCID50/mL in combination with intravenous infusions
of 3mg/kg ipilimumab. This is a single arm, open label Phase II trial, to evaluate the
efficacy, safety and tolerability of HF10 treatment in combination with administration of the
immunologic checkpoint inhibitor, ipilimumab (anti-CTLA-4 monoclonal antibody). The study
population will include patients with Stage IIIB, IIIC or IV unresectable or metastatic
malignant melanoma who are ipilimumab-eligible.

Patients will receive the dose of 1 x 10^7 TCID50/mL HF10 (for a total of 6 injections; the
first 4 injections at 1-week intervals; the remaining 2 injections at 3-week intervals) +
ipilimumab at 3 mg/kg ipilimumab (for a total of 4 intravenous infusions, each administered
at 3-week intervals).

Following combination therapy, patients may continue to receive the same dose level of HF10
(1 x 10^7 TCID50/mL) alone for up to an additional 13 injections (total of 19 injections = 1
year) if they have tolerated the study treatment, are responding, have stable disease, or
have progressive disease that is not clinically significant in the judgment of the
Investigator.

Inclusion Criteria:

1. Patients must have Stage IIIB, IIIC or IV melanoma, which is unresectable/unresected
or histologically confirmed diagnosis of metastatic malignant melanoma.

2. Patients must have measurable non-visceral lesion(s) that are evaluable by the
modified World Health Organization (mWHO) criteria and immune-related response
criteria (irRC).

3. Patients must be ≥ 18 years of age.

4. Patients must have a life expectancy ≥ 24 weeks.

5. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0, 1, or 2.

6. Patients must have adequate hepatic function, defined as

- Total bilirubin levels ≤ 1.5 x upper limit of normal [ULN] (except for patients
with Gilbert's Syndrome, who must have a total bilirubin of less than 3.0 mg/dL)

- AST/ALT levels ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.

7. Patients must have adequate renal function, defined as serum creatinine ≤ 1.5 x ULN or
creatinine clearance (calculated) ≥ 60 mL/min/1.73 m2 for patients with creatinine >
1.5 x ULN.

8. Patients must have adequate bone marrow function, defined as

- Absolute neutrophil count ≥1,500/µL and

- Platelet count ≥ 75,000/ µL

9. Patients must have no known bleeding diathesis or coagulopathy that would make
intratumoral injection or biopsy unsafe.

10. Patients must be ipilimumab-eligible. (This includes: 1) patients previously untreated
with ipilimumab; 2) patients previously treated (more than 1 year previously) with
ipilimumab using a route of administration other than intravenous infusion; and 3)
patients previously treated with antitumor agents other than intravenous ipilimumab).

11. Men and women of childbearing potential must agree to use adequate contraception from
the time of consent through 30 days after final study treatment.

12. Females of childbearing potential must have a negative urine or serum pregnancy test
within one week prior to start of treatment.

13. Patients must be able to understand and willing to sign a written informed consent
document.

Exclusion Criteria:

1. Patients receiving chemotherapy or radiotherapy within 4 weeks of injection of HF10,
or history of Grade 4 adverse events or presence of adverse events Grade 2 or greater,
except alopecia, resulting from anticancer agents administered more than 4 weeks prior
to HF10 injection.

2. Patients receiving anti-herpes medication within 1 week prior to initiating HF10
treatment.

3. Patients with a history of significant tumor bleeding, or coagulation or bleeding
disorders.

4. Patients with target tumors that could potentially invade a major vascular structure
(e.g., innominate artery, carotid artery), based on unequivocal imaging findings.

5. Patients with Grade 2 or greater pre-existing neurologic abnormalities (CTCAE version
4.0), including Grade 2 or greater peripheral neuropathy caused by previous
treatments.

6. Patients with clinically evident Human Immunodeficiency Virus (HIV), Hepatitis B Virus
(HBV), Hepatitis C virus (HCV), or Epstein-Barr virus (EBV) infection are excluded.

7. Medical history of autoimmune disease (e.g., Crohn's disease, ulcerative colitis) or
other diseases requiring systemic glucocorticoid or immunosuppressive therapy.

8. Patients who were previously treated with ipilimumab administered by intravenous
infusion.

9. Concurrent use of any other investigational agents.

10. Patients with active CNS metastases or carcinomatous meningitis, except patients with
CNS lesions that have been treated and have no evidence of progression in the brain on
CT/MRI for ≥ 3 months.

11. Pregnant or breastfeeding women; women desiring to become pregnant within the
timeframe of the study are also excluded.

12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements, as determined by the investigator.