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.
