Novel RNA-nanoparticle Vaccine for the Treatment of Early Melanoma Recurrence Following Adjuvant Anti-PD-1 Antibody Therapy

Study Overview
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Brief Summary
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The goal of this phase I trial is to evaluate the toxicity and feasibility of a tumor-specific RNA-NP vaccine in patients with stage IIB-IV melanoma who have progressed on anti-PD1 (a-PD1) adjuvant therapy.

Official Title
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Novel RNA-nanoparticle Vaccine for the Treatment of Early Melanoma Recurrence Following Adjuvant Anti-PD-1 Antibody Therapy

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Autologous total tumor mRNA loaded DOTAP liposome vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥ 18 years old Must have evidence of progressive disease (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 Must have received either PD1 or combination aPD1/CTLA-4 inhibition as adjuvant treatment for stage IIB-IV melanoma following surgical resection Must be BRAF wildtype ECOG performance ≤ 1 Lab values within the specified ranges: Serum direct bilirubin ≤ 1.5 x ULN (upper limit of normal) AST and 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 amendable to surgical sampling for RNA-NP vaccine development Subjects must not have more than one active malignancy at the time of enrollment (subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen [as determined by the treating physician and approved by the PI] may be included) Written informed consent obtained from the subject. Subject agrees to comply with all the study-related procedures. 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 Exclusion Criteria: Subjects that have an active second malignancy, however, previously treated early stage malignancies (non-melanoma skin cancers, ductal carcinoma in situ, or prostate confined prostate cancer) with no evidence of disease recurrence after 5 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 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 Subjects with uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within seven days prior to tissue collection for vaccine creation or within even 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 Clinically relevant active autoimmune disease Symptomatic congestive heart failure (NYHA 3 or 4) Subjects with unstable angina pectoris Subjects who are post-splenectomy Known hypersensitivity to the active substance or to any of the excipients Subjects with 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mRNA-nanoparticle (mRNA-NP) vaccine<br> | Biological: Autologous total tumor mRNA loaded DOTAP liposome vaccine<br>* All participants will receive three doses of RNA-NP vaccine (1 dose every 2 weeks) intravenously. The vaccine dose given will be determined by a 3 + 3 design. The first cohort of 3 participants will be enrolled on a low vaccine dose (0.02 mg/kg mRNA encapsulated in 0.3 mg/kg NPs). If no dose limiting toxicity (DLT) is observed, then a new cohort will be enrolled at the next dose of vaccine (0.04 mg/kg mRNA encapsulated in 0.6 mg/kg NPs). However, if > 1 in 3 subjects experience a DLT, an additional 3 subjects will be enrolled at initial dose cohort. If no more than 2 subjects in 6 experience a DLT, then the criteria for MTD has not been met and dose escalation will continue with an additional cohort enrolled at a high dose vaccine level (0.08 mg mRNA encapsulated in 1.2 mg/kg NPs). However, should 3 or more of the initial 6 subjects experience a DLT, then the initial starting dose will be reduced (dose de-escalation) to 0.01 mg/kg mRNA encapsulated in 0.15mg/kg NPs.<br>* Other names: mRNA-NP (nanoparticle) vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Determine the maximum tolerated dose of RNA-NP vaccine | 2 months | 
| Feasibility of treatment with RNA-NP vaccine | Determine the feasibility of treatment with RNA-NP vaccine, defined as the percentage of subjects who undergo tumor sampling and vaccine generation who can have sufficient vaccine produced for treatment across the full three dose vaccination series and within a time window of 4 weeks from time of tumor sampling to vaccine delivery for use. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Determine the overall response rate, defined as the percentage of subjects who attain either a complete or partial response by RECIST 1.1 criteria following completion of the three dose vaccination series. | 4 weeks | 
| Progression-free survival | Determine the the rate of progression free survival (PFS), defined as the time from study enrollment until progression | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic melanoma, immunotherapy, vaccines, RNA-NP