Enhanced Melanoma Vaccine for the Treatment of Stage IIB-IV Melanoma
- For individuals with primary cutaneous, mucosal, or unknown melanoma, an individual must have stage IB ulcerated, II, III, or IV melanoma at original diagnosis or at restaging after recurrence, and be rendered clinically free of disease by surgery, other therapy, or spontaneous remission within 6 months prior to registration. This would include: * An individual who has undergone resection of a primary cutaneous or mucosal melanoma with no known history of melanoma metastasis (stage IB ulcerated, stage II) who does not have another Food and Drug Administration (FDA)-approved therapy, other than interferon (IFN) alfa, which is no longer recommended by the National Comprehensive Cancer Network (NCCN) guidelines (version [v]3.2019) for adjuvant treatment * An individual who has undergone resection of regional or distant melanoma metastases (stage III-IV at original diagnosis or after restaging for recurrence) if they have refused or are not eligible for effective approved agents including PD-1/PD-L1 antibody, CTLA4 antibody, and/or, for BRAF V600 mutated melanomas, combined treatment with inhibitors of mutated BRAF and MEK (e.g. dabrafenib/trametinib). Individuals with nodal metastases are not required to have complete lymph node dissection if there is no clinical evidence of residual disease after resection
- For patients with stage II, III, or IV uveal melanoma, patients must be rendered clinically free of disease by surgery, other therapy, or spontaneous remission within 6 months prior to registration. This would include: * Patients with disease localized to the eye treated definitively with plaque therapy, if treated within 6 months prior to registration * An individual who has undergone resection of regional or distant melanoma metastases (stage III-IV at original diagnosis or after restaging for recurrence). These individuals should also have definitive treatment or the primary lesion
- An individual with small radiologic or clinical findings of an indeterminate nature may still be eligible: examples include a new 5 mm lung nodule that is too small to characterize or an asymptomatic 12 mm bony lucency that is not classic for malignancy, where clinical care may otherwise be to follow the patient with repeat imaging rather than to treat the lesion
- An individual may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma
- An individual must have at least 6-10 nevi at least 4 mm in diameter that are located on truncal or non-acral extremity sites and are accessible for biopsy and observation
- Diagnosis of melanoma must be confirmed by cytological or histological examination. Staging of cutaneous melanoma will be based on version 8 American Joint Committee on Cancer (AJCC) staging system
- Individuals will be required to have radiological studies to rule out radiologically evident melanoma metastasis. Required studies include: * Chest computed tomography (CT) scan * Abdominal and pelvic CT scan, and * Head CT scan or magnetic resonance imaging (MRI) ** Scans are not required for participants with stage IB ulcerated or IIA melanoma ** Note: positron emission tomography (PET)/CT fusion scan may replace scans of the chest, abdomen, and pelvis
- Individuals 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 * No brain metastasis is > 2 cm in diameter at the time of registration * Any neurologic symptoms attributable to brain metastases have returned to baseline * There is no evidence of new or enlarging brain metastases
- The most recent surgical resections or gamma-knife therapy for malignant melanoma must have been completed >= 1 week and =< 6 months 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
- HgbA1c =< 8.5%
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limits of normal (ULN)
- Bilirubin =< 2.5 x ULN (except in patients with Gilbert’s disease, where bilirubin up to 4 x ULN is allowed)
- Alkaline phosphatase =< 2.5 x ULN
- Creatinine =< 1.5 x ULN
- Age 18 years or older at registration
- Individuals must have at least two intact (undissected) axillary and/or inguinal lymph node basins
- For females and males of reproductive potential: agreement to use adequate contraception during study participation and for an additional 3 months after receiving the last dose of study drug
- Individuals 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 * High doses of systemic corticosteroids, with the following qualifications and exceptions: ** In patients with adrenal or pituitary insufficiency replacement steroid doses are allowed; however, daily doses of 10 mg or more of prednisone (or equivalent) per day administered parenterally or orally are not allowed in patients with normal adrenal and pituitary function ** Inhaled steroids (e.g.: Advair, Flovent, Azmacort) are permitted at low doses (less than 500 mcg fluticasone per day, or equivalent) ** Topical, nasal, and intra-articular 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
- Individuals who are currently receiving nitrosoureas or who have received this therapy within 6 weeks of registration
- Individuals who are currently receiving a checkpoint molecule blockade therapy, or who have received this therapy within 12 weeks of registration
- Individuals with known or suspected allergies to any component of the vaccine
- Individuals who have received prior melanoma vaccinations with 6MHP plus the mutated BRAF peptide. However, participants who have received prior vaccinations will be eligible to enroll 12 weeks following their last vaccination if they have recurred during or after administration of the vaccine, and if their vaccines did not include all of the synthetic peptides included in this protocol
- Individuals who have previously received CDX-1140 or another CD40 agonistic antibody
- Pregnancy. Female individuals of childbearing potential must have a negative pregnancy test (urinary or serum beta-human chorionic gonadotropin [HCG]) obtained within 2 weeks prior to registration
- Human immunodeficiency virus (HIV) positivity or evidence of active hepatitis C virus (testing to be done within 6 months of study entry)
- Female individuals must not be breastfeeding
- Individuals in whom there is a medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator
- Individuals classified according to the New York Heart Association classification as having class III or IV heart disease
- Individuals must not have had prior autoimmune disorders requiring systemic 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 ANA titer) without symptoms * Clinical evidence of vitiligo * Other forms of depigmenting illness * Mild arthritis requiring non-steroidal anti-inflammatory drugs (NSAID) medications * Resolved childhood asthma/atopy * Endocrinopathies on stable hormone replacement therapy
- Individuals 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
- Individuals with current pneumonitis. Individuals must not have had pneumonitis within 30 days of registration. Pneumonitis is a known adverse event associated with CDX-1140; thus, full systemic dosing is not recommended for individuals with a history of non-infection pneumonitis. However, the dose that will be given as part of this clinical trial is more than one log lower than the maximum tolerated disease (MTD) for CDX-1140; so, patients who have had complete resolution of prior pneumonitis will be eligible
- Individuals who have received a live vaccine within 30 days of registration
- Body weight < 110 pounds (50 kg) at registration, due to the amount and frequency with which blood will be drawn
I. To test the safety of anti-CD40 agonist monoclonal antibody CDX-1140 (CDX-1140) (agonistic human IgG2 antibody to human CD40) administered concurrently with a melanoma peptide vaccine plus polyICLC.
II. To determine whether the addition of CDX-1140 to a melanoma vaccine improves the persistence of CD4+ Th1 responses to vaccine antigens.
I. To assess whether the CDX-1140 antibody decreases regulatory T cells (FoxP3+ cells) in the vaccine site microenvironment.
II. To determine whether the addition of CDX-1140 to a melanoma vaccine:
IIa. Decreases circulating regulatory T cells.
IIb. Improves the frequency of CD4+ Th1 responses to vaccine antigens.
IIc. Increases the CD4+ Th1 memory response to vaccine antigens.
I. To assess the impact of CDX-1140 on induction of:
Ia. Antibodies to the melanoma peptides in the vaccine.
Ib. CD8+ T cell responses to melanoma antigens in the vaccine, or to other antigens by epitope spreading
Ic. CD4+ T cell activation versus exhaustion.
Id. Induction of tertiary lymphoid structures (TLS) in the vaccine site.
II. To obtain preliminary estimates of disease-free survival (DFS) and overall survival (OS).
III. To obtain data on the effect of vaccination on nevi.
IV. To describe how the schedule of CDX-1140 administration impacts the vaccine-site microenvironment (VSME) and the immune response in the sentinel immunized node (SIN).
OUTLINE: Patients are randomized to 1 of 2 cohorts.
COHORT A: Patients receive 6 melanoma helper peptide vaccine (6MHP), BRAF585-614 (V600E) Peptide (NeoAg-mBRAF), and poly ICLC, and CDX-1140 subcutaneously (SC) and intradermally (ID) at the primary vaccine site on days 1, 8, 15, 36, 57, and 78 and at the replicate vaccine site on day 1, and 6MHP, NeoAg-mBRAF, and poly ICLC SC and ID at the replicate vaccine site on days 8 and 15 in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients receive 6MHP, NeoAg-mBRAF, poly ICLC, and CDX-1140 SC and ID at the primary vaccine site on days 1, 36, 57, and 78 and at the replicate vaccine site on days 1, 8, and 15, and 6MHP, NeoAg-mBRAF, and poly ICLC SC and ID at the primary vaccine site on days 8 and 15 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 49 days and 98 days after stopping treatment and then every 12 months thereafter.
Trial Phase Phase I/II
Trial Type Treatment
University of Virginia Cancer Center
Craig Lee Slingluff
- Primary ID HSR200006
- Secondary IDs NCI-2021-00634, MEL-66
- Clinicaltrials.gov ID NCT04364230