Recurrent High-grade Glioma, Recurrent Pulmonary Osteosarcoma
Conditions
Keywords
pulmonary osteosarcoma, RNA-LP, vaccines, immunotherapy, high-grade glioma, brain tumor
Brief summary
The Investigators have demonstrated in preclinical studies that RNA liposomes activate APCs, induce antigen-specific T cell immunity, and can supplant DCs in a cell therapy model for HGG and have shown feasibility and activity of this approach in preclinical models and in canine patients with a spontaneous malignant glioma. In one arm of this study, we will investigate the safety and immunologic activity of RNA-LP vaccines in pediatric patients with recurrent pHGG. The investigators have also 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. The investigators 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 manufacturing feasibility, safety and immunologic activity of RNA-LP vaccine in patients with recurrent pulmonary or unresectable osteosarcoma and recurrent pHGG.
Detailed description
For recurrent pHGG there will be two non-randomized arms assigned at the discretion of the patient and treatment team: * Arm 1-A single neoadjuvant pp65 RNA-LP (DP1) will be administered prior to surgical resection/biopsy, and then two adjuvant DP1. * Arm 2-Surgical resection/biopsy will occur first and all three DP1 will be administered in the adjuvant setting For recurrent OSA there will be three arms based on disease status on enrollment: * Arm 1-Patients with unilateral pulmonary-only metastatic recurrent OSA * Arm 2-Patients with bilateral pulmonary-only metastatic recurrent OSA * Arm 3-Patients with unresectable OSA in any location. The Phase I dose-escalation study for either recurrent/progressive pHGG or recurrent OSA cohort will be performed in 18 subjects using a 3+3 design. Both recurrent pHGG trial arms will be enrolled together as a single cohort for safety, and similarly all recurrent OSA trial arms will be enrolled together as a single cohort for safety during phase I.
Interventions
BIOLOGICALpp65 RNA LP (DP1)
This is an off the shelf RNA-LP vaccine used to prime for the immune response while we produce the patient specific pp65/tumor mRNA RNA-LP (DP2)
BIOLOGICALpp65/tumor mRNA RNA-LP (DP2)
This is a patient specific RNA-LP vaccine generated from the patient's tumor RNA.
PROCEDURESurgical Biopsy/Resection
Eligible participants will be enrolled and undergo sterile collection of tumor material .
Sponsors
University of Florida
The V Foundation for Cancer Research
National Pediatric Cancer Foundation
Alex's Lemonade Stand Foundation
The Osteosarcoma Institute
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 39 Years
Healthy volunteers
No
Inclusion criteria
Patients with recurrent or progressive pediatric high-grade glioma (pHGG) Patients must be age 3-25 years Diagnosis: Patients must have had a prior histologically-diagnosed pHGG(including but not limited to: Astrocytoma WHO Grade 3 or 4 and Glioblastoma WHO Grade 4 by histopathology or molecular studies, per 2021 WHO Classification of Tumors of the CNS57, WHO CNS5). * Patients with M+ disease without gliomatosis cerebri (see definition under
Exclusion criteria
) ARE eligible. * 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. Patients must have recurred or progressed after receiving surgery/biopsy and radiation therapy as frontline standard-of-care treatments in primary disease. Patients must have MRI evidence of probable recurrent pHGG. Patients must be clinically eligible for standard-of-care surgical resection/biopsy and sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles. Performance Level Karnofsky ≥ 60% for patients ≥ 16 years of age and Lansky ≥ 60% for patients ≤ 16 years of age * 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. Prior Therapy Patients must have recovered from all acute toxic effects of all prior anti-cancer therapy (all adverse events must have improved to grade 1 or better): * 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 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: All systemically administered corticosteroids must be stable or decreasing for ≥ 1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m2/day. Corticosteroid physiologic replacement therapy for management of pituitary/adrenal axis insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed. * 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, 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. * Prior use of RNA-LP therapy: Patients must not have received prior exposure to pp65-directed therapy or any RNA-LP therapy. Organ Function Requirements Adequate bone marrow function as defined as: * Absolute neutrophil count (ANC) ≥ 1,000/µl * Platelets ≥ 100,000/µl (transfusion-independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Hemoglobin ≥ 8 g/dL (transfusion-independent, defined as not receiving packed red blood cell transfusions for at least 7 days prior to enrollment) Adequate renal function as defined as: * A creatinine based on age/gender * Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 Adequate liver function as defined as: * Total bilirubin ≤ 3x institutional upper limits of normal for age * ALT ≤ 5x institutional upper limits of normal for age * AST ≤ 5x institutional upper limits of normal for age Adequate pulmonary function defined as baseline pulse oximetry of at least 92% on room air. All patients must be willing to take an antiepileptic medication such as levetiracetam for the duration of RNA-LP vaccinations. Contraception * 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. 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. Inclusion Criteria: Patients with osteosarcoma (OSA) Age: Patients must be age 3-39 years. Diagnosis * For Arms 1 and 2: Patients must be clinically eligible for standard-of-care surgical resection of suspected OSA recurrence with pulmonary-only metastases. * For Arm 3: Patients must undergo standard-of-care biopsy of suspected or known recurrent, unresectable OSA. Disease Status * 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. Patients must have sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles. Performance Level: Karnofsky ≥ 60% for patients \> 16 years of age and Lansky ≥ 60% for patients \< 16 years of age. * NOTE: 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. Prior Therapy: Patients must have recovered from all acute toxic effects of all prior anti-cancer therapy (all adverse events must have improved to grade 1 or better): Prior Therapy: Patients must have recovered from all acute toxic effects of all prior anti-cancer therapy (all adverse events must have improved to grade 1 or better): 1. 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. 2. 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. 3. 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. 4. Corticosteroids: All systemically administered corticosteroids must be stable or decreasing for ≥ 1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m2/day. Corticosteroid physiologic replacement therapy for management of pituitary/adrenal axis insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed. 5. 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. 6. Interleukins, Interferons, and Cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon, or cytokines. 7. Stem cell infusions (with or without TBI): Autologous stem cell infusion including boost infusion: ≥ 30 days. 8. Cellular Therapy: ≥ 42 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.). 9. 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 BM radiation. 10. Radiopharmaceutical therapy (e.g., radiolabeled antibody): ≥ 42 days after systematically administered radiopharmaceutical therapy. 11. Other therapeutic clinical trials: ≥ 14 days after last dose of investigational agent, unless otherwise defined above 12. Prior use of RNA-LP therapy: Patients must not have received prior exposure to pp65-directed therapy or any RNA-LP therapy. Organ Function Requirements Adequate bone marrow function as defined as: * Absolute neutrophil count (ANC) ≥ 1,000/µl * Platelets ≥ 100,000/µl (transfusion-independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Hemoglobin ≥ 8 g/dL (transfusion-independent, defined as not receiving packed red blood cell transfusions for at least 7 days prior to enrollment) Adequate renal function as defined as: * A creatinine based on age/gender * Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 Adequate liver function as defined as: * Total bilirubin ≤ 3x institutional upper limits of normal for age * ALT ≤ 5x institutional upper limits of normal for age * AST ≤ 5x institutional upper limits of normal for age Adequate pulmonary function defined as baseline pulse oximetry of at least 92% on room air. Contraception * 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. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose | 14 months | Determine the maximum tolerated dose of RNA-LP vaccine based on frequency of dose-limiting toxicities. |
| Feasibility of generating RNA-LP | 14 months | Ability to generate patient-specific pp65/tumor mRNA RNA-LP that meet release criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival rate | 3 years | Determine the survival in patients with recurrent pHGG or oseteosarcoma receiving RNA-LP vaccine. |
| Immune activation | 3 years | Determine if immune cells in patients receiving RNA-LPs become activated in both peripheral blood and in the tumor. |
Countries
United States
Contacts
STUDY_CHAIRJohn Ligon, MD
University of Florida
Outcome results
None listed