RNA-Lipid Particle Vaccine for the Treatment of Early Melanoma Recurrence after Anti-PD-1 Antibody Therapy

Inclusion Criteria

• Adults ≥ 18 years old
• Must have measurable disease with evidence of progression (progressive disease, or PD) by RECIST 1.1 criteria while receiving adjuvant aPD1 therapy, or progression within 6 months after completing adjuvant treatment for stage IIB-IV melanoma
• Patients with stage IV nonresectable disease with rare melanoma subtypes: (mucosal, acral, uveal, non-sun exposed) are eligible for the study if they fail to response to initial immunotherapy given in the first line metastatic setting. These rare subtypes do not respond to aPD1 blockade at the same rate or degree as cutaneous melanomas and behave more like adjuvant failure patients in response to aPD1. These patients must have disease amenable to sampling and in the opinion of the treating physician have appropriate bridging therapy available to reach vaccination series, have no other approved therapeutic options/or decline their use
• Patients of any stage treated with immune checkpoint inhibition with primary or secondary immunotherapy resistance. Primary resistance is defined as a minimum drug exposure requirement of 8–12 weeks or roughly two doses of the immunotherapy with lack of benefit defined as PD at the time of the first planned assessment or stable disease (SD) lasting less than 6 months. Secondary resistance is defined as exposure to immune checkpoint inhibition for at least 6 months with best response initially including a complete remission (CR), partial remission (PR), or SD lasting for greater than 6 months with subsequent progression while receiving checkpoint inhibition, or within 6 months of completing a planned course of immunotherapy. These patients are eligible for enrollment if their disease is amenable to sampling for vaccine generation and they are not contraindicated to continuation of immune checkpoint therapy, and do not have rapidly progressing disease, and have no other viable clinical options or choose not to pursue current approved salvage options for therapy
• Must have received either aPD1, combination aPD1/CTLA-4 inhibition, or PD1/LAG-3 inhibitor as adjuvant or definitive metastatic treatment for stage IIB-IV melanoma following surgical resection
• Must be BRAF wildtype, or have BRAF mutation but contra-indication to BRAF/MEK inhibitor use, have progressed while on BRAF/MEK therapy, or decline the option to utilize BRAF/MEK therapy
• Eastern Cooperative Oncology Group (ECOG) performance ≤ 2
• Hemoglobin ≥ 8 G/DL
• Platelets ≥ 150 thou/cumm
• Absolute neutrophil count (ANC) ≥ 1500 thou/cumm
• Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN. If confirmed liver metastases: AST and ALT ≤ 5 x ULN)
• Creatinine clearance (CrCl) ≥ 15 ml/min (based on modified Cockcroft and Gault formula)
• Must have disease that is amenable to surgical sampling for RNA extraction, amplification, and loading of lipid particles (LPs)
• Written informed consent obtained from the subject
• Female subjects of childbearing potential must have a negative serum pregnancy test at screening
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least four months after the last dose of study treatment to minimize the risk of pregnancy. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. WOCBP includes any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal Post-menopause is defined as: * Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or * For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
• Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for four months following the last dose of study treatment and must agree to not donate sperm during the study treatment period or for four months following the last dose of study treatment

Exclusion Criteria

• Subjects that have an active second malignancy, however, previously treated early stage malignancies with no evidence of disease recurrence after 3 years of follow-up will be allowed
• Subjects with a history of immune-mediated treatment-related adverse reactions leading to discontinuation of prior aPD1 therapy or severe hypersensitivity reaction to any monoclonal antibody or any other baseline risk in the opinion of the investigator that precludes continued use of aPD1 therapy
• Patients with active and symptomatic brain metastases or leptomeningeal metastases at time of inclusion. Patients with isolated brain lesions that have been treated with stereotactic radiosurgery (SRS) or surgical resection as part of oligometastatic initial management prior to start of immunotherapy may be eligible as long as they have no new disease and are asymptomatic at time of inclusion
• If patients develop new brain metastases during the time between tumor sampling and vaccine generation and administration, patients may remain on study as long as they can receive definitive SRS or surgery to brain metastases and be able to resume systemic therapy within 6 weeks of discovery of new brain metastases
• Subjects who received an investigational drug in another clinical trial must wait 28 days or at least 5 half-lives of the study drug, whichever is shorter, prior to enrollment in this study
• Patients must not have required corticosteroids (anything greater than 10mg of prednisone of equivalent, daily) or other immunosuppressive medications within 14 days of the start of trial treatment
• Subjects with uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within seven days prior to tissue collection for vaccine creation or within seven days prior to vaccine administration (subjects on prophylactic agents are acceptable)
• Subjects with any life-threatening illness, medical condition, or organ system dysfunction, which in the investigator’s opinion, could compromise subject safety
• Subjects with known active hepatitis B virus or untreated hepatitis C virus. Patients with previous history of hepatitis C who completed treatment for hepatitis C virus (HCV) would not be excluded as long as they have no detectable viral load
• Clinically relevant active autoimmune disease that would pose significant risk to the patient’s life should a flare ensue. Patients with chronic autoimmune rheumatologic endocrine, or psoriatic skin diseases may still be eligible pending they are not receiving systemic immunosuppression at the time of treatment as previously described and that patients are aware of the increased risk of flare provocation with treatment
• Symptomatic congestive heart failure (New York Heart Association [NYHA] class 3 or 4)
• Subjects with unstable angina pectoris
• Subjects who are post-splenectomy, otherwise asplenic, or have moderate to severe splenomegaly (defined as a spleen larger than 13 cm in cranial-caudal height or longest diameter)
• Personal history of anaphylactic reaction to previous vaccination
• Known hypersensitivity to the active substance or to any of the excipients
• Subjects with known human immunodeficiency virus with CD4+T cells ≤ 350 cells/ul, a positive viral load as determined by institutional standard testing, or a history of AIDS defining opportunistic infection within the last 12 months
• Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 months after the last dose of study treatment
• Females who are confirmed to be pregnant or breastfeeding
• History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician
• Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment. Prohibited Concomitant Therapy. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose. Non-live versions of the COVID vaccine are allowed
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness