PERFORMANCE: Peptide Targets for Glioblastoma Against Novel Cytomegalovirus Antigens
Eligible patients will be screened and enrolled prior to completion of post-surgical
chemoradiation. Final eligibility to remain on study for safety endpoint will occur after
completion of chemoradiation and prior to initiation of adjuvant TMZ regimen. Immediately
post-chemoradiation and prior to initiation of cycle 1 of adjuvant TMZ, all patients will
receive 500 µg of PEP-CMV vaccine weekly for a total of 3 vaccines starting 1-3 days after
chemoradiation is complete. Prior to initiation of TMZ cycle 1, patients will be randomized
to one of three arms (1:1:1) to receive (1) standard TMZ (200 mg/m^2/day x 5 days) with
vaccination on Day 6-8 of each monthly TMZ cycle, (2) standard TMZ (200 mg/m^2/day x 5 days)
with vaccination on Day 22-24 of each monthly TMZ cycle, or (3) dose-intensified TMZ (100
mg/m^2/day x 21 days) with vaccination on day 22-24 of each monthly TMZ cycle. Each cohort
will have 20 patients. Up to 150 patients will be consented in order to obtain 60 evaluable
The primary safety assessment for dose-limiting toxicity (DLT) will be determined one week
after the third weekly vaccine. A DLT will be defined as any irreversible Grade 3 toxicity,
any Grade 4 toxicity, or any life threatening-event not attributable to concomitant
medication, co-morbid event, or disease progression. Initially 6 patients will be accrued to
the study (2 per arm) after which accrual will be suspended to review the toxicity
experienced by these patients during the first 3 weekly vaccinations. If 0 or 1 of these
patients experience DLT, accrual of the remaining patients will commence. Otherwise,
modifications of the protocol will be considered before accruing additional patients.
The prevalence of DLT occurring during the initial 3 weekly vaccinations or the vaccinations
administered concurrently with temozolomide will be continuously monitored. If more than
25% of accrued patients experience DLT, then accrual will be suspended and reported toxicity
will be carefully reviewed to determine if modifications to the protocol treatment should
occur. Peptide vaccinations employing GM-CSF and Montanide ISA-51 as adjuvants have
generally been well tolerated in human patients in numerous phase I-III trials.
Treatment Plan: One week after the 3rd weekly vaccination, cycles of TMZ will begin. The
start of all subsequent cycles will be scheduled every 4 weeks after the first daily dose of
the preceding cycle. During monthly TMZ cycles, vaccinations will occur on day 6-8 or day
22-24 of each cycle, depending on randomization arm. All vaccines will be given i.d.
approximately 10cm below the inguinal ligament bilaterally. A target of six cycles with
maximum of twelve cycles of TMZ may be given if the patient demonstrates continued
improvement on MRI scan, decreased corticosteroid requirement, improvement in performance
status, or improvement in neurologic function at the discretion of the treating
neuro-oncologist. Vaccines will continue monthly after TMZ cycles until tumor progression
Patients will be imaged with contrast-enhanced MRI pre & post-surgical resection (prior to
initiation of chemoradiation), post-chemoradiation and prior to TMZ cycle 1, prior to TMZ
cycle 4, 7 (if administered), and 10 (if administered). MRI imaging every 3 months during
post-chemoradiation is preferable, but every 2 months is allowed at the discretion of the
treating neuro-oncologist. MRI imaging will be conducted every 3 months after completion of
TMZ for 1 year, and then every 6 months thereafter, or at frequency indicated by clinical
presentation. The modified Response Assessment in Neuro-Oncology (RANO) criteria will be
used for assessment of pseudoprogression and patients demonstrating definitive progression
will be removed from study. Any patient removed for definitive tumor progression prior to
receiving third vaccine and post vaccination immune monitoring blood draw will be replaced
for safety and immunologic endpoints. Clinical endpoint comparisons will be made amongst
patients successfully randomized to adjuvant TMZ treatment arms.
Blood for immune monitoring will be obtained prior to vaccines 1-4, 7 and 13, and at tumor
progression. Patients seen by the Duke neuro-oncology team between these vaccine visits may
have blood drawn for immune monitoring at the discretion of the study team.
As part of standard care for these patients, upon tumor progression, participants may
undergo stereotactic biopsy or resection. As this is not a research procedure, consent will
be obtained separately. Patients that have this procedure done here at Duke University
Health System, may be approached to participate in the Duke Brain Tumor Center Biorepository
study. Tissue obtained from patients who consented to the Duke Brain Tumor Center
Biorepository will be used to assess immunologic cell infiltration, antigen expression, and
biomarkers for immunologic response.
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the optimal & safe peptide vaccination regimen with TMZ through dose-limiting toxicity (DLT) measurements. The primary safety assessment for DLT will be determined 1 week after the 3rd weekly vaccine. A DLT will be defined as any irreversible Grade 3 toxicity, any Grade 4 toxicity, or any life threatening-event not attributable to concomitant medication, co-morbid event, or disease progression. Initially 6 patients will be accrued to the study (2 per arm) after which accrual will be suspended to review the toxicity experienced by these patients during the first 3 weekly vaccinations. If 0 or 1 of these patients experience DLT, accrual of the remaining patients will commence. Otherwise, modifications of the protocol will be considered before accruing additional patients.
John H Sampson, M.D., Ph.D.
United States: Food and Drug Administration
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