Evaluate Efficacy, Immunological Response of Intratumoral/Intralesional Oncolytic Virus (OBP-301) in Metastatic Melanoma Patients

Primary Objective:

The primary objective of this study is to evaluate the overall tumor sites response
(objective response rate [ORR]) to OBP-301 in both injected and noninjected lesions up to and
including Week 24 in patients with unresectable/unresected Stage III and IV melanoma. The ORR
is defined as the rate of complete response (CR) and partial response (PR) based on the
modified immune-related response criteria (irRC) 1.0. The modification is to allow the
identification of up to 10 cutaneous, subcutaneous, and/or lymph node tumor lesions and
identify the lesions as target and nontarget lesions.

Secondary Objectives:

- To evaluate the ORR up to and including Week 24 in injected target lesions based on the
modified irRC 1.0 and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

- To evaluate the ORR up to and including Week 24 in noninjected target lesions based on
modified irRC 1.0 and RECIST 1.1

- To evaluate the ORR in both injected and noninjected target lesions at Week 12 based on
the modified irRC 1.0 and RECIST 1.1

- To evaluate duration of response and time to response

- To evaluate progression free survival (PFS) at Week 24 and Week 48

- To evaluate overall survival (OS) at Week 24 and Week 48

- To evaluate the safety of OBP 301

Exploratory Objective (optional):

The optional exploratory objective of this study is to investigate the tumor immunological
response in blood and tumor tissue following treatment with OBP-301.

Inclusion Criteria:

1. Histologically or cytologically confirmed malignant melanoma at Screeningthat is
unresectable/unresected Stage IIIB, IIIC, IIID or IV. Patients with unresectable
mucosal melanoma may be enrolled after consultation with the Medical Monitor.

2. Patients must have received and failed or refused available therapy for
unresectable/unresected Stage III or IV melanoma.

3. Patients must be ≥ 18 years of age.

4. At least 2 cutaneous, subcutaneous and/or lymph node target lesions that are greater
or equal to 1 cm in the longest diameter. One of the cutaneous, subcutaneous and/or
lymph node target lesions should be designated at Screening as a noninjected target
lesion. Willing to have biopsy specimens taken at Screening and at Week 6.

5. Life expectancy of ≥ 6 months from the first OBP-301 treatment.

6. Karnofsky Performance Status Scale (KPS) score of ≥ 70.

7. Adequate organ function, hematologic status, coagulation status, kidney function, and
liver function as follows:

- Absolute neutrophils > 1,500/µL

- Hemoglobin > 9 g/dL, without transfusion or hematopoietic growth factor

- Platelets > 100,000/µL. Patients with ≤ 100,000 platelet count may be allowed
into the study on a case-by-case basis after consultation with the Medical
Monitor.

- Serum creatinine < 2 × upper limit of normal (ULN)

- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2 × ULN except for
patients with known liver metastases, in which case aspartate transaminase or
alanime transaminase may be ≤ 5.0 × ULN

- Total bilirubin < 2.0 mg/dL (≤ 3.0 mg/dL for patients with known Gilbert's
syndrome)

- Serum lactate dehydrogenase (LDH) levels < 1.5 × ULN

8. Understand the study requirements and the treatment procedures, and is willing to
comply with all specified follow-up evaluations, and provides written informed consent
before any study-specific tests or procedures are performed.

9. Patients of reproductive potential must use effective contraception for the duration
of the study and for 3 months (90 days) after the last administered injection of
OBP-301. Effective contraception includes oral contraceptives, implantable hormonal
contraception, double-barrier method or intrauterine device.

Exclusion Criteria:

1. Patients who have had administration of chemotherapy, target therapy, and/or
immunotherapy within the last 4 weeks before the first OBP-301 administration.

2. Patients who have received other investigational medication within the last 4 weeks or
a period of its 5 half-lives (whichever is shorter) before the first OBP-301
administration.

3. Patients who have had radiotherapy within the last 4 weeks before the first OBP-301
administration.

4. Effects of any other prior therapies not reverted to ≤ Grade 1 (or ≤ Grade 2 for
alopecia and peripheral neuropathy).

5. Patients who have any liver metastases or visceral metastasis of ≥ 3 cm, plus evidence
of progression meeting irRC 1.0 within 1 month before the first OBP-301
administration.

6. Patients with clinically active brain metastases. However, patients with previously
currently stable brain metastases on medication (i.e., steroids and/or anti-seizure
medications) may be enrolled after consultation with the Medical Monitor.

7. Patients known to have acute or chronic active hepatitis B virus (HBV), hepatitis C
virus (HCV) or human immunodeficiency virus (HIV).

8. Patients diagnosed with additional malignancy within 3 years before the first OBP-301
administration with the exception of curatively treated basal cell carcinoma of the
skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical
and/or breast cancers.

9. Patients requiring chronic systemic immunosuppressive medication including
pharmacologic dose of glucocorticoids or cyclosporine should be evaluated by the
Medical Monitor for enrollment eligibility.

10. Uncontrolled intercurrent illness including, but not limited to, uncontrolled
diabetes, ongoing or active infection, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/psychological
incompetence, whereby in the opinion of the Investigator the patient is assessed as
being unable to provide information, consent, or comply with the study requirements
and procedures.

11. Patients who are pregnant or breastfeeding, or expecting to conceive or father
children within the projected timeframe of the study, starting from the time of the
Screening Visit through 3 months (90 days) after the last OBP-301 administration.
Females of childbearing potential must have a negative serum pregnancy test at
Screening and a negative urine pregnancy test at each visit before administration of
OPB-301. A female not of childbearing potential is one who has undergone bilateral
oophorectomy or who has had no menses for 12 consecutive months.