A Vaccine (RNA-LP) for the Treatment of Recurrent Pediatric High-Grade Glioma and Recurrent Osteosarcoma, RNA PRIME Trial

Inclusion Criteria

• pHGG PATIENTS: * Patients must be age 3-25 years * The first patient enrolled at each dose level must be ≥ 12 years
• pHGG PATIENTS: * For both arms: ** Patients must have had a prior histologically-diagnosed pHGG (astrocytoma World Health Organization [WHO] grade 3 or 4 and glioblastoma WHO grade 4 by histopathology or molecular studies, per 2021 WHO Classification of Tumors of the Central Nervous System [CNS], WHO CNS5) ** Patients must have MRI evidence of probable recurrent pHGG ** Patients must consent to have sterile collection of tumor material in a manner suitable for ribonucleic acid (RNA) extraction, amplification, and loading of lipid particles ** Recurrent pHGG involving the midline structures other than those intrinsically located within the pons ARE eligible ** Patients with mismatch repair deficient (MMRD) tumors refractory to immune checkpoint inhibitors ARE eligible
• pHGG PATIENTS: * Patients must be clinically eligible for standard-of-care surgical resection/biopsy
• pHGG PATIENTS: * Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. Patients must have a Karnofsky or Lansky score ≥ 60% * Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score * Participants with post-surgical neurological deficits should have deficits that are stable for a minimum of 2 week prior to enrollment
• pHGG PATIENTS: * Patients must have recurred or progressed after receiving surgery and radiation therapy as frontline standard-of-care treatments in primary disease * Patients must have fully recovered from all acute toxic effects of all prior anti-cancer therapy (all adverse events have resolved to grade 1 or better) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately ** Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: ≥ 21 days after the last dose of myelosuppressive chemotherapy. If questions, the agent and duration can be discussed with the study chair ** Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): ≥ 14 days after the last dose of agent. If questions, the agent and duration can be discussed with the study chair ** Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade ≤ 1 ** Corticosteroids: Patients may be on no greater than physiologic doses of steroids for at least 14 days prior to enrollment with a stable neurologic status ** Hematopoietic growth factors: 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur ** Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon, or cytokines ** Stem cell infusions (with or without total-body irradiation [TBI]): *** Autologous stem cell infusion including boost infusion: ≥ 30 days ** Cellular therapy: ≥ 42 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) ** XRT/external beam irradiation, including protons: ≥ 90 days after local XRT unless recurrence is a new enhancement on MRI outside the radiation treatment field; ≥ 150 days after TBI, craniospinal XRT or if radiation to ≥ 50% of the pelvis ** Radiopharmaceutical therapy (e.g., radiolabeled antibody): ≥ 42 days after systematically administered radiopharmaceutical therapy ** Other therapeutic clinical trials: ≥ 14 days after last dose of investigational agent, unless otherwise defined above ** Patients must not have received prior exposure to pp65-directed therapy or any RNA-LP therapy
• pHGG PATIENTS: * Absolute neutrophil count (ANC) ≥ 1,000/µl
• pHGG PATIENTS: * Platelets ≥ 100,000/µl (transfusion-independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• pHGG PATIENTS: * Hemoglobin ≥ 8 g/dL (transfusion-independent, defined as not receiving packed red blood cell transfusions for at least 7 days prior to enrollment)
• pHGG PATIENTS: * Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2 or * A creatinine based on age/gender as follows: ** 1 to < 2 years: male =< 0.6 mg/dL and female =< 0.6 mg/dL ** 2 to < 6 years: male =< 0.8 mg/dL and female =< 0.8 mg/dL ** 6 to < 10 years: male =< 1 mg/dL and female =< 1 mg/dL ** 10 to < 13 years: male =< 1.2 mg/dL and female =< 1.2 mg/dL ** 13 to < 16 years: male =< 1.5 mg/dL and female =< 1.4 mg/dL ** >= 16 years: male =< 1.7 mg/dL and female =< 1.4 mg/dL
• pHGG PATIENTS: * Total bilirubin ≤ 3 x institutional upper limits of normal for age
• pHGG PATIENTS: * Alanine aminotransferase (ALT) ≤ 5 x institutional upper limits of normal for age
• pHGG PATIENTS: * Aspartate aminotransferase (AST) ≤ 5 x institutional upper limits of normal for age
• pHGG PATIENTS: * Baseline pulse oximetry of at least 92% on room air
• pHGG PATIENTS: * All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent/assent document * All patients must be willing to take an antiepileptic medication such as levetiracetam for the duration of RNA-LP vaccinations * For women of childbearing potential, negative serum/urine pregnancy test is required at enrollment and before each vaccine administration * Women of childbearing potential must agree to use of at least 2 forms of acceptable contraceptive methods or abstinence to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug * Men with female partners of childbearing potential must agree to use of at least 2 forms of acceptable contraceptive methods or abstinence throughout the study and should avoid conceiving children for at least 24 weeks following the last dose of study drug
• OSA PATIENTS: * Patients must be age 3-39 years * The first patient enrolled and treated at each dose level must be ≥ 12 years
• OSA PATIENTS: * For arms 1 and 2: Patients must undergo standard-of-care surgical resection of suspected OSA recurrence with pulmonary-only metastases. Diagnosis of recurrent OSA pulmonary metastases must be histopathologically confirmed following surgical resection or biopsy * For arm 3: Patients must undergo standard-of-care biopsy of suspected or known recurrent, unresectable OSA. Diagnosis of OSA must be histopathologically confirmed following biopsy
• OSA PATIENTS: * For arm 1: Patients must be eligible for single-sided thoracotomy for planned surgical resection of all OSA pulmonary metastases * For arm 2: Patients must be eligible for staged two-sided thoracotomies for planned surgical resection of all OSA pulmonary metastases * For arm 3: Patients must have unresectable OSA. Patients must have sufficient disease on diagnostic contrast-enhanced MRI wherein surgical biopsy is feasible * For all arms: Patients must have 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
• OSA PATIENTS: * Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. Patients must have a Karnofsky or Lansky score ≥ 60% * Participants who are unable to walk because of amputation, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• OSA PATIENTS: * Patients must have fully recovered from all acute toxic effects of all prior anti-cancer therapy (all adverse events have resolved to grade 1 or better) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately ** Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: ≥ 14 days after the last dose of myelosuppressive chemotherapy. If questions, the agent and duration can be discussed with the study chair ** Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or ANC counts): ≥ 7 days after the last dose of agent. If questions, the agent and duration can be discussed with the study chair ** Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade ≤ 1 ** Corticosteroids: Patients may be on no greater than physiologic doses of steroids for at least 14 days prior to enrollment with a stable neurologic status ** Hematopoietic growth factors: 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur ** Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon, or cytokines ** Stem cell infusions (with or without TBI): *** Autologous stem cell infusion including boost infusion: ≥ 30 days ** Cellular therapy: ≥ 42 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) ** XRT/external beam irradiation, including protons: ≥ 90 days after local XRT unless recurrence is a new enhancement on MRI outside the radiation treatment field; ≥ 150 days after TBI or if radiation to ≥ 50% of the pelvis; ≥ 42 days if other substantial bone marrow (BM) radiation ** Radiopharmaceutical therapy (e.g., radiolabeled antibody): ≥ 42 days after systematically administered radiopharmaceutical therapy ** Other therapeutic clinical trials: ≥ 14 days after last dose of investigational agent, unless otherwise defined above ** Patients must not have received prior exposure to pp65-directed therapy or any RNA-LP therapy * Prior to starting pp65/tumor mRNA RNA-LP (drug product [DP]2), patients must recover from all effects of surgery/biopsy and all postoperative complications so that all surgically-based toxicity would be considered grade ≤ 1
• OSA PATIENTS: * Absolute neutrophil count (ANC) ≥ 1,000/µl
• OSA PATIENTS: * Platelets ≥ 100,000/µl (transfusion-independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• OSA PATIENTS: * Hemoglobin ≥ 8 g/dL (transfusion-independent, defined as not receiving packed red blood cell transfusions for at least 7 days prior to enrollment)
• OSA PATIENTS: * Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2 or * A creatinine based on age/gender as follows: ** 1 to < 2 years: male =< 0.6 mg/dL and female =< 0.6 mg/dL ** 2 to < 6 years: male =< 0.8 mg/dL and female =< 0.8 mg/dL ** 6 to < 10 years: male =< 1 mg/dL and female =< 1 mg/dL ** 10 to < 13 years: male =< 1.2 mg/dL and female =< 1.2 mg/dL ** 13 to < 16 years: male =< 1.5 mg/dL and female =< 1.4 mg/dL ** >= 16 years: male =< 1.7 mg/dL and female =< 1.4 mg/dL
• OSA PATIENTS: * Total bilirubin ≤ 3 x institutional upper limits of normal for age
• OSA PATIENTS: * ALT ≤ 5 x institutional upper limits of normal for age
• OSA PATIENTS: * AST ≤ 5 x institutional upper limits of normal for age
• OSA PATIENTS: * Baseline pulse oximetry of at least 92% on room air
• OSA PATIENTS: * All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent/assent document * For women of childbearing potential, negative serum/urine pregnancy test is required at enrollment and before each vaccine administration * Women of childbearing potential must agree to use of at least 2 forms of acceptable contraceptive methods or abstinence to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug * Men with female partners of childbearing potential must agree to use of at least 2 forms of acceptable contraceptive methods or abstinence throughout the study and should avoid conceiving children for at least 24 weeks following the last dose of study drug

Exclusion Criteria

• ALL PATIENTS: * Diffuse intrinsic pontine glioma
• ALL PATIENTS: * Pregnant or breastfeeding women will not be entered on this study because there is yet no available information regarding human fetal or teratogenic toxicities and the study drug. Pregnancy tests must be obtained in women of childbearing potential (i.e., post-menarche). Males or females may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method for the duration of the study. Abstinence is an acceptable method of birth control
• ALL PATIENTS: * Known active immunosuppressive disease * Unstable angina and/or congestive heart failure requiring hospitalization * Unstable cardiac arrhythmias, abnormalities, or transmural myocardial infarction within the last 6 months * Uncontrolled infection * Chronic obstructive pulmonary disease (COPD) exacerbation or other known respiratory illness requiring hospitalization or precluding study therapy * Hepatic insufficiency resulting in clinical jaundice and/or clinically significant coagulation defects * Patients with autoimmune disease requiring medical management with immunosuppressants * Major medical illnesses or psychiatric impairments that, in the investigators’ opinions, will prevent administration or completion of protocol therapy * Prior history of brachial neuritis or Guillain-Barre syndrome * Uncontrolled seizure disorder
• ALL PATIENTS: * History of myocarditis
• ALL PATIENTS: * Receipt of any live vaccine within 30 days prior to day 1 of treatment
• ALL PATIENTS: * Participants who are unwilling or unable to receive treatment and undergo follow-up evaluations, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study
• ALL PATIENTS: * Patients who have received an allogeneic (non-autologous) bone marrow or stem cell transplant, or any allogeneic stem cell infusion including DLI or boost infusion
• ALL PATIENTS: * Patients who are receiving other investigational agents