ISF35 and Pembrolizumab in Treating Patients with Refractory Metastatic Stage IIIB-IV Melanoma

Inclusion Criteria

• 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 resent than the number the current dose level requires since one lesion will be left untreated
• 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
• Patients who have tested positive for a v-Raf murine sarcoma viral oncogene homolog B (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
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1 within 30 days of signing informed consent
• 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
• Platelet count greater than or equal to 100,000/mm^3
• White blood cells (WBC) >= 3000/mm^3
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 the upper limit of normal (ULN); < 5 ULN if there is liver involvement secondary to the tumor
• Serum creatinine =< 2.0 mg/dl
• Seronegative for human immunodeficiency virus (HIV) antibody
• 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)
• 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

• Patients who have previously received anti CD40 (agonistic) therapy prior adjuvant interferon (IFN), is allowed if last dose was received at least 6 months from enrolling to protocol
• Active autoimmune disease requiring disease modifying therapy
• Concurrent systemic steroid therapy higher than physiologic dose (> 7.5 mg/day of prednisone)
• Any form of active primary or secondary immunodeficiency
• 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
• Subjects who have received prior oncolytic therapy or prior therapy with and toll-like receptor (TLR) agonist including topical agents; subjects that have received experimental vaccines or other immune therapies should be discussed with the medical monitor or the primary investigator (PI) to confirm eligibility
• Active systemic infections requiring intravenous antibiotics
• 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
• Patients who are pregnant or nursing