Safety Study of a Helper Peptide Vaccine Plus Pembrolizumab

Inclusion Criteria

• Subjects with unresectable American Joint Committee on Cancer (AJCC) stage IIIB or stage IIIC melanoma, or stage IV metastatic melanoma that have clinical or radiological evidence of disease. Subjects may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma. Staging must be confirmed by cytological or histological examination. Staging of cutaneous melanoma will be based on the revised AJCC staging system
• Ability to provide written informed consent/assent for the trial.
• ≥18 years of age
• A subject may be naïve for immunotherapy agents or have received interferon-alpha, ipilimumab or other cytotoxic T lymphocyte antigen (CTLA)-4 antibody, Programmed death-1 (PD-1) antibody (or anti-PD-L1 antibody), interleukin-2, or prior cancer vaccines other than the 6MHP vaccine. Patients who have received a PD-1/PD-L1 antibody may be enrolled in either of the following settings:
• A patient who has experienced progression of melanoma during that therapy or after having completed that therapy,
• A patient who fails to experience an objective clinical response (partial response or complete response by RECIST 1.1 criteria) after either 12 weeks of continuous anti-PD1 antibody or anti-CTLA4/anti-PD1 combination therapy, and is a candidate to receive pembrolizumab therapy
• Measurable disease based on RECIST 1.1.

Subjects will be required to have radiological studies to define radiologically evident disease. Required studies include:

• Chest CT scan,
• Abdominal and pelvic CT scan, and
• Head CT scan or MRI Positron emission tomography (PET)/CT fusion scan may replace scans of the chest, abdomen, and pelvis.
• Subjects who have metastatic melanoma available for biopsy pretreatment and on day 22 must consent to having those biopsies. These metastases may be in nodes, skin, soft tissue, liver, or other sites that can be accessed safely by needle biopsy, incisional or excisional biopsy, with or without image guidance. The lesions to be biopsied must be specified at study enrollment and not included as target lesions for RECIST calculations. In instances where disease that is accessible to biopsy is limited, archival tissue specimens collected after a subject's last systemic therapy may be used for baseline measures.

Subjects must have measurable disease in addition to the lesion(s) to be biopsied.

• Subjects who have had brain metastases will be eligible if all of the following are true:
• Each brain metastasis must have been completely removed by surgery or each unresected brain metastasis must have been treated with stereotactic radiosurgery.
• There has been no evident growth of any brain metastasis since the most recent treatment
• No brain metastasis is > 2 cm in diameter at the time of registration.
• Neurologic symptoms have returned to baseline,
• There is no evidence of new or enlarging brain metastases,
• Subjects are not using steroids for at least 7 days prior to registration.
• The most recent surgical resections or gamma-knife therapy for malignant melanoma must have been completed ≥ 1 week prior to registration.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate organ function.
• Two intact (undissected) axillary and/or inguinal lymph node basins.

Exclusion Criteria

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
• Is currently receiving Interferon (e.g. Intron-A®), growth factors (e.g. Procrit®, Aranesp®, Neulasta®), or interleukins (e.g. Proleukin®), or has received these agents within 4 weeks of the first dose of treatment.
• Is currently receiving nitrosureas or has received this therapy within the preceding 6 weeks of first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the