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

NCT04573140

Description:

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).

Related Conditions:
  • Glioblastoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: OCR32702-Adults
  • NCT ID: NCT04573140

Conditions

  • Adult Glioblastoma

Interventions

DrugSynonymsArms
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)Phase I adult (Stratum 1)

Purpose

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).

Detailed Description

      This is a first in human Phase I/II study of RNA-LP vaccines for newly diagnosed adult MGMT
      unmethylated glioblastoma (GBM). The phase I portion of the study will involve a
      dose-escalation study to identify the maximally tolerated dose (MTD). Up to 28 participants
      may be enrolled.

      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). Tumor material will be sent to the University of Florida (UF). 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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I adult (Stratum 1)ExperimentalA maximum of 28 adult patients will be enrolled in dose-escalation study using the BOIN design with an initial embedded accelerated titration design (ATD).
  • 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)

Eligibility Criteria

        Inclusion Criteria:

          -  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 (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 enronllment.

        Exclusion Criteria:

          -  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

          -  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.

          -  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.

          -  ParticipantParticipants 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:21 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Manufacturing feasibility
Time Frame:from the date of surgery until adminstration of third vaccine, up to 20 weeks
Safety Issue:
Description:Potentially eligible subjectsparticipants 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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Florida

Trial Keywords

  • Immunotherapy
  • Brain Tumor
  • Adult
  • newly diagnosed
  • clinical trial

Last Updated

September 28, 2020