Study of RNA-lipid Particle (RNA-LP) Vaccines for Recurrent Pulmonary Osteosarcoma (OSA)

Study Overview
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Brief Summary
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The investigators have shown that intravenous administration of tumor mRNA loaded lipid particles (LPs) localizes primarily to lung, transfect antigen presenting cells (APCs) and lead to an activated T cell response for induction of anti-tumor immunity. In contrast to other formulations, RNA-LPs recruit multiple arms of the immune system (i.e. innate/adaptive), and remodel the systemic/intratumoral immune milieu, which remain potent barriers for vaccine, cellular, and checkpoint inhibiting immunotherapies. After only a single RNA-LP vaccine, the bulk of systemic and intratumoral dendritic cells (DCs) in mice display an activated phenotype; these activated DCs (harvested from tumors) expand antigen specific T cell immunity. In immunologically resistant pulmonary osteosacroma murine tumor models (i.e. K7M2), RNA-LPs induce robust anti-tumor efficacy in settings where immune checkpoint inhibitors (i.e. anti-PD-L1 therapy) do not confer therapeutic benefit. We have already demonstrated safety of RNA-LPs in acute/chronic murine toxicity studies, and in client-owned canine trial. In this study, we will investigate the safety and immunologic activity of RNA-LP vaccine in patients with recurrent pulmonary osteosarcoma.

Official Title
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Study of RNA-lipid Particle (RNA-LP) Vaccines for Recurrent Pulmonary Osteosarcoma (OSA)

Conditions
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Pulmonary Osteosarcoma

Intervention / Treatment
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* Biological: RNA-LP vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age < 39 years. Histopathologically proven recurrent pulmonary osteosarcoma. Must be eligible for thoracotomy (Arms 1 and 2 only). Patient must have been enrolled on a screening consent and have had sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs). Patients must have recovered from the effects of surgery, biopsy, postoperative infection, and other complications. Karnofsky Performance Status (KPS) or Lansky Performance Status (LPS) ≥ 60. Bone Marrow: ANC (Absolute neutrophil count) ≥ 1,000µl (absent treatment) Platelets ≥ 100,000/µl (absent treatment for at least 3 days) Hemoglobin > 8 g/dL Renal: BUN ≤ 25 mg/dl Creatinine ≤ 1.7 mg/dl Hepatic Bilirubin ≤ 2.0 mg/dl ALT ≤ 5 times institutional upper limits of normal for age AST ≤ 5 times institutional upper limits of normal for age Signed informed consent. If the patient's mental status precludes his/her giving informed consent, written informed consent may be given by the legally authorized representative per institutional policy. For subjects of childbearing potential (SOCBP), negative urine or serum pregnancy test at enrollment. SOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug. Subjects with partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug. Exclusion Criteria: HIV, Hepatitis B, CMV, or Hepatitis C seropositive. Known active infection or immunosuppressive disease. Known severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization. Unstable cardiac arrhythmias, abnormalities, or transmural myocardial infarction within the last 6 months. Acute bacterial or fungal infection requiring intravenous antibiotics Chronic Obstructive Pulmonary Disease exacerbation or other known respiratory illness requiring hospitalization or precluding study therapy Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Patients with autoimmune disease requiring medical management with immunosuppressants. Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy. Known active connective tissue disorders such as lupus or scleroderma that, in the investigator's opinion, place the patient at high risk for radiation toxicity. Pregnancy or subjects of childbearing potential and their partners who are sexually active and who are unwilling or unable to use an acceptable method of contraception for the entire study period; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Subjects must not be pregnant or breast-feeding. Subjects who require systemic corticosteroids above physiologic doses or not weaned to physiologic dosing within 1 week of scheduled vaccination. Subjects who are receiving any other investigational agents or who have been treated on any other therapeutic clinical protocols within 30 days prior to study entry. Subjects who are unwilling or unable to receive treatment and undergo follow-up evaluations at the enrolled Sunshine Consortium treatment site.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 39 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: RNA-LP vaccine<br> | Biological: RNA-LP vaccine<br>* All subjects will receive two doses of RNA-LP vaccine every two weeks and then once monthly for 12 months afterward. Subjects on the phase 1 portion of the study will be assigned to receive either 0.01 mg/kg mRNA encapsulated in 0.15 mg/kg LPs (dose level -1), 0.02 mg/kg mRNA encapsulated in 0.3 mg/kg LPs (dose level 0), 0.04 mg mRNA encapsulated in 0.6 mg/kg LPs (dose level +1), 0.08 mg mRNA encapsulated in 1.2 mg/kg LPs (dose level +2) following a 3 + 3 design. All subjects on the Phase II portion will receive the maximum tolerated dose determined in the phase I portion of the study.<br>|

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-LP vaccine. | 14 months | 
| 12 month event-free survival | Determine if RN-LP vaccine therapy extends 12 month event-free survival. Event-free survival is defined as the time from start of treatment to either disease progression or death, whichever occurs first. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Determine the event-free survival in patients with recurrent pulmonary oseteosarcoma receiving RNA-LP vaccine. Event-free survival is defined as the time from start of treatment to either disease progression or death, whichever occurs first. | 3 years | 
| Overall survival | Determine the overall survival in patients with recurrent pulmonary oseteosarcoma receiving RNA-LP vaccine. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary osteosarcoma, RNA-LP, vaccines, immunotherapy