A Study of RNA-lipid Particle (RNA-LP) Vaccines for Newly Diagnosed Pediatric High-Grade Gliomas (pHGG) and Adult Glioblastoma (GBM)

Phase 1

Recruiting

• Conditions: High Grade Glioma; WHO Grade III or IV Malignant Glioma; Adult Glioblastoma
• Interventions: Biological: 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)

• Registration Number: NCT04573140
• Lead Sponsor: University of Florida

Brief Summary

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

Detailed Description

This is a first in human Phase I study of RNA-LP vaccines for newly diagnosed adult MGMT unmethylated (low level or undetected) glioblastoma (GBM) and pediatric patients with newly diagnosed HGG (pHGG). The phase I portion of the study will involve a dose-escalation study to identify the maximally tolerated dose (MTD). Up to 28 adult participants and 24 pediatric participants may be enrolled in the Phase I study. The GBM portion of the study is single site (UF) and the pediatric portion will be multisite.

This clinical trial will consist of three parts: Surgery, Radiation, and Immunotherapy. Surgery and chemoradiation will be standard of care for patients with GBM. 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). Pediatric participants will have tumor material sent to the University of Florida (UF) from qualified PNOC sites. Adult GBM participants must have surgery for collection of tumor material at the University of Florida. Following surgical resection with confirmatory pathologic diagnosis, patients will be enrolled in the trial after informed consent has been obtained.

The RNA-LP vaccination will begin within 4 weeks following radiation and after review of post-radiation MRI (for baseline). After radiation patients will receive three RNA-LP vaccines every 2 weeks before beginning 12 cycles of adjuvant monthly RNA- LP vaccines for a total of 15 vaccines.

Participants may receive RNA-LP vaccines for up to 14 months.

Participants will be followed until death due to any cause. MRI and clinical evaluation for assessment of disease progression will be conducted every 3 months for the first-year post-immunotherapy and then every 6-12 months over the next 2 years.

Study Timeline

• Study First Submitted: 2020-09-14
• Study First Submitted QC: 2020-09-28
• Study First Posted: 2020-10-05
• Study Start: 2021-12-13
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-27
• Last Update Posted: 2025-03-04
• Primary Completion: 2026-09-01
• Study Completion: 2028-09-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 52

Inclusion Criteria

Not provided

Exclusion Criteria

Stratum 1 (Adult GBM)

• 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.

• Recurrent or multifocal malignant gliomas.

• Metastatic or leptomeningeal disease

• Residual post-surgical disease burden > 3 cm as defined by longest perpendicular diameter on MRI.

• Known HIV, Hepatitis B, or Hepatitis C seropositive.

• Known active infection or immunosuppressive disease.

• Participants who require corticosteroids above physiologic doses or not weaned to physiologic dosing within 1 week of scheduled vaccination.

• Prior chemotherapy or radiosensitizers (including Gliadel wafers) for cancers of the head and neck region, other than TMZ prescribed during radiation for GBM (prior chemotherapy for a different cancer is allowable).

• Prior radiotherapy to the head or neck, resulting in overlap of radiation fields. Radiosurgery is not permitted.

• 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 at initiation of XRT/TMZ.
  • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at initiation of XRT/TMZ.
  • 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.
  • 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 women of childbearing potential and men 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.

• Women of childbearing potential must not be pregnant or breast-feeding.

• Prior history of brachial neuritis or Guillain-Barré syndrome.

• Participants 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.

• Participants who are unwilling or unable to receive treatment and undergo follow-up evaluations

Stratum 2 (Pediatric HGG)

• Diffuse intrinsic pontine glioma, brainstem diffuse midline glioma, or BRAFV600E+
• Gliomatosis
• Metastatic or leptomeningeal disease
• Residual post-surgical disease burden > 3 cm as defined by longest diameter on MRI.
• Known HIV, Hepatitis B, or Hepatitis C seropositive.
• Uncontrolled seizure disorder
• History of myocarditis
• Receipt of any live vaccine within 30 days prior to enrollment
• Known active infection or immunosuppressive disease.
• Participants with significant renal, cardiac (congestive cardiac failure, myocardial infarction, myocarditis), pulmonary, hepatic or other organ dysfunction.
• Participants who are anticipated to require corticosteroids above physiologic doses or not weaned to physiologic dosing within 1 week of scheduled vaccination.
• Severe or unstable concurrent medical conditions.
• Women must not be pregnant or breast-feeding.
• Participants 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.
• Participants who are unwilling or unable to receive treatment and undergo follow-up evaluations.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I adult (Stratum 1)	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)	A maximum of 28 adult patients will be enrolled in dose-escalation study using the BOIN design with an initial embedded accelerated titration design (ATD).
Phase I pediatric (Stratum 2)	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)	A maximum of 24 adult patients will be enrolled in dose-escalation study using 3+3 study design.

Primary Outcome Measures

Name	Time	Method
Manufacturing feasibility	from the date of surgery until adminstration of third vaccine, up to 20 weeks	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.
Determination of Maximum Tolerated Dose	up to 30 months	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.
Safety of RNA-LP vaccine	First vaccine through 14 days after administration of the 3rd 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.

Trial Locations

Locations (1)

UF Health; 🇺🇸 Gainesville, Florida, United States