Dose Escalation and Cohort Expansion of Safety and Tolerability Study of Intratumoral rAd.CD40L (ISF35) in Combination of Systemic Pembrolizumab in Patients With Refractory Metastatic Melanoma

Inclusion Criteria:

1. Dose escalation: Patients with metastatic melanoma with measurable, stage III (in transit lesions) or stage IVA, IVB or IVC disease (at least 2 measurable lesions/tumors. Patients will be required to have one more lesion present than the number the current dose level requires since one lesion will be left untreated.
2. Expansion cohorts: Patients with metastatic melanoma with measurable, stage III (in transit lesions) or stage IVA, IVB or IVC disease at least two measurable lesions/tumors
3. Patients who have tested positive for a BRAF mutation may have received prior BRAF inhibitor therapy as a prior line of systemic therapy. Patients may have received up to 2 prior lines of therapy with a checkpoint inhibitor (CPI), which may have included pembrolizumab, nivolumab, or ipilimumab. These agents may have been administered as single-agent treatment, in combination with each other, or in combination with other agents. Patients who have received prior treatment with ipilimumab must have relapsed after achieving a response to prior ipilimumab treatment. This response may have been achieved with ipilimumab administered as single-agent therapy or in combination with another treatment. Patients who have received prior treatment with pembrolizumab or nivolumab must have progression of disease after at least 4 doses of either drug alone or in combination with other agents.
4. Age \>/= 18 years
5. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1 within 30 days of signing informed consent.
6. Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
7. Platelet count greater than or equal to 100,000/mm3
8. white blood cell count (WBC) \>/=3000/mm3
9. Serum ALT and AST \<3 the upper limit of normal (ULN); \<5 ULN if there is liver involvement secondary to the tumor
10. Serum creatinine \</= 2.0 mg/dl
11. Seronegative for HIV antibody
12. Patients with a negative pregnancy test (urine or serum) must be documented within 14 days of screening for women of childbearing potential (WOCBP). A WOCBP has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who has not had menses at any time in the preceding 12 consecutive months).
13. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the patient agrees to continue to use a barrier method of contraception throughout the study such as: condom, diaphragm, hormonal, intrauterine device (IUD), or sponge plus spermicide. Abstinence is an acceptable form of birth control.

Exclusion Criteria:

1. Patients who have previously received anti cluster of designation antigen 40 (CD40) (Agonistic) therapy prior Adjuvant Interferon (IFN-α), is allowed if last dose was received at least 6 months from enrolling to protocol.
2. Active autoimmune disease requiring disease modifying therapy.
3. Concurrent systemic steroid therapy higher than physiologic dose (\>7.5 mg/Day of prednisone).
4. Any form of active primary or secondary immunodeficiency.
5. Prior malignancy except the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any cancer from which the patient has been disease-free for 2 years.
6. Subjects who have received prior oncolytic therapy or prior therapy with and TLR agonist including topical agents. Subjects that have received experimental vaccines or other immune therapies should be discussed with the medical monitor or the Principal Investigator (PI) to confirm eligibility.
7. Active systemic infections requiring intravenous antibiotics.
8. Prior systemic therapy, radiation therapy, or surgery within 28 days of starting study treatment. Palliative radiotherapy to a limited field or palliative cryoablation is allowed after consultation with the principle Investigator, at any time during the study participation including screening.
9. Patients who are pregnant or nursing.