Dabrafenib Mesylate, Trametinib, and 6 Melanoma Helper Peptide Vaccine in Treating Patients with Stage IIIB-IV Melanoma

Inclusion Criteria

• COHORT 1 (ADVANCED): Measurable stage IIIB, IIIC, IIID or IV melanoma with clinical or radiological evidence of disease. These participants 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 American Joint Committee on Cancer (AJCC) 8th edition staging system.
• COHORT 2 (NEO-ADJUVANT): Resectable stage IIIB, IIIC, IIID, or IV melanoma at initial presentation or subsequent recurrence. These participants have disease amenable to complete surgical resection at the time of enrollment in the study. The resectable disease does not need to be measurable by Response Evaluation Criteria in Solid Tumors RECIST version (v)1.1 criteria.
• COHORT 3 (ADJUVANT): Participants with stage IIIA, IIIB, IIIC, IIID or IV melanoma resected to no evidence of disease. Participants must initiate therapy within 12 weeks of last surgical resection and within 12 weeks of being rendered clinically free of disease by non-surgical approaches Patients that have undergone ablative therapy to a metastatic lesion (e.g. GKRS, radiofrequency ablation) that manifest no additional sites of disease at enrollment are eligible for treatment on cohort 3
• Participants must be eligible to be treated with BRAF inhibitor and MEK inhibitor combination, based on clinician judgment within standard of care, including the presence of the BRAF V600E or V600K mutation. Other BRAF V600 mutations will be considered with approval of principal investigator
• Participants with prior therapy with targeted therapies specific for mutated BRAF including BRAF and/or MEK inhibitors are eligible provided that there was clinical benefit to prior therapy with these agents as judged by the treating physician. There must be an interval of at least 6 months from the last BRAFi/MEKi therapy and enrollment in this clinical study
• Participants will be required to have radiological studies at baseline to establish measurable disease for cohort 1 or to prove lack of distant metastases for cohorts 2 and 3. Required studies include: * Chest computed tomography (CT) scan. * Abdominal and pelvic CT scan. * Head CT scan or magnetic resonance imaging (MRI). ** Positron emission tomography (PET)/CT fusion scan may replace scans of the chest, abdomen, and pelvis.
• Participants in cohorts 1 and 2 who have metastatic melanoma safely 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 by needle biopsy, incisional or excisional biopsy, with or without image guidance. The lesion(s) must be large enough to enable biopsy of at least 0.1 cm^3 of tumor tissue (ideally 0.3 cm^3 or more) in 5 core biopsies (ideally 14-16 gauge) or incisional/excisional biopsies at both time points. The lesions to be biopsied must be specified at study enrollment and not included as target lesions for RECIST calculations. For participants in cohort 1, there must be measurable disease in addition to the lesion(s) to be biopsied; so if the only biopsiable disease is the measurable disease, then biopsy is not required. For cohorts 1 and 2, it is acceptable to perform a biopsy pretreatment and to use tissue biopsied up to 12 weeks prior to study enrollment as long as that tissue is available for research use and there has been no intervening therapy. Subsequently, it is acceptable then to perform a complete excision at day 22, even under general anesthesia if needed. In order to reach target accrual of 14 participants with biopsies at pretreatment and day 22 the following accrual limits will be placed up the number of accrued participants without biopsiable disease. Up to 19 participants without metastatic disease available and sufficient for those biopsies may enroll in the study as well. Once that number has completed enrollment, subsequent participants must have biopsiable disease and agree to the biopsies
• Participants 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 or systemic immunotherapy * There has been no evident growth of any brain metastasis since the most recent treatment if the last treatment is > 4 weeks prior to enrollment * No brain metastasis is > 2 cm in diameter at the time of registration * Neurologic symptoms have returned to baseline off steroids * 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 0-2.
• Participants must have the ability and willingness to give informed consent.
• Absolute neutrophil count (ANC) > 1000/mm^3.
• Platelets > 100,000/mm^3.
• Hemoglobin (Hgb) > 9 g/dL.
• Hemoglobin A1c (HgB-A1c) =< 8.5%.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) up to 2.5 x upper limits of normal (ULN)
• Bilirubin up to 2.5 x ULN. Patients known to have Gilbert’s disease may be eligible with bilirubin up to 5 x ULN
• Alkaline phosphatase up to 2.5 x ULN.
• Creatinine up to 1.5 x ULN.
• Age 18 years or older at registration
• Participants must have at least two intact (undissected) axillary and/or inguinal lymph node basins.

Exclusion Criteria

• Participants who have received the following medications or treatments at any time within 4 weeks of registration: * Chemotherapy * Interferon (e.g. Intron-A). * Radiation therapy (stereotactic radiotherapy, such as gamma knife, can be used >= 1 week and =< 6 months prior to registration). * Allergy desensitization injections. * Corticosteroids, administered transdermally, parenterally or orally. Inhaled steroids (e.g.: Advair, Flovent, Azmacort) are not permitted. Topical corticosteroids and steroids administered to replace corticosteroid deficiency are acceptable. * Growth factors (e.g. Procrit, Aranesp, Neulasta). * Interleukins (e.g. Proleukin). * Any investigational medication, except that participation in the UVA AM004 clinical trial is acceptable. AM004 is a FUSA-specific radiology study that uses an investigational imaging tracer to identify activated T cells; the tracer is not intended to treat any medical condition. Participation in the AM004 clinical trial is not expected to affect safety or efficacy of the Mel 61 study therapy.
• Human immunodeficiency virus (HIV) positivity or evidence of active hepatitis C virus.
• Participants who are currently receiving nitrosoureas or who have received this therapy 6 weeks prior to registration.
• Participants who are currently receiving a checkpoint molecule blockade therapy, or who have received this therapy within 3 weeks prior to registration.
• Participants with known or suspected allergies to any component of the vaccine.
• Participants vaccinated previously with any of the synthetic peptides included in this protocol. Participants who have received vaccinations containing agents other than the synthetic peptides included in this protocol and have recurred during or after administration of the vaccine will be eligible to enroll 12 weeks following their last vaccination.
• Pregnancy. Female participants of childbearing potential must have a negative pregnancy test (urinary or serum beta-human chorionic gonadotropin [HCG]) obtained within 2 weeks prior to registration. Males and females must agree, in the consent form, to use effective birth control methods during the course of vaccination.
• Female participants must not be breastfeeding.
• Participants in whom there is a medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator.
• Participants classified according to the New York Heart Association classification as having class III or IV heart disease.
• Participants with uncontrolled diabetes, defined as having a HgB-A1c > 8.5%.
• Participants must not have had prior autoimmune disorders requiring cytotoxic or immunosuppressive therapy, or autoimmune disorders with visceral involvement. Participants with an active autoimmune disorder requiring these therapies are also excluded. The following will not be exclusionary: * The presence of laboratory evidence of autoimmune disease (e.g. positive antinuclear antibody [ANA] titer) without symptoms * Clinical evidence of vitiligo. * Other forms of depigmenting illness. * Mild arthritis requiring nonsteroidal anti-inflammatory drug (NSAID) medications.
• Participants who have another cancer diagnosis, except that the following diagnoses will be allowed: * Squamous cell cancer of the skin without known metastasis. * Basal cell cancer of the skin without known metastasis * Carcinoma in situ of the breast (ductal breast carcinoma in situ [DCIS] or lobular breast carcinoma in situ [LCIS]). * Carcinoma in situ of the cervix. * Any cancer without distant metastasis that has been treated successfully, without evidence of recurrence or metastasis for over 3 years.
• Participants with known addiction to alcohol or drugs who are actively taking those agents, or participants with recent (within 1 year of registration) or ongoing illicit intravenous (IV) drug use.
• Body weight < 110 pounds (without clothes) at registration, due to the amount and frequency with which blood will be drawn.
• Participants with a known history of glucose-6-phosphate dehydrogenase deficiency.