Peptide Targets for Glioblastoma Against Novel Cytomegalovirus Antigens
Condition: Glioblastoma; Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: 5-day TMZ; 21-day TMZ; PEP-CMV: Component A; Tetanus-Diphtheria booster; Tetanus Pre-Conditioning; PEP-CMV: Component B
Intervention description: Chemotherapy agent FDA approved to treat newly-diagnosed glioblastoma given as cycles of 150-200 mg/m^2/day on days 1-5 of each 28 day cycle; Chemotherapy agent FDA approved to treat newly-diagnosed glioblastoma given as cycles of dose-intensified TMZ (75-100 mg/m2/day on days 1-21 of each 28 day cycle); 500 µg of PEP-CMV Component A (a synthetic long peptide) mixed with Montanide ISA-51 intradermally administered; At time of enrollment, after signing consent and undergoing immune monitoring blood work, patients will receive Tetanus-diphtheria booster vaccination with 0.5 mL of Td (tetanus, diphtheria toxoid, absorbed); All patients will receive a tetanus pre-conditioning injection in the right groin intradermally on day 22 (±1 day) of the first post-radiation cycle of TMZ; 500 µg of PEP-CMV Component B (a neutralizing antibody epitope from human CMV glycoprotein B conjugated to Keyhole Limpet Hemocyanin) mixed in 150 µg of GM-CSF intradermally administered
Intervention MeSH terms: Temozolomide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PERFORMANCE; Pro00034208; Cytomegalovirus; Ashley

Summary:

      Newly diagnosed glioblastoma (GBM) patients with complete or partial surgical resection who
      were CMV seropositive patients were eligible to enroll on this trial. Patients were enrolled
      following standard of care chemoradiation and prior to initiation of post-radiation cycles of
      temozolomide (TMZ) provided they met all eligibility criteria. All eligible patients received
      a tetanus-diphtheria (Td) vaccination. Patients enrolled on study were randomized to receive
      either standard TMZ or dose-intensified TMZ (excluding the safety cohort who only received
      standard TMZ). All patients received a pre-conditioning injection of tetanus on day 22 of the
      first post-radiation cycle of TMZ. The following day, patients received the first of 3
      intradermal (i.d.) injections of the study drug cytomegalovirus peptide (PEP-CMV), which
      contained either a combination of Component A and Component B or Component A only depending
      upon when they enrolled on study. Vaccines #2 and #3 will be given at 2 week intervals.
      Patients who were O[6]-methylguanine-DNA methyltransferase (MGMT) unmethylated received one
      adjuvant cycle of the TMZ regimen according to their assigned TMZ arm. Patients who were MGMT
      methylated or whose methylation status was inconclusive continue with up to 12 cycles of TMZ.
      After the completion of a patient's last TMZ cycle, vaccines continued every 4-6 weeks for a
      maximum number of 20 vaccines (unless tumor progression occurred). The study ended
      prematurely due to lack of funds. The preliminary results suggest that the vaccine may be
      capable of generating an immune response.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 18 years.

          2. Histopathologically proven newly-diagnosed primary glioblastoma with complete or
             partial surgical resection. Biopsy not acceptable.

          3. Patients must be cytomegalovirus (CMV) seropositive.

          4. The tumor must be supratentorial.

          5. Karnofsky performance status of ≥ 70.

          6. Stable or decreasing steroid dose (≤ 4 mg/day) at time of post-radiation treatment
             (XRT) adjuvant TMZ initiation. If patients are decreasing steroid use, once they are
             at 2 mg/day, they may be supplemented with physiologic replacement hydrocortisone
             therapy (20-30 mg/day in divided doses), at the discretion of the treating oncologist.

          7. Hematology: absolute neutrophil count (ANC) ≥ 1500 cells/µL, Platelet count ≥ 100,000
             cells/µL, Hemoglobin ≥ 9.0 g/dl

          8. Chemistry: ALT/AST ≤ 3.0 times the upper limit of normal (ULN), Total bilirubin ≤ 1.5
             mg x ULN (Exception: Patient has known Gilbert's Syndrome or patient has suspected
             Gilbert's Syndrome, for which additional lab testing of direct and/or indirect
             bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x
             ULN is acceptable.)

        Exclusion Criteria:

          1. Radiographic or cytologic evidence of leptomeningeal or multifocal disease at any time
             prior to study entry.

          2. Prior conventional antitumor therapy, other than steroids, RT or TMZ therapy given for
             glioblastoma.

          3. Pregnant or need to breast feed during the study period.

          4. Not adhering to pregnancy prevention recommendations.

          5. Active infection requiring intravenous antibiotics or an unexplained febrile (> 101.5
             F) illness.

          6. Immunosuppressive disease or human immunodeficiency virus infection.

          7. Patients with unstable or severe intercurrent medical conditions such as severe heart
             or lung disease.

          8. Allergic or unable to tolerate TMZ for any reason. Any patient that successfully
             completed at least 5 weeks of Temodar during standard of care XRT/TMZ and whose blood
             counts meet the eligibility requirements (inclusion #7) within 4 weeks post XRT/TMZ is
             eligible.

          9. Patients with previous inguinal lymph node dissection, radiosurgery, brachytherapy, or
             radiolabeled monoclonal antibodies.

         10. Prior allogeneic solid organ transplant.

         11. Currently receiving or ever received immunosuppressive therapy for an autoimmune
             disorder or an organ transplant.