6MHP Vaccine and Ipilimumab in Treating Patients with Stage IIA-IV Melanoma
- Participants with stage IIA (with class 2 DecisionDx Score) through IV melanoma in cohorts defined below. These participants may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma. The diagnosis of melanoma must be confirmed by cytological or histological examination. Staging of cutaneous melanoma will be based on the revised American Joint Committee on Cancer (AJCC) staging system. Participants must be eligible to be treated with ipilimumab based on clinician judgment within standard of care * Cohort 1 (Advanced Patients): unresectable stage III or IV melanoma that have clinical or radiographic evidence of disease * Cohort 2 (Neoadjuvant therapy): primary melanoma with clinically apparent lymph node or in transit/satellite lesions with or without lymph node involvement, in transit recurrence or metastatic recurrence amenable to complete resection to no evidence of disease * Cohort 3 (Adjuvant therapy): stage IIA (with class 2 DecisionDx Score), IIB-IV melanoma resected to no evidence of disease
- Participants 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
- Participants who have melanoma available for biopsy pre-treatment and on day 22 must consent to having those biopsies. * Melanoma lesions may be in nodes, skin, soft tissue, liver, or other sites that can be accessed by core needle biopsy, or 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 cm3 or more) in 5 core biopsies (ideally 14-16 gauge, but 18 gauge is acceptable) or incisional/excisional biopsies at both time points. Biopsies may be taken from a single lesion or multiple lesions at each of the time points depending on the size of each lesion. Different lesions may be sampled at each time point. It is acceptable to perform a biopsy pretreatment, and then to perform an excision at day 22, even under general anesthesia if needed. The lesions to be biopsied must be specified at study enrollment and not included as target lesions for RECIST calculations. There must be measurable disease in addition to the lesion(s) to be biopsied for cohort 1. Up to 15 participants whose metastases are not available for biopsy may be enrolled in the first stage of enrollment, and up to 17 participants whose metastases are not available for biopsy may be enrolled in the second stage of enrollment
- Participants who have had brain metastases will be eligible if all of the following are true: * Each brain metastasis must have been treated by surgical removal, stereotactic radiosurgery or managed to complete resolution with immunotherapy. Patients with brain lesions managed by immunotherapy without excision or radiosurgery are included provided that the brain metastases have completely resolved after systemic therapy and there are no neurologic symptoms or need for systemic therapy to control central nervous system (CNS)-disease related symptoms * There has been no evident growth of any brain metastasis since the most recent treatment. If a patient has been managed by immunotherapy alone, the prior lesions must be completely resolved * No brain metastasis is > 2 cm in diameter at the time of 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
- Ability and willingness to give informed consent
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Platelets >= 100,000/mm^3
- Hemoglobin (Hgb) >= 9 g/dL
- Hgb-A1C =< 7.5%
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) =< 2.5 x upper limits of normal (ULN)
- Bilirubin =< 1.5 x ULN (except in patients with Gilbert’s disease, where bilirubin to 4 x ULN is allowed)
- Alkaline phosphatase =< 2.5 x ULN
- Creatinine =< 1.5 x ULN
- Participants must have at least two intact (undissected) axillary and/or inguinal lymph node basins
- 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 prior to registration) * Allergy desensitization injections * High doses of systemic corticosteroids, with the following qualifications and exceptions: ** Daily doses of 10 mg prednisone (or equivalent) per day administered parenterally or orally are not allowed in patients with normal adrenal and pituitary function. ** In patients with adrenal or pituitary insufficiency replacement steroid doses are allowed ** Inhaled steroids (e.g.: Advair, Flovent, Azmacort) are permitted at low doses (less than 500 mcg fluticasone per day, or equivalent) ** Topical and nasal corticosteroids are acceptable. * Growth factors (e.g. Procrit, Aranesp, Neulasta) * Interleukins (e.g. Proleukin) * Any investigational medication * Targeted therapies specific for mutated BRAF or for MEK
- Human immunodeficiency virus (HIV) positivity or evidence of active Hepatitis C virus (testing to be done within 6 months of study entry)
- Participants who are currently receiving nitrosoureas or who have received this therapy within the preceding 6 weeks
- Participants who are currently receiving a checkpoint molecule blockade therapy, or who have received this therapy within the preceding 6 weeks, with the following exception * Participants who have received a PD-1 blocking antibody (eg: pembrolizumab or nivolumab) may be enrolled 3 weeks after receiving the last dose of that antibody * Participants who have been treated previously with a CTLA-4 blocking antibody either as monotherapy or as part of combination CTLA-4/PD-1 blockade will be ineligible if CTLA-4 therapy: ** Was discontinued early for toxicity, or ** Did not induce stable disease or objective clinical response (by RECIST or irRC criteria) lasting 6 months or more *** Note: Patients may be eligible if they have experienced progression after a period of stable disease (6 months or more) or an objective clinical response (by irRC or RECIST) (6 months or more) induced by CTLA-4 blockade or combination CTLA-4/PD-1 blockade *** Note: Similar guidelines will apply for tremelimumab or other CTLA-4 blocking antibodies
- Participants with known or suspected allergies to any component of the vaccine
- Participants may not have been 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. This is consistent with existing standards of practice for vaccine and chemotherapy protocols
- 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 > 7.5%
- 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 drugs (NSAID) medications * A history of immune-related adverse events with immune therapy, if they have resolved completely
- 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 carcinoma in situ [DCIS] or lobular 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 2 years
- Participants with known addiction to alcohol or drugs who are actively taking those agents, or participants with recent (within 1 year) or ongoing illicit IV drug use
- Body weight < 110 pounds at registration, due to the amount and frequency with which blood will be drawn
I. To determine whether the combination of 6MHP vaccine plus ipilimumab is safe as evaluated by adverse event assessments, including Common Terminology Criteria for Adverse Events (CTCAE) 4.03 and sub-classified by immune-related adverse event (irAE) categories.
II. To estimate in the blood and in the sentinel immunized node the CD4 positive (+) T cell response rate to 6MHP peptides in patients treated with 6MHP vaccine plus ipilimumab.
I. To estimate the proportion of patients in whom the combination of 6MHP vaccine plus ipilimumab induces epitope-spreading CD8+ T cells in the blood and in the sentinel immunized node that are reactive to a panel of defined melanoma antigens.
I. To estimate the production of serum immunoglobulin G (IgG) reactive to 6MHP in patients treated with 6MHP vaccines plus ipilimumab.
II. To obtain preliminary estimates of clinical outcomes including overall survival, progression-free survival, and clinical response by immune-related response criteria (irRC) following administration of the combination of 6MHP vaccine plus ipilimumab. (Cohort 1)
III. To obtain preliminary data on risk of recurrence and time to recurrence after resection of tumor to no evidence of disease and administration of the combination of 6MHP vaccine plus ipilimumab. (Cohorts 2 and 3)
IV. To obtain preliminary estimates of the associations between T cell and antibody responses to melanoma antigens and survival and with disease control.
V. To determine whether the combination of 6MHP vaccine plus ipilimumab increases infiltration of CD8+ and/or CD4+FoxP3neg T cells into melanoma metastases in at least 50% of patients with tumor evaluable pre- and post- treatment.
Patients receive 6MHP vaccine intradermally (ID) and subcutaneously (SC) on days 1, 8, 15, 43, 64, and 85, and receive ipilimumab intravenously (IV) on days 1, 22, 43, and 64 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 18, 24 and 27 weeks, then at 1 and 2 years.
Trial Phase Phase I/II
Trial Type Treatment
University of Virginia Cancer Center
Elizabeth M. Gaughan
- Primary ID 17780
- Secondary IDs NCI-2018-01626, Mel 62
- Clinicaltrials.gov ID NCT02385669