The primary objective will be to demonstrate the manufacturing feasibility and safety, and to determine the maximum tolerated dose (MTD) of RNA-LP vaccines in (Stratum 1) adult patients with newly diagnosed GBM (MGMT low level or unmethylated in adults only) and (Stratum 2) in pediatric patients with newly diagnosed HGG (pHGG). Funding Source - FDA OOPD
Age ≥ 21 years.
Histopathologically proven newly-diagnosed de novo GBM (WHO Grade IV glioma, secondary GBM not eligible) that is MGMT low level or unmethylated.
The tumor must have a supratentorial component.
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).
Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. (For example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible.)
MGMT Methylated tumors
Gliomatosis Cerebri
Metastases detected below the tentorium or beyond the cranial vault and leptomeningeal involvement.
Parallel
Autologous total tumor mRNA and pp65 full length (fl) lysosomal associated membrane protein (LAMP) mRNA loaded DOTAP liposome vaccine administered intravenously (RNA loaded lipid particles, RNA-LPs)
Biological/VaccineRNA-LP vaccines will be administered intravenous. Three RNA-LP vaccines will be administered every 2 weeks followed by 12 cycles of adjuvant monthly RNA-LP vaccines for a total of 15 vaccines.
Manufacturing feasibility
Potentially eligible participants will be enrolled on a screening consent for the sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs). Tumor material will be sent to the University of Florida (UF) where tumor specific RNA-LP vaccines will be manufactured. Manufacturing feasibility will be determined based on the percentage of vaccines that are successfully manufactured in the DLT window during the first three vaccines. If two-thirds of vaccines are successfully manufactured with QA/QC clearance, we will conclude that RNA-LPs can be successfully manufactured.
Safety of RNA-LP vaccine
A DLT will be defined as any immunotherapy-related (possible, probable or definite): * Grade ≥ 3 non-hematologic toxicity that does not improve to ≤ Grade 2 within 72 hours; hepatic or renal dysfunction that does not improve to ≤ grade 2 within 7 days * Grade ≥3 cytokine release syndrome that does not improve to ≤ Grade 2 within 72 hours * Grade ≥ 3 encephalopathy as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Immune Effector Cell-Associated Encephalopathy criteriaGrade 3 or greater non-neurologic, non-hematologic toxicity * Grade 3 neurologic toxicity that does not improve to Grade II or better within 7 days * Grade 3-4 hematologic toxicity that does not improve to Grade 2 or better within 14 days * Grade 3 autoimmune encephalomyelitis * Grade 4 neurologic toxicity.
Determination of Maximum Tolerated Dose
The Phase I Stratum 1 dose-escalation study will be performed in up to 28 adult participants using a Bayesian optimal interval (BOIN) design with an initial embedded accelerated titration design (ATD) to efficiently identify the maximally tolerated dose (MTD). For the initial ATD, patients will be enrolled and treated in cohorts of size 1 starting at dose level -4 to dose level -1. After the first DLT is observed or if dose level 0 is reached without prior DLT in dose level -4 to -1, the study will expand to a BOIN design with a cohort size of 3 to identify the MTD. For the initial ATD, patients will be enrolled and treated in cohorts of size 1 starting at dose level -4 to dose level -1, and will expand to a cohort size of 3 after the first DLT is observed or at dose level 0. There are 8 dose levels to potentially be assessed including the possibility of 4 dose levels for the ATD and 4 for the BOIN.
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University of Florida
Lead sponsor
Pediatric Neuro-Oncology Consortium
Collaborator
University of California, San Francisco
Collaborator
CureSearch
Collaborator
Team Jack Foundation
Collaborator
Florida Department of Health
Collaborator
Food and Drug Administration (FDA)
Collaborator
