6 Melanoma Helper Peptide Vaccine and Pembrolizumab in Treating Patients with Unresectable Stage IIIB, IIIC or IV Melanoma

Inclusion Criteria

• Subjects with unresectable stage IIIB or IIIC melanoma, or stage IV metastatic melanoma that have clinical or radiological evidence of disease. Stage definition may occur at original diagnosis or after recurrence. These 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 American Joint Committee on Cancer (AJCC) version (v) 7 staging system. Subjects must be eligible to be treated with pembrolizumab based on clinician judgement.
• A subject must be willing and able to provide written informed consent/assent for the trial.
• A subject may be naive for immunotherapy agents or have received interferon-alpha, ipilimumab or other CTLA-4 antibody, PD-1 antibody (or anti-PD-L1 antibody), interleukin-2, or prior cancer vaccines other than the 6 MHP 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.
• A subject must have measurable disease based on RECIST 1.1. Subjects will be required to have radiological studies to define radiologically evident disease. Required studies include: * Chest computed tomography (CT) scan, * Abdominal and pelvic CT scan, and * Head CT scan or magnetic resonance imaging (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 melanoma lesions 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.
• A subject must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.
• Absolute neutrophil count (ANC) >= 1,500 /mcL (within 28 days of treatment initiation).
• Platelets >= 100,000/mcL (within 28 days of treatment initiation).
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 28 days of treatment initiation).
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 28 days of treatment initiation). (Glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance). * Creatinine clearance should be calculated per institutional standard.
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 28 days of treatment initiation).
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 28 days of treatment initiation).
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial prothrombin time (PTT) is within therapeutic range of intended use of anticoagulants.
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 28 days of treatment initiation).
• Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
• Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
• Blood is to be collected for human leukocyte antigen (HLA) typing (class I and class II), which will be analyzed as part of the immunologic endpoints, but HLA type will not be an inclusion/exclusion criterion.
• A subject must have at least 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 nitrosoureas 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 registration with the following exceptions (which are permitted): * Replacement steroid doses in patients with adrenal or pituitary insufficiency * Intra-articular steroid injections * Inhaled steroids (e.g.: Advair, Flovent, Azmacort) at low doses (less than 500 mcg fluticasone per day, or equivalent) * Topical and nasal corticosteroids * Non-steroidal anti-inflammatory drugs
• Has had a prior monoclonal antibody within 3 weeks prior to study day 1 or who has not recovered (i.e. =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or external beam radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study. - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include carcinoma in situ of the breast (ductal breast carcinoma in situ [DCIS] or lobular breast carcinoma in situ [LCIS]), basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Exceptions to this criterion include: * Subjects with vitiligo or other depigmenting illness. * Resolved childhood asthma/atopy * Intermittent use of bronchodilators or local steroid injections * Hypothyroidism stable on hormone replacement or Sjogren’s syndrome * The presence of laboratory evidence of autoimmune disease (e.g. positive ANA titer) without symptoms * Mild arthritis requiring nonsteroidal antiinflammatory drug (NSAID) medications
• Has a history of (non-infectious) pneumonitis that required steroids or current evidence of interstitial lung disease or pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Is human immunodeficiency virus (HIV) positive or has evidence of active hepatitis C virus (testing to be done within 6 months of study entry) or active hepatitis B virus.
• Has received a live vaccine or allergy desensitization injections within 30 days prior to the first dose of trial treatment.
• Has known or suspected allergies to any component of the vaccine.
• Has been vaccinated previously with any of the synthetic peptides included in this protocol.
• Is classified according to the New York Heart Association classification as having class III or IV heart disease.
• Has uncontrolled diabetes, defined as having a glycosylated hemoglobin (HGBA1C) > 8.5%.
• Has a body weight < 110 pounds (without clothes) at enrollment, due to the amount and frequency with which blood will be drawn.