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

Launched by UNIVERSITY OF FLORIDA · Sep 28, 2020

Keywords

ClinConnect Summary

This clinical trial is studying a new type of vaccine called RNA-lipid particle (RNA-LP) vaccines to see if they are safe and effective for treating newly diagnosed high-grade gliomas in both children and adults. Glioblastoma (GBM) is a particularly aggressive form of brain cancer that this trial focuses on, especially in adults with certain tumor characteristics. The main goals are to ensure the vaccines can be made safely and to find the highest dose that can be given without causing serious side effects.

To participate in this study, adults must be at least 21 years old with a confirmed diagnosis of GBM that meets specific criteria, while pediatric participants should be between 3 and 25 years old with newly diagnosed high-grade gliomas. Participants will undergo surgery to remove their tumors and will need to meet several health requirements before joining the trial. Those who take part will receive the vaccine and will be closely monitored for any effects. It's important to note that both male and female participants of childbearing age need to use effective contraception during the study to avoid pregnancy. Overall, this trial is an important step in exploring new treatments for challenging brain cancers.

Gender

ALL

Eligibility criteria

• • Stratum 1 (Adult GBM)
• • 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).
• • 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) ≥ 1,000µl (unsupported)
• • Platelets ≥ 150/µl (unsupported for at least 7 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 (e.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 HGG)
• • Age \> 3 and \< 25 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 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 7 days 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) ≥ 1,000/µl (unsupported)
• • 2. Platelets ≥ 100/µl (unsupported for at least 7 days)
• • 3. Hemoglobin \> 8 g/dL (may be supported)
• • Renal: Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or acceptable serum creatinine based on age/gender
• * Hepatic:
• • 1. Bilirubin ≤ 3 times upper limit of institutional normal for age.
• • 2. SGPT (ALT) ≤ 5 times upper limit of institutional normal for age.
• • 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 of child-fathering potential must agree to use physician-approved contraceptive methods (e.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.
• • Patients must be enrolled on PNOC COMP prior to enrollment on PNOC020 if PNOC COMP is open to accrual at the enrolling institution.
• 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.