A Vaccine (6MHP) with or without CDX-1127 for the Treatment of Stage IIB-IV Melanoma
This phase I/II trial studies the side effects and how well a vaccine (6MHP) with or without CDX-1127 work for the treatment of stage IIB-IV melanoma. Vaccines, such as 6MHP, may help the body build an effective immune response to kill tumor cells. Immunotherapy with monoclonal antibodies, such as CDX-1127, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial is being done to see what effects 6MHP alone and in combination with CDX-1127 have on changes in the immune system.
Inclusion Criteria
- Patients with stage IIB, IIC, III, or IV melanoma at original diagnosis or at restaging after recurrence, rendered clinically free of disease by surgery, other therapy, or spontaneous remission within 6 months prior to registration. Patients with high-risk stage IIA melanoma (by DecisionDx Melanoma test, Castle Biosciences, Inc., Friendswood, TX) also may be eligible
- Patients 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 Participants may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma. 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. Patients with primary uveal melanoma that are considered high-risk by DecisionDX will not require pathologic review
- Participants 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) * Positron emission tomography (PET)/CT fusion scan may replace scans of the chest, abdomen, and pelvis
- 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 * 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 to 4 x ULN is allowed)
- Alkaline phosphatase =< 2.5 x ULN
- Creatinine =< 1.5 x ULN
- Age 18 years or older at registration
- Participants must have at least one intact (undissected) axillary and/or inguinal lymph node basin
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 * 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
- Participants who are currently receiving nitrosoureas or who have received this therapy within 6 weeks of registration
- Participants who are currently receiving a checkpoint molecule blockade therapy, or who have received this therapy within 12 weeks of registration
- Participants with known or suspected allergies to any component of the vaccine
- Participants who were vaccinated previously with 6MHP are excluded. 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
- Participants who have previously received CDX-1127 or other CD27 agonistic antibody
- 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 active study treatment and for up to 70 days after the last dose of study treatment
- Human immunodeficiency virus (HIV) positivity or evidence of active hepatitis C virus (testing to be done within 6 months of study entry)
- 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 an HgbA1c > 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 * Resolved childhood asthma/atopy * Intermittent use of bronchodilators or local steroid injections * Hypothyroidism stable on hormone * Replacement for Addison’s disease titer) without symptoms
- 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
- Participants who have received a live vaccine within 30 days of registration
- Body weight < 110 pounds at registration, due to the amount and frequency with which blood will be drawn
- Participants with prior autoimmune pneumonitis
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03617328.
PRIMARY OBJECTIVES:
I. To test the safety of varlilumab (CDX-1127) administered concurrently with a melanoma vaccine (6 melanoma helper peptide vaccine [6MHP]).
II. To determine whether addition of CD27 antibody to a melanoma vaccine improves the persistence of CD4+ Th1 responses to vaccine antigens.
SECONDARY OBJECTIVES:
I. To assess whether CD27 antibody decreases regulatory T cells (FoxP3+ cells) in the vaccine site microenvironment at weeks 3 and 12.
II. To determine whether addition of CD27 antibody to a melanoma vaccine,
IIa. Decreases circulating regulatory T cells.
IIb. Improves the frequency of CD4+ Th1 responses to vaccine antigens.
IIc. Improves the frequency of durable CD4+ Th1 responses to vaccine antigens (dRsp).
IId. Increases the CD4+ Th1 memory response (mRsp) to vaccine antigens at 6 months.
EXPLORATORY OBJECTIVES:
I. To assess the impact of CD27 antibody on induction of
Ia. Antibodies to helper peptides in 6MHP (assessed in serum by enzyme-linked immunosorbent assay [ELISA] for IgG).
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.
II. To obtain preliminary estimates of disease-free survival (DFS) and overall survival.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive 6MHP vaccine and polyICLC in an emulsion of montanide ISA-51 adjuvant subcutaneously (SC) and intradermally on days 1, 8, 15, and 36. Patients then receive 6MHP in an emulsion of montanide ISA-51 adjuvant as part of a booster vaccine on day 176 in the absence of disease progression or unacceptable toxicity. Patients also receive varlilumab intravenously (IV) over 90 minutes on days 1, 36, and 78 in the absence of disease progression or unacceptable toxicity
ARM B: Patients receive 6MHP vaccine, polyICLC, and montanide ISA-51 as in arm A.
After completion of study treatment, patients are followed up at 7 and 30 days and then annually thereafter.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationUniversity of Virginia Cancer Center
Principal InvestigatorCraig Lee Slingluff
- Primary ID20085
- Secondary IDsNCI-2019-06213, Mel 65
- ClinicalTrials.gov IDNCT03617328