Clinical trial NCT05660408: RNA Lipid Particles Targeting Pediatric Recurrent Intracranial Malignancies and Other systEmic Solid Tumors
Official title: RNA PRIME - RNA Lipid Particles Targeting Pediatric Recurrent Intracranial Malignancies and Other systEmic Solid Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Recurrent Pulmonary Osteosarcoma
Recurrent High-grade Glioma
Keywords: pulmonary osteosarcoma
RNA-LP
vaccines
immunotherapy
high-grade glioma
brain tumor
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: The V Foundation for Cancer Research
name: National Pediatric Cancer Foundation
name: Alex's Lemonade Stand Foundation
name: The Osteosarcoma Institute
name: National Cancer Institute (NCI)
First posted: 2022-12-21
Enrollment: 36
Sex: ALL
Minimum age (years): 3
Maximum age (years): 39
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

Patients with recurrent or progressive pediatric high-grade glioma (pHGG)

* Patients must be age 3-25 years

For both Arms:

* Patients must have had a prior histologically-diagnosed pHGG (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 must have MRI evidence of probable recurrent pHGG.
* Patients must consent to have sterile collection of tumor material in a manner suitable for 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.

Disease Status -Patients must be clinically eligible for standard-of-care surgical resection/biopsy

Performance Level

- 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.)

Prior Therapy

* 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 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 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.

  6. 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:

- 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.

Other

* 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.

Inclusion Criteria:

Patients with osteosarcoma (OSA)

- Patients must be age 3-39 years.

Diagnosis

* 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.

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.
* 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.

Performance Level - 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.)

Prior Therapy

* 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 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 (DP2), patients must recover from all effects of surgery/biopsy and all postoperative complications so that all surgically-based toxicity would be considered Grade ≤ 1.

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:

- 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

* 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 for all Strata Diagnosis - Diffuse intrinsic pontine glioma

Pregnancy or Breastfeeding

- 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.

Severe, active co-morbidity, defined as follows:

* 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

History of myocarditis

Receipt of any live vaccine within 30 days prior to day 1 of treatment.

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.

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.

Patients who are receiving other investigational agents.

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: 14 months
measure: Feasibility of generating RNA-LP
timeFrame: 14 months
Secondary outcomes:
measure: Overall survival rate
timeFrame: 3 years
measure: Immune activation
timeFrame: 3 years
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: UF Health
state: Florida
Study officials:
affiliation: University of Florida
name: John Ligon, MD
role: PRINCIPAL_INVESTIGATOR
References: