A Study of Combination with TBI-1401(HF10) and Ipilimumab in Japanese Patients with Unresectable or Metastatic Melanoma

The purpose of this study is to determine if TBI-1401(HF10) in combination with ipilimumab is effective in Japanese patients with stages IIIB, IIIC, or IV unresectable or metastatic melanoma.

The study is designed to assess efficacy and safety with repeated administration of intratumoral injections of TBI-1401(HF10) at 1x10\^7 TCID50/mL in combination with intravenous infusions of 3mg/kg ipilimumab in Japanese patients.

This is a single arm, open label Phase II study, to evaluate the efficacy and safety of TBI-1401(HF10) treatment in combination with 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 1x10\^7 TCID50/mL TBI-1401(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 (for a total of 4 intravenous infusions, each administered at 3-week intervals).

Following combination therapy, patients may continue to receive the 1x10\^7 TCID50/mL TBI-1401(HF10) 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.

Eligibility Criteria:
Inclusion Criteria:

* Patients with histologically confirmed Stage IIIB, IIIC or IV unresectable or metastatic melanoma except uveal melanoma, who must have a history of treatment (chemotherapy, molecular targeted therapy, or anti PD-1 antibody therapy).
* 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).
* Patients must be ≥ 20 years of age.
* Patients must have a life expectancy ≥ 24 weeks.
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* Patients must have adequate organ 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.
  * Creatinine ≤ 1.5 x ULN or creatinine clearance (calculated) ≥ 60 mL/min/1.73 m\^2 for patients with creatinine \> 1.5 x ULN.
  * Absolute neutrophil count ≥1,500/µL and
  * Platelet count ≥ 75,000/ µL
* Men and women of childbearing potential must agree to use adequate contraception from the time of consent through 30 days after final study treatment.
* Females of childbearing potential must have a negative urine or serum pregnancy test within 1 week prior to start of treatment.
* Patients must be able to understand and willing to sign a written informed consent document.

Exclusion Criteria:

* Patients who were previously treated with ipilimumab by intravenous infusion.
* Patients receiving chemotherapy or molecularly targeted drug or anti-PD-1 antibody treatment or radiotherapy or immunotherapy within 4 weeks prior to initiating study treatment.
* Patients with a history of Grade 4 adverse events caused by chemotherapy, molecularly targeted drug, anti-PD-1 antibody treatment, radiotherapy or immunotherapy conducted more than 4 weeks prior to TBI-1401(HF10) treatment, or presence of such adverse events of Grade 2 or greater, except alopecia and adverse events controlled by a treatment.
* Patients receiving anti-herpes medication within 1 week prior to initiating TBI-1401(HF10) administration, except local treatment such as ointment.
* Patients with a history of significant tumor bleeding, or coagulation or bleeding disorders.
* Patients with target tumors that could potentially invade a major vascular structure (e.g., innominate artery, carotid artery), based on unequivocal imaging findings.
* Patients with Grade 2 or greater neurologic abnormalities (CTCAE version 4.0), including Grade 2 or greater peripheral neuropathy caused by previous treatments.
* Patients with clinically evident Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C virus (HCV), or Epstein-Barr virus (EBV) infection.
* Patients requiring systemic glucocorticoid (except 10 mg/day/body prednisolone or less) or immunosuppressive therapy because of the presence or history of autoimmune disease (e.g., Crohn's disease, ulcerative colitis) or other diseases.
* Concurrent use of any other investigational agents within 4 weeks prior to initiating study treatment.
* 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.
* Pregnant or breastfeeding women (excluding the case in which breastfeeding is discontinued and will not resume it); women desiring to become pregnant within the timeframe of the study are also excluded.
* 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.