In this study, we will investigate  the safety and immunologic activity of RNA-LP vaccines in adult patients with newly diagnosed GBM (MGMT unmethylated in adults only) and pediatric patients with pHGG.

Dendritic cell (DC) vaccination targeting pp65 and unfractionated tumor antigens in adults and children with malignant brain tumors has been shown to be feasible and safe in patients with GBM and with recurrent MB/PNETs during our recently completed phase I trials. However, DC vaccines remain limited by cost, complexity and manufacturing delays making it difficult to generate readily available vaccines for patients with intracranial malignancies. To circumvent the challenges of cellular therapeutics and develop an immunotherapeutic strategy that could be available expeditiously, we have investigated commercially available and clinically translatable DOTAP liposomes to deliver tumor RNA to antigen presenting cells (APCs) in vivo.  In this study, we will investigate  the safety and immunologic activity of RNA-LP vaccines in adult patients with newly diagnosed GBM (MGMT unmethylated in adults only) and pediatric patients with pHGG.

Phase I  (Stratum 1 and 2)

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 unmethylated in adults only) and (Stratum 2) in pediatric patients with newly diagnosed HGG (pHGG).

Phase II (Stratum 2 only)

To determine if RNA-LP vaccine therapy extends 12-month progression-free survival (PFS-12) compared to historical controls.

Inclusion Criteria:

Stratum 1 (Adult)

• Age >/= 21 years.
• Histopathologically proven newly-diagnosed de novo GBM (WHO Grade IV glioma) (secondary GBM not eligible) that is MGMT 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).
• Residual post-surgical disease burden < 3 cm as defined by longest perpendicular diameter of tumor on post-operative MRI.
• Patients must have recovered from the effects of surgery, postoperative infection, and other complications.
• A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively. Pre-op MRI must be performed within 28 days prior to study enrollment. Post-op MRI must be completed within 48 hours after surgery. Preoperative and postoperative scans must be the same type.
• Performance Score: (KPS) ≥ 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.
• Bone Marrow:
  • ANC (Absolute neutrophil count) ≥ 1,500µl (unsupported)
  • Platelets ≥ 150/µl (unsupported for at least 3 days)
  • Hemoglobin > 8 g/dL
• Renal:
  • BUN ≤ 25 mg/dl
  • Creatinine ≤ 1.7 mg/dl
• Hepatic
  • Bilirubin ≤ 2.0 mg/dl
  • ALT ≤ 5 times institutional upper limits of normal for age
  • AST ≤ 5 times institutional upper limits of normal for age
• Signed informed consent. If the patient’s mental status precludes his/her giving informed consent, written informed consent may be given by the legally authorized representative.
• For women of childbearing potential (WOCBP), negative serum/urine pregnancy test at enrollment (test will be repeated within 72 hours prior to starting TMZ in Stratum 1 patients).
• WOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug. Refer to Appendix F for definition of WOCBP and guidance on acceptable contraceptive methods.
• Males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.
• Participants with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.

Stratum 2 (Pediatric)

• Age > 3 and < 21 years
• Histologically confirmed WHO Grade III or IV malignant glioma
• 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).
• Residual post-surgical disease burden < 3 cm as defined by longest perpendicular diameter of tumor on post-operative MRI.
• Patients must have recovered from the effects of surgery, postoperative infection, and other complications.
• A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively. Pre-op MRI must be performed within 28 days prior to study enrollment. Post-op MRI must be completed within 48 hours after surgery. Preoperative and postoperative scans must be the same type.
• Performance Score: Karnofsky ≥ 60 for participants > 16 years of age and Lansky ≥ 60 for participants < 16 years of age (See Appendix A) assessed within 2 weeks prior to enrollment. 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.
• Bone Marrow:

1. ANC (Absolute neutrophil count) ≥ 1,500/µl (unsupported)
2. Platelets ≥ 150/µl (unsupported for at least 3 days)
3. Hemoglobin > 8 g/dL

• Renal: Creatinine clearance or radioisotope GFR ³ 70mL/min/1.73 m² or a serum creatinine based on age/gender as follows:

The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.⁴⁸

• Hepatic:

1. Bilirubin ≤ 2 times upper limit of institutional normal for age.
2. SGPT (ALT) ≤ 5 times upper limit of institutional normal for
3. SGOT (AST) ≤ 5 times upper limit of institutional normal for age.

• A legal parent/guardian or patient must be able to understand, and be willing to sign a written informed consent and assent document, as appropriate.
• For women of childbearing potential (WOCBP), negative serum/urine pregnancy test at enrollment
• WOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug. Refer to Appendix F for definition of WOCBP and guidance on acceptable contraceptive methods.
• Males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.
• Participants with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.

Exclusion Criteria:

Stratum 1 (Adult)

• 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
• 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 (see protocol)
• 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)

• Diffuse intrinsic pontine glioma
• Gliomatosis Cerebri
• Metastases detected below the tentorium or beyond the cranial vault and leptomeningeal involvement.
• Metastatic or leptomeningeal disease
• Residual post-surgical disease burden > 3 cm as defined by longest perpendicular diameter on
• Known HIV, Hepatitis B, or Hepatitis C seropositive.
• 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 require corticosteroids above physiologic doses or not weaned to physiologic dosing within 1 week of scheduled vaccination.
• Severe or unstable concurrent medical conditions.
• Women of childbearing potential 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

Funding is provided by CureSearch