RNA Lipid Particles Targeting Pediatric Recurrent Intracranial Malignancies and Other systEmic Solid Tumors

NCT05660408 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: MCC23450OCR43060
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Recurrent Pulmonary Osteosarcoma; Recurrent High-grade Glioma

Keywords

pulmonary osteosarcoma; RNA-LP; vaccines; immunotherapy; high-grade glioma; brain tumor

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose

  Determine the maximum tolerated dose of RNA-LP vaccine based on frequency of dose-limiting toxicities.

  14 months

• Feasibility of generating RNA-LP

  Ability to generate patient-specific pp65/tumor mRNA RNA-LP that meet release criteria.

  14 months

Secondary Outcomes (2)

• Overall survival rate

  3 years

• Immune activation

  3 years

Study Arms (5)

Recurrent pHGG, Arm 1

EXPERIMENTAL

pHGG Arm 1-A single dose of pp65 RNA-LP (DP1) will be administered prior to standard of care surgical resection/biopsy, followed by at least two adjuvant DP1. During production of pp65/tumor mRNA RNA-LP (DP2) vaccines, treatment with DP1 will continue every 2 weeks. DP1 vaccines may continue until production of DP2 is complete (expected 5-8 weeks following initial surgery/biopsy). pp65/tumor mRNA RNA-LP (DP2) vaccinations will begin 7-14 days after the last dose of pp65 RNA-LP (DP1). DP2 treatment will occur approximately every 2 weeks for the first 3 doses. Following the first 3 doses of DP2, patients will receive 9 cycles of monthly DP2 for a total of 12 DP2 vaccines (minimum of 15 overall vaccines).

Biological: pp65 RNA LP (DP1); Biological: pp65/tumor mRNA RNA-LP (DP2); Procedure: Surgical Biopsy/Resection

Recurrent pHGG, Arm 2

EXPERIMENTAL

pHGG Arm 2-Standard of care surgical resection/biopsy will occur first and all three pp65 RNA-LP (DP1) will be administered in the adjuvant setting. During production of DP2, treatment will begin with DP1 every 2 weeks, beginning a minimum of 7-14 days after surgery/biopsy. DP1 vaccines may continue until production of DP2 is complete (expected 5-8 weeks following initial surgery/biopsy). pp65/tumor mRNA RNA-LP (DP2) vaccinations will begin 7-14 days after the last dose of pp65 RNA-LP (DP1). DP2 treatment will occur approximately every 2 weeks for the first 3 doses. Following the first 3 doses of DP2, patients will receive 9 cycles of monthly DP2 for a total of 12 DP2 vaccines (minimum of 15 overall vaccines).

Biological: pp65 RNA LP (DP1); Biological: pp65/tumor mRNA RNA-LP (DP2); Procedure: Surgical Biopsy/Resection

Arm 1-Patients with unilateral pulmonary-only metastatic recurrent OSA

EXPERIMENTAL

OSA Arm 1-Patients with unilateral pulmonary-only metastatic recurrent OSA Participants will undergo surgical resection for sterile collection of tumor material to make pp65/tumor mRNA RNA-LP (DP2). During production of DP2 vaccines, participants will begin treatment with off-the-shelf pp65 RNA-LP (DP1) vaccines every 2 weeks. A minimum of 3 DP1 vaccines will be administered and may continue until production of DP2 is complete (expected 5-8 weeks following initial surgery/biopsy). DP2 vaccinations will begin 7-14 days after the last dose of DP1. DP2 treatment will occur approximately every 2 weeks for the first 3 doses. Participants will receive 9 cycles of monthly DP2 for a total of 12 DP2 vaccines (minimum of 15 overall vaccines).

Biological: pp65 RNA LP (DP1); Biological: pp65/tumor mRNA RNA-LP (DP2); Procedure: Surgical Biopsy/Resection

Arm 2-Patients with bilateral pulmonary-only metastatic recurrent OSA

EXPERIMENTAL

OSA Arm 2-Patients with bilateral pulmonary-only metastatic recurrent OSA Participants will undergo surgical resection for sterile collection of tumor material to make pp65/tumor mRNA RNA-LP (DP2). For subjects in Arm 2, surgery will be again performed on contralateral lung nodules within 7 days following DP1 Vaccine #3. During production of pp65/tumor mRNA RNA-LP (DP2) vaccines, participants will begin treatment with off-the-shelf pp65 RNA-LP (DP1) vaccines every 2 weeks. A minimum of 3 DP1 vaccines will be administered and may continue until production of DP2 is complete (expected 5-8 weeks following initial surgery/biopsy). DP2 vaccinations will begin 14 days after 2nd surgical pulmonary metastectomy. DP2 treatment will occur approximately every 2 weeks for the first 3 doses. Participants will receive 9 cycles of monthly DP2 for a total of 12 DP2 vaccines (minimum of 15 overall vaccines).

Biological: pp65 RNA LP (DP1); Biological: pp65/tumor mRNA RNA-LP (DP2); Procedure: Surgical Biopsy/Resection

Arm 3-Patients with unresectable OSA in any location

EXPERIMENTAL

Arm 3-Patients with unresectable OSA in any location. Participants will undergo surgical biopsy for sterile collection of tumor material to make pp65/tumor mRNA RNA-LP (DP2). For adult subjects only in Arm 3, optional biopsy will be repeated within 7 days following DP2 Vaccine #3 administration once hematologic recovery to eligibility criteria, unless medically contraindicated. During production of DP) vaccines, participants will begin treatment with off-the-shelf pp65 RNA-LP (DP1) vaccines every 2 weeks, beginning a minimum of 7 days after initial surgery/biopsy. A minimum of 3 DP1 vaccines will be administered and may continue until production of DP2 is complete (expected 5-8 weeks following initial surgery/biopsy). DP2 vaccinations will begin 7-14 days after the last dose of DP1. DP2 treatment will occur approximately every 2 weeks for the first 3 doses. Participants will receive 9 cycles of monthly DP2 for a total of 12 DP2 vaccines (minimum of 15 overall vaccines).

Biological: pp65 RNA LP (DP1); Biological: pp65/tumor mRNA RNA-LP (DP2); Procedure: Surgical Biopsy/Resection

Interventions

pp65/tumor mRNA RNA-LP (DP2) BIOLOGICAL

This is a patient specific RNA-LP vaccine generated from the patient's tumor RNA.

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; Recurrent pHGG, Arm 1; Recurrent pHGG, Arm 2

Surgical Biopsy/Resection PROCEDURE

Eligible participants will be enrolled and undergo sterile collection of tumor material .

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; Recurrent pHGG, Arm 1; Recurrent pHGG, Arm 2

pp65 RNA LP (DP1) BIOLOGICAL

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)

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; Recurrent pHGG, Arm 1; Recurrent pHGG, Arm 2

Eligibility Criteria

• Age: 3 Years - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead
• National Pediatric Cancer Foundation: collaborator
• Alex's Lemonade Stand Foundation: collaborator
• The Osteosarcoma Institute: collaborator
• National Cancer Institute (NCI): collaborator
• The V Foundation for Cancer Research: collaborator

Study Sites (1)

UF Health

Gainesville, Florida, 32608, United States

Location

Related Publications (1)

• Villanueva MT. RNA delivery heats up cold tumours. Nat Rev Drug Discov. 2024 Jul;23(7):497. doi: 10.1038/d41573-024-00098-0. No abstract available.

  PMID: 38858569 DERIVED

MeSH Terms

Conditions

Glioma; Brain Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• John Ligon, MD

  University of Florida

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 13, 2022
• First Posted: December 21, 2022
• Study Start: March 12, 2025
• Primary Completion (Estimated): October 1, 2033
• Study Completion (Estimated): October 1, 2035
• Last Updated: March 9, 2026

Record last verified: 2026-01

Locations

US (1)